Irv Arons' Journal

AMD Update 16: Visualization of Drusen and RPE With New Software Application for Zeiss HD-OCT: A New Aid for Assessing Both Dry and Wet AMD

2012-01-26T16:58:00.000-05:00

As noted below, by both Drs. Rosenfeld and Puliafito, this new diagnostic tool will play an important role in assessing and speeding the development of new treatments for both dry and wet AMD that are being researched and brought to the market.

In an announcement on January 20th, Carl Zeiss Meditec said that it had added new dry age-related macular degeneration (Dry AMD) and new glaucoma diagnostic tools for its Cirrus HD-OCT (High Definition Optical Coherence Tomography), and the new software, version 6.0, had received clearance from the US Food and Drug Administration (FDA).

Zeiss Meditec Cirrus HD-OCT

"Designed to help ophthalmologists manage the growing number of patients with serious eye diseases, the new Cirrus application package offers a more comprehensive approach to disease management, delivering more thorough and more meaningful clinical analysis within the retina and glaucoma workplaces", said Dr. Ludwin Monz, President and CEO of Carl Zeiss Meditec AG.

The new Cirrus HD-OCT retina application provides Advanced Retinal Pigment Epithelium (RPE) Analysis, which enables clinicians to objectively monitor changes associated with dry AMD. The application tracks change in RPE elevation area and volume often associated with drusen. It also identifies and measures the area of transparent regions in the RPE that can develop with geographic atrophy. Unlike blue light fundus autofluorescence (FAF), Cirrus measurements are not affected by macular pigment in the fovea and provide an objective assessment of geographic atrophy status as part of a standard OCT exam.

Further expanding Carl Zeiss Meditec's retina workplace, the Cirrus HD-OCT application package also includes Enhanced Depth Imaging (EDI), which allows for better visualization of deeper tissues, such as the choroid, enabling doctors to better understand the role of this anatomy in retinal disease.


A Look at the Retinal Layers Able to be Visualized

"The new integrated RPE Analysis software now offers clinicians the opportunity to objectively analyze all stages of AMD, especially the progression of dry AMD. Now one imaging technique, the Cirrus HD-OCT, can quantitate drusen and geographic atrophy, as well as choroidal neovascularization (CNV) and any elevation of the RPE associated with wet AMD," said Dr. Philip J. Rosenfeld, Professor of Ophthalmology at the Bascom Palmer Eye Institute and collaborator with Carl Zeiss Meditec in developing the techniques underlying the new applications. "Now we don't have to move patients between different instruments to visualize drusen, geographic atrophy, and CNV. These analyses will help clinicians stage and monitor disease progression today and will be critical to managing response to therapy as new treatments come to market."

As pointed out by Carmen Puliafito, MD, speaking at Retina 2012, held last week in Hawaii, “New algorithms to translate spectral domain optical coherence tomography images have begun to allow retinal specialists to measure drusen volume and area for the first time and may offer a better understanding of age-related macular degeneration. We now have some really objective tools that we can use to look at disease progression and then perhaps come to a better understanding of the pathophysiology of what exactly this disease is."

Fundus photography allows ophthalmologists to see drusen, but trying to count or measure it is nearly impossible, Dr. Puliafito said. These new methods will allow ophthalmologists to view the internal limiting membrane and the retinal pigment epithelium and where the retinal pigment epithelium should be, resulting in elevations that correspond to drusen, he said. This provides a major step forward in quantification.

"Drusen come, drusen go. And in their wake can be geographic atrophy, choroidal neovascularization or absolutely nothing," Dr. Puliafito said. "We now have some really objective tools to look at disease progression" to better understand AMD.

The new Cirrus HD-OCT application package also extends Carl Zeiss Meditec`s comprehensive suite of glaucoma diagnostic tools, adding new Ganglion Cell Analysis and Optic Nerve Head Progression Analysis. The Ganglion Cell Analysis evaluates the thickness of the combined ganglion cell and inner plexiform layers and compares the results to normative data. The new software package also expands Guided Progression Analysis (GPA) to automatically track progression of average cup-to-disc ratio and other optic nerve head parameters.

With these new clinical applications, Cirrus HD-OCT now spans the full spectrum of visualization and structural assessment in glaucoma: angle assessment, central corneal thickness measurement and analyses of retinal nerve fiber layer, ganglion cell layer and optic nerve head.

The new software package addresses a global market by adding user interfaces in Japanese, Chinese, Korean, German, French, Italian and Spanish to the original English interface. The software received its CE mark for distribution to major European markets in November, 2011.

Stem Cells in Ophthalmology Update 16: Results of First Embryonic Stem Cells in Treatment of Eye Disease Reported in Peer-Reviewed Journal

2012-01-23T19:53:00.000-05:00

Two significant events were reported today by Advanced Cell Technology. First, the company said that a peer-reviewed publication of clinical results from its first patients treated at UCLA Jules Stein Eye Institute had been placed online by the UK’s The Lancet. The study reported on the four-month results of a safety study initiated in human patients last July. In that study, one eye of a patient with Stargardt’s macular dystrophy (SMD), and another with the dry form of AMD were given doses of human embryonic stem cell-derived retinal pigment epithelial (RPE) cells.

The second event was the announcement that the first patient had been treated with stem cells in the UK arm of the Stargardt’s study, at Moorfields Eye Hospital last Friday. (See Update 10 for more information.)

As reported in The Lancet article, Embryonic Stem Cell Trials for Macular Degeneration: A Preliminary Report, in addition to showing no adverse safety issues, structural evidence confirmed that the hESC-derived cells survived and continued to persist during the study period reported. Both patients had measurable improvements in their vision that persisted for more than four months.

As noted by the lead author (Dr. Steven Schwartz), in his findings: “Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behavior and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt’s macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).”

At four months following treatment, no hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection were observed in either patient at any time. Detailed clinical and diagnostic laboratory assessments were performed at multiple post-transplantation evaluations. Abnormal growth (or tumor formation) would be considered a significant safety concern for stem-cell based therapies, in particular those derived from hESCs due to their pluripotency; it is therefore critical to control the differentiation of hESCs. Results reported indicate that stem cell differentiation was well controlled in these patients. No adverse safety signals were detected.

Anatomic evidence of successful stem cell derived RPE transplantation was observed clinically and with high resolution imaging technology in the patient with SMD. This evidence included increasing pigmentation at the level of RPE, within the area of the transplant, beginning one week after transplantation and throughout the follow-up period. Transplanted stem cell derived RPE appeared to engraft in the proper location and assume normal RPE morphology. Engraftment and increasing pigmentation were not detected in the dry AMD patient. However, both patients showed some visual improvement at the four month follow-up period. (Emphasis added by editor.)

Measuring visual improvement in patients with very low vision is difficult, and no regulatory consensus exists regarding on how best to measure visual changes in these patients. As reported in The Lancet, the visual acuity of the Stargardt's patient improved from hand motions only to 20/800 vision. Before treatment, the patient was unable to read any letter on the ETDRS visual acuity chart. However, by two weeks post-transplantation, she was able to start reading letters, which improved to five letters at one to three months in the treated eye.

"It has been over a decade since the discovery of human embryonic stem cells," said Robert Lanza, M.D., chief scientific officer of ACT, and co-senior author of the paper. "This is the first report of hESC-derived cells transplanted into patients, and the safety and engraftment data to date look very encouraging. Although several new drugs are available for the treatment of the wet type of AMD, no proven treatments currently exist for either dry AMD or Stargardt's disease. Despite the progressive nature of these conditions, the vision of both patients appears to have improved after transplantation of the cells, even at the lowest dosage. This is particularly important, since the ultimate goal of this therapy will be to treat patients earlier in the course of the disease where more significant results might potentially be expected. We would like to thank the patients for their willingness to participate in these safety studies. It has provided the scientific community with important data and experience that will help advance efforts in the regenerative medicine field."

Human embryonic stem cells can provide a superior source of replacement tissue by producing an unlimited number of healthy "young" cells with potentially reduced immunogenicity. The eye is an immune privileged site due to the protection of the subretinal space by a blood-ocular barrier, and as a result only low and transient doses of immunosuppression were used. No signs of rejection or inflammation were observed in either patient, and doctors will continue to monitor both patients.

"We are extremely pleased with these first clinical results from our ongoing studies to determine the safety and tolerability of subretinal transplantation of hESC-derived RPE cells," said Gary Rabin, chairman and CEO of ACT. "This represents an important milestone not only for ACT and UCLA"s Jules Stein Eye Institute but also for the field of regenerative medicine. The publication of these data in The Lancet demonstrates their quality and importance. We would like to thank the team, patients and principal investigator for their contributions to this study which have resulted in this outstanding publication. The data underscore the potential of stem cell therapies and regenerative medicine to realize the possibility repairing or replacing tissues damaged from disease. We are looking forward to the continuation of our clinical programs and the generation of additional data."

The hESC-derived RPE cells underwent extensive safety studies prior to transplantation. The cells were confirmed to be free of animal and human pathogens, and a high sensitivity assay was performed to rule out the presence of any undifferentiated hESCs in the final product, a risk factor for tumor formation. Controlled hESC differentiation resulted in near-100 percent pure RPE. A central feature of hESCs is that the stage of in vitro differentiation can be controlled to maximize survival and functionality. The data here show that the extent of RPE maturity and pigmentation may dramatically impact subsequent attachment and growth of the cells after transplantation.

"It is an honor to initiate the translational research process as we begin to take stem cell biology out of the laboratory and into the operating room," said Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute, principal investigator of the study and author of the publication. "The scientific and regulatory teams, as well as the leadership at ACT have been exemplary. Recognizing that we are reporting positive preliminary safety data, and a functional signal that there may be a biological benefit to patients in terms of visual increase, makes this is an exciting time for ophthalmology and regenerative medicine."

Both trials are prospective, open-label studies designed to determine the safety and tolerability of hESC-derived RPE cells following sub-retinal transplantation into patients with SMD and dry AMD at 12 months, the studies' primary endpoint. Each trial will enroll 12 patients each, with cohorts of three patients each in an ascending dosage format. Both the SMD and dry AMD patient had subretinal transplantation of the smallest dose (50,000 cells) of fully-differentiated RPE cells derived from hESCs.

The paper's other authors are Jean-Pierre Hubschman, Gad Heilwell, Valentina Franco-Cardenas, Carolyn K. Pan, and Rosaleen M Ostrick at UCLA and the Jules Stein Institute; and Edmund Mickunas, Roger Gay, and Irina Klimanskaya at ACT.

Editor’s Note: It should be noted that the smallest dosage allowed was used in these first patients in a safety study, in severely affected patients. Although some vision improvement was noted, it should be expected that higher doses, and in less-affected patients, might provide even better outcomes. Time will tell.

Stem Cells in Ophthalmology Update 15: Wills Eye Joins ACT’s Clinical Trials for Dry AMD Using Embryonic Stem Cell-derived RPE

2012-01-18T17:37:00.001-05:00

Advanced Cell Technology announced yesterday that the Wills Eye Institute in Philadelphia had received institutional review board (IRB) approval to become a site for the Phase I/II clinical trial for dry age-related macular degeneration (Dry AMD) using human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells. Wills will join UCLA’s Jules Stein Eye Institute and Moorfields Eye Hospital in London as sites participating in the clinical trials for Dry AMD, under ACT’s National Clinical Trials protocols.

"The participation of Wills Eye Institute in this trial will significantly enhance our clinical program," said Robert Lanza, M.D., ACT's chief scientific officer. "Wills Eye Institute is the oldest eye-care facility in the United States and is consistently ranked as one of the best ophthalmology hospitals in the country by the U.S. News & World Report. We are looking forward to working with Dr. Regillo and his team to address the unmet medical needs of degenerative diseases of the retina. With this latest approval, the company continues to assemble a clinical team that includes the best eye hospitals and surgeons in the world in our effort to find an effective therapy for this devastating eye disease."

The Phase I/II trial for dry AMD is a prospective, open-label study designed to determine the safety and tolerability of the hESC-derived RPE cells following sub-retinal transplantation into patients with dry AMD. The trial will ultimately enroll 12 patients, with cohorts of three patients each in an ascending dosage format. Which patients will be enrolled at the Wills Eye Institute will be determined in the near future.

"Degenerative diseases of the retina often lead to a significant visual impairment," said Carl Regillo, M.D., director of clinical retina research at Wills Eye Institute and professor of ophthalmology at Thomas Jefferson University. "Replacing lost or damaged cells with functional and healthy cells may provide a treatment option that could slow vision loss, and perhaps even reverse the effects of disease. We are looking forward to collaborating with ACT to evaluate the potential of the stem cell-derived RPE cells for debilitating diseases such as Stargardt's macular dystrophy and dry AMD."

Dry AMD, or "central geographic atrophy," is the "dry" form of advanced age-related macular degeneration. Dry AMD occurs when the light-sensitive cells (photoreceptors) in the macula slowly break down, gradually blurring central vision in the affected eye. Over time, as less of the macula functions, central vision is gradually lost in the affected eye, often progressing to blindness. The loss of photoreceptors is a direct result of a preceding degeneration of the retinal pigment epithelial (RPE) layer of cells just below the retina. As many as 30 million people in the United States and Europe suffer from macular degeneration, which represents a $25-30 billion worldwide market that has yet to be effectively addressed. Approximately 10% of people ages 66 to 74 will have symptoms of macular degeneration, the vast majority suffering from the "dry" form of AMD -- which is currently untreatable. The prevalence increases to 30% in patients 75 to 85 years of age.

"We are honored to have the opportunity to work with one of the foremost eye care centers in the world", said Gary Rabin, chairman and chief executive officer of ACT. "This clinical trial represents the culmination of years of innovation and hard work by ACT's scientific team. The whole world is focused on our trials, most especially patients suffering from dry AMD and other forms of macular degeneration. Wills Eye Institute has a strong tradition of innovation and discovery, and we are excited at their participation in bringing this cutting-edge technology through the clinic."

Additional details about these studies, for which the Jules Stein Institute at the University of California, Los Angeles and Moorfields Eye Hospital in London have also received IRB approval, can be found at ClinicalTrials.gov Identifier: NCT01344993.

Editors Note: As noted in the above quote from Dr. Regillo, it can be speculated that Wills Eye will soon join both Jules Stein and Moorfields in also treating Stargardt’s disease, under ACT’s National Clinical Trials NCT01345006 and NCT01469832.

It should also be noted that Wills Eye is also one of the clinical sites participating in the Centecor (J&J) clinical study of Dry AMD using adult stem cells from umbilical cord blood, NTC01226628.

Breaking News – as of January 19th, Wills Eye had been added to ACT’s clinical protocol for treating Dry AMD with embryonic stem cell-derived RPE cells, and was actively recruiting patients.

About Wills Eye Institute

Wills Eye Institute is a global leader in ophthalmology, established in 1832 as the nation's first hospital specializing in eye care. U.S. News & World Report has consistently ranked Wills Eye as one of America's top three ophthalmology centers since the survey began in 1990. Wills Eye is a premier training site for all levels of medical education. Its resident and post-graduate training programs are among the most competitive in the country. One of the core strengths of Wills is the close connection between innovative research and advanced patient care. Wills provides the full range of primary and subspecialty eye care for improving and preserving sight, including cataract, cornea, retina, emergency care, glaucoma, neuro-ophthalmology, ocular oncology, oculoplastics, pathology, pediatric ophthalmology and ocular genetics, refractive surgery and retina. Ocular Services include the Wills Laser Correction Center, Low Vision Service, and Diagnostic Center. Its 24/7 Emergency Service is the only one of its kind in the region. Wills Eye also has a network of nine multi-specialty, ambulatory surgery centers throughout the tri-state area. To learn more, please visit www.willseye.org .

Gene Therapy in Ophthalmology Update 8: Promising Results in the Treatment of Leber’s Congenital Amaurosis (LCA)

2012-01-14T16:05:00.000-05:00

As noted in the Gene Therapy in Ophthalmology by Application table shown in Update 7, there are seven clinical trials underway at various institutions aimed at the treatment of Leber’s Disease. Some of these trials have been underway for several years with multiple patients having been treated.

When I sent a copy of the table to Dr. Stephen Rose, chief research officer for the Foundation Fighting Blindness for comments and review, I also asked the question, “Who is tracking and reporting on the results of the patients already treated?” I didn’t get a direct response, but a few days later, the FFB reported the following story on its web site, providing some insight into the results being obtained.

Pennsylvania-Florida Team Reports Promising Three-Year Results for LCA Clinical Trial

Foundation Fighting Blindness

January 13, 2012 - Three years after it began, the landmark Phase I gene therapy clinical trial for people with Leber congenital amaurosis (LCA) at the Universities of Pennsylvania and Florida (NCT00481546) continues to go very well. Overall safety and vision improvements have been sustained. All 15 participants in the study, ranging in age from 11 to 30, have demonstrated vision improvement to varying degrees, including increases in visual field, night vision and mobility. Improvements in visual acuity only occurred in those who entered the trial with the lowest visual acuity.

"We are extremely pleased with the latest report coming from the Penn-Florida study. It is imperative that we demonstrate long-term safety and effectiveness of the treatment, and the team is doing that superbly," says Dr. Stephen Rose, chief research officer, Foundation Fighting Blindness. "We are also impressed by the depth and scope of their analyses of the treatment, which not only validate their results, but will greatly increase the chances of success for future gene therapy clinical trials for LCA and other retinal diseases."

The University of Pennsylvania's Dr. Samuel Jacobson, lead investigator for the clinical trial, and Dr. Artur Cideciyan, his co-investigator, say their team has learned that targeting certain areas of the retina for injection of the treatment is critical to both safety and effectiveness. Specifically, injections underneath the fovea, the central area of the retina with the highest concentration of cones, didn't improve vision and could potentially lead to damage or detachment. They believe that a strategy of two or three injections at different points outside the fovea will be optimal for treating many of these LCA patients.

Dr. William Hauswirth, a Foundation-funded gene therapy development expert and trial co-investigator from the University of Florida, is conducting lab studies of a gene therapy injection approach that may reduce the overall risk of retinal damage and detachment. As a potentially safer alternative to subretinal injections, he is evaluating intravitreal injections made near the front of the retina. The challenge with the intravitreal approach is ensuring that the treatment, which is contained in a tiny drop of liquid, gets to the retinal cells that need it. Dr. Hauswirth notes that different injection sites and strategies might be warranted for different diseases.

In addition to the Universities of Pennsylvania and Florida study, four other clinical trials are underway for gene therapy for LCA caused by mutations in the RPE65 gene. Those studies are being conducted by: The Children's Hospital of Philadelphia (CHOP), Moorfields Eye Hospital in London, Hadassah Medical Organization in Jerusalem, and Oregon Health & Science University, for the company AGTC. The Foundation is funding the clinical trials at CHOP and Moorfields, and funded much of the preclinical work that made them all possible.

All of the gene therapies in these clinical trials use a manmade adeno-associated virus, or AAV, to deliver normal copies of the RPE65 gene to replace the mutated copies in the retina. More than 40 people have been treated in the five RPE65 gene therapy clinical trials.

For additional information about this study, also see Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations, published in the Archives of Ophthalmology, September 12, 2011.

Gene Therapy in Ophthalmology Update 7: 2012 the Year for Gene Therapy?

2012-01-14T13:39:00.001-05:00

While I have previously written about the progress being made in the use of stem cells in ophthalmology (see Stem Cell Update 13) and described the 9-10 clinical trials currently underway or about to start (see Stem Cell Update 14), recent events point to 2012 becoming a breakthrough year for the use of gene therapy to overcome genetic defects that cause several ophthalmic diseases.

In the accompanying table, I list the fourteen clinical trials that I know about in the use of gene therapy in treating ophthalmic disease. Half of the trials are aimed at treating Leber’s Congenital Amaurosis (LCA), while three are for treating the wet form of AMD; one is underway for treating Choroideremia; one for Stargardt’s Disease; and two are aimed at different forms of retinitis pigmentosa (Autosomal Recessive RP and Usher Syndrome 1b).

In addition, I show at least twenty four clinical trials in either the pre-clinical (animal study) mode, or a couple in the IND-preparation mode. That is close to forty clinical trials using gene therapy to treat ophthalmic diseases.

The treatment of Leber’s using gene therapy has been ongoing for at least three years and, as I will show in the next update (Gene Therapy Update 8), those trials are going quite well, with many of the patients showing improved vision.

Finally, as another indicator that gene therapy will play an important role in ophthalmology in this year, Ocular Surgery News is about to begin a special section, OSN Retina, to be part of it’s coverage of the ophthalmic scene. The January 25 issue of Ocular Surgery News will include OSN Retina - a leading destination that will provide retina specialists with more relevant information specific to their field.. The premiere issue will include a feature on how “Retinal gene therapy may pave the way for attempts to reverse genetic disease: Advancements in retinal gene therapy have prompted a collaborative effort to attain FDA approval.”

For those of you who wish a better understanding of how gene therapy works, and until I write the Primer on the Use of Gene Therapy in Ophthalmology, which I have threatened to write for the past year and a half, you can gain an understanding by reading my first article about gene therapy, written back in November 2010, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD by Retrosense.

Here then is my latest version of Gene Therapy in Ophthalmology by Application:

A pdf file of the table is available by email request.

Stem Cells in Ophthalmology Update 14: Current Stem Cell Clinical Trials

2012-01-11T23:24:00.000-05:00

Thanks to new friend, Alexey Bersenev, and his stem cell blog, Hematopoiesis, I have been able to add several companies and medical institutions to my list of those involved in ophthalmic clinical trials using stem cells. Alexey recently posted a blog entry, Cell therapy clinical trials in 2011, describing his efforts to put together a list of entities undertaking stem cell clinical trials. He came up with a total of 151 clinical trials underway, of which eight were in ophthalmology.

I am able to add one that he missed, giving a total of nine clinical trials underway (and another about to start). The new list, showing the trials by ophthalmic application, are presented in the accompanying table.

Anyone wishing a pdf file of the table can get it by sending me an email request.

Stem Cells in Ophthalmology Update 13: Advanced Cell Technology Update

2012-01-10T17:28:00.001-05:00

In the wake of the 60 Minutes expose of illegitimate stem cell activities, I thought I would bring you good news about a couple of legitimate, government approved clinical trials using stem cells.

As part of the Biotech Showcase 2012 conference program, being held in San Francisco, ACT company chairman and CEO, Gary Rabin will present talks on his company’s progress as part of two panels at the Regenerative Medicine State of the Industry Briefing. In advance of his two talks, the company released a statement about the ongoing clinical trials, results and timing, on his From the Chairman company blog.

In his statement, reproduced below, Rabin commented on the progress of two of the three government approved clinical trials currently underway at UCLA’s Jules Stein Eye Institute on treating Stargardt’s Macular Dystrophy and the dry form of age-related macular degeneration (Dry AMD). (See Update 8 and Update 9 for additional information.) (The other clinical trial, also for treating Stargardt’s, is taking place in the UK at Moorfields Eye Hospital in London.[Update 10])

As I reported last July, in Update 9, the first two patients in each of the UCLA trials were treated on July 12th. Since these are safety studies, the investigators are carefully watching the first patients response to the treatment before treating other patients in the twelve patient trials.

Rabin stated, “As you are no doubt aware, the trials at UCLA are being conducted by Dr. Steven Schwartz of JSEI and overseen by our chief scientific officer, Dr. Robert Lanza. Each patient has received an injection of 50,000 hESC-derived RPE cells in one eye. Both trials will involve twelve patients, and are designed to evaluate the safety and tolerability of the injected RPE cells. Based on the results of the first patient in each study, we are authorized by the Data and Safety Monitoring Board (DSMB) to move forward with the next two patients in the studies, each of whom will also be treated with 50,000 RPE cells.” (Emphasis added by editor.)

Rabin went on to say, “I am delighted to inform you that we are currently scheduled to treat our first patient in the UK at the end of next week or early the following week, and that we will be treating four additional US patients beginning that same following week.”

As for publishing the results of the studies, he said that the company would take the appropriate approach of “publishing it in the form of a paper in a prestigious, peer-reviewed medical journal. However, the peer-review process takes time. The process typically takes several months, so I am actually quite thrilled that we are now moving toward the final stages of completing it, less than six months after the first patients were treated. We are far enough along that at this point the additional waiting time will be measured only in weeks, not months.”

So, this is good news for the cell stem treatment of retinal diseases.

I have also just learned about several other clinical studies now underway in this field and will discuss them in a followup report (Update 14) to be published either later today or early tomorrow.

Now, here is the complete statement from Mr. Rabin, as taken from his company’s website:

January 10, 2012

Clinical Trials, Results, and Timing

Greetings,

For many of us, the New Year is a time not just for looking forward but for reflecting on events, achievements and lessons learned over the past year. I anticipate an amazing year ahead for ACT, and at the same time I also cannot help but reflect with pride on how far the company has come with its clinical programs over the past year.

IND Filing and Clinical Trials

I will never forget the moment I learned that the company's Investigational New Drug Application (IND) for its human clinical trial for Stargardt's Macular Dystrophy (SMD) had been approved by the FDA. It was clear then that ACT truly was on the road to potentially making medical history. So much has happened in the interim that it is hard to believe that happened only a bit over one year ago, in late November, 2010!

Shortly after that, our IND for Dry Age Related Macular Degeneration (Dry AMD) was also approved. The brief time since then has been a whirlwind of activity in preparation for the clinical trials, and we were enormously pleased and proud to start them in July, at the first site, UCLA's Jules Stein Eye Institute (JSEI).

As you are no doubt aware, the trials at UCLA are being conducted by Dr. Steven Schwartz of JSEI and overseen by our chief scientific officer, Dr. Robert Lanza. Each patient has received an injection of 50,000 hESC-derived RPE cells in one eye. Both trials will involve twelve patients, and are designed to evaluate the safety and tolerability of the injected RPE cells. Based on the results of the first patient in each study, we are authorized by the Data and Safety Monitoring Board (DSMB) to move forward with the next two patients in the studies, each of whom will also be treated with 50,000 RPE cells.

Part of what makes research and development in the regenerative medicine sector so exciting is that it involves sailing into largely uncharted waters. ACT's two trials are the only ongoing human embryonic stem cell-based trials, period. We are quite literally creating a new area of medicine. This means there is tremendous pressure on us to "get it right." The responsibility to provide the first-ever validation for this enormously promising new sector rests entirely on our shoulders.

I hope, then, that our many fans and followers can understand why this process takes some time. All eyes are on us, both from the standpoint of support and scrutiny. Should our trials succeed, it could provide the validation that the regenerative medicine sector has been in need of for some time. This is why, in every stage, we are bending over backwards to make sure we cross all our t's and dot all our i's. As the saying goes, Rome wasn't built in a day. If we can successfully complete these trials and bring these therapies to market, though, the potential benefits would be manifold:

* The potential to at least partially restore sight to millions of people suffering from Dry AMD, the most common cause of blindness for people over age 55.

* Provide a much-needed validation to the entire regenerative medicine sector.

* Provide an enormously useful base of scientific knowledge on which we and others can develop other treatments and cures.

* Last but not least, reward our investors for their patience and support with a return on their investment as befits a company with the only approved treatment for Dry AMD, which has a potential market size of $25-30 Billion in the US and Europe alone, as well as for SMD.

For many years, I was an equity market investment manager. That is an industry where you can evaluate results on a daily basis. Just because you can do that, though, does not mean that you should. The best investors, by far, look at long-term investment opportunities. Running a biotech company is not the same. I am well aware that we have many shareholders who want to know why we don't just treat patients and release results as fast we can, and as fast as available. To do so would be beyond foolhardy for a company like ACT. If there is anything this industry has had some issues with, it is credibility in the mainstream healthcare world. We plan to change that. But to do that, it can't happen overnight. Patient selection, clinical site selection, the timing of patient treatment, and unexpected non-ocular conditions of patients found in health screenings are among the major factors that impact patient treatment. Another factor in the timing of treating these new patients is that we will have at our disposal a new kind of three-dimensional retinal imaging technique, which has not previously been available. Believe me, the timing of patient surgeries has nothing to do with safety, efficacy or availability of suitable patients.

I know that many investors want us to go as fast as possible in treating patients. But there is a tortoise/hare effect here that I simply won't discuss now. I know that it is hard to be patient, but we are making every decision for the best interest of the company in the long run. We don't get bonus points for finishing the trial a few months earlier as compared to making it a truly game-changing medical opportunity. I know that many of you don't know me from Adam, but I'm a very methodical person. Look who we recently added to the Board - one of the leading scientists in the world; one of the best entrepreneurs in the world (founder of Life Alert and eFax), and the CFO of a highly-regarded biotech company considered to have made excellent, value-preserving large bio/pharma partnering deals. We have this under control.

One ill-conceived decision could set the company on a downward path (ACT has been there). Highly prestigious peer-reviewed medical journals do substantial review and due diligence. Top-rated eye hospitals and surgeons are very process-oriented and sometimes bureaucratic. Pushing them harder to move faster doesn't earn you any credibility or success.

Nevertheless, I am delighted to inform you that we are currently scheduled to treat our first patient in the UK at the end of next week or early the following week, and that we will be treating four additional US patients beginning that same following week.

Publishing Data

The question that inevitably comes up asks when we are going to publish the initial data from the trials. We are eagerly anticipating doing so but we are not going to just post it in raw form. This trial has the potential to make medical history and we want to share the initial results with the world in a strategic way.

The only appropriate approach with data this significant is publishing it in the form of a paper in a prestigious, peer-reviewed medical journal. However, the peer-review process takes time. The process typically takes several months, so I am actually quite thrilled that we are now moving toward the final stages of completing it, less than six months after the first patients were treated. We are far enough along that at this point the additional waiting time will be measured only in weeks, not months. We are coordinating the scientific publication with a general mainstream media release strategy (see below). When the paper is published, rest assured that we plan to leverage it to make sure it is very broadly known, not only in medicine, but in the broader medical and scientific community, as well as the investment community.

We sincerely appreciate everyone's patience as we continue this process. We are keenly aware that our investors, fans and other followers are anxious to see the data.

Thank you for your patience and thank you, as always, for your interest and support.

Gary Rabin

Chairman and CEO

Advanced Cell Technology, Inc.

Gene Therapy in Ophthalmology Update 6: First-Ever Clinical Trial for the Autosomal Recessive Form of Retinitis Pigmentosa (arRP) is Underway

2011-12-23T12:52:00.001-05:00

It has been difficult keeping up with the changing world of gene therapy in ophthalmology, but thanks to the Foundation Fighting Blindness, I learned yesterday about this new, and first clinical study for treating a rare form of retinitis pigmentosa, underway in Saudi Arabia.

Here is the story, as reported by the FFB’s website:

First Gene Therapy Clinical Trial for Recessive RP is Underway

December 22, 2011 - The field of gene therapy for retinal degenerative diseases is taking a big step forward with the launch of the first-ever clinical trial for people with an autosomal recessive form of retinitis pigmentosa (arRP). The human study, underway at King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, is evaluating gene replacement for individuals with mutations in the gene MERTK, which is a frequent cause of arRP in people of Middle Eastern descent.

While the primary goal of the six-participant, Phase I trial is to evaluate the treatment's safety, investigators will also be looking at its effect on vision.

The treatment works by using a manmade adeno-associated virus, or AAV, to deliver healthy copies of the MERTK gene to cells in the retina. The treatment is contained in a tiny drop of liquid that is injected underneath the retina and absorbed by a layer of cells called the retinal pigment epithelium (RPE).

The MERTK gene plays an important role in the daily maintenance and regeneration of photoreceptors, the retinal cells that enable people to see. During sleep, the tips of photoreceptors are shed and disposed of by the RPE through a process called phagocytosis. Subsequently, the tips grow back. However, when the MERTK gene is defective, the disposal and regeneration process doesn't work properly, and debris and waste products accumulate, causing photoreceptor death and vision loss

"It is great to see clinical trials of gene therapy expanding into more forms of retinal disease and targeting additional mechanisms of disease such as defects in phagocytosis," says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "If successful, it broadens the range of retinal conditions that are amenable to gene therapy."

Dr. Rose notes that, for years, the Foundation has funded several MERTK and phagocytosis research projects, which helped make the current study possible. In addition, the AAV being used for gene delivery is similar to the one used in clinical trials of gene therapy that have restored vision in children and young adults virtually blind from Leber congenital amaurosis.

The MERTK gene therapy trial is being led by Drs. Kang Zhang of the University of California, San Diego, and Fowzan Alkuraya of King Khaled Eye Specialist Hospital. Dr. William Hauswirth, a Foundation-funded gene therapy development expert from the University of Florida, is also on the study team. His lab developed the AAV used in the trial and carried out preclinical safety studies to gain approval for the trial in Saudi Arabia.

Editor’s Note: I have been trying to keep track of the many pre-clinical and clinical studies underway in this ever changing field. I have put together a table of all of the activities underway that I have been able to identify and offer it to all interested parties. Gene Therapy Companies/Institutions Active in Ophthalmology, Version 8, updated as of yesterday, is available in a Word version to any that request it. Use the Email Me! link shown in the right-hand column.

Gene Therapy in Ophthalmology Update 5: A Complement-Based Gene Therapy for AMD

2011-12-01T12:02:00.002-05:00

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations

Here is another overview of a presentation made during the Retina SubSpecialty Day Meeting.

Dr. Elias Reichel, of Tufts University School of Medicine and a founder of Hemera Biosciences, Inc., of Boston, MA, presented on a new approach to treating the dry form of age-related macula degeneration. His paper was based on the research being done by Hemera Biosciences on HMR59, a naturally occurring protein that protects retinal cells from damage by MAC (Membrane Attack Complex), that can be delivered for long-lasting activity via a gene therapy approach.

HMR59 was developed at Tufts University and subsequently licensed to Hermera Biosciences.

Complement Regulation via Gene Therapy for Dry AMD

Elias Reichel, M.D., Professor of Ophthalmology, Tufts University School of Medicine, Boston, MA

HMR59 is a novel therapy primarily targeted at geographic atrophy and other forms of dry age related macular degeneration (Dry AMD) by blocking the final stage of the complement cascade, membrane attack complex (MAC). The complement cascade is implicated via genetic studies as playing a critical role in both wet and dry AMD.

HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death.

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles.

HMR59 will be injected directly into the vitreous cavity in an office setting. Such a procedure is currently performed by all retinal specialists using other medications quite commonly. Using the gene therapy approach offers the opportunity to reduce the number of injections needed over a patient's lifetime as the ocular cells will act as factories to produce sCD59, thus addressing the issue of drug delivery.

In summary:

• The complement pathway is strongly associated with AMD

• Membrane attack complex (MAC) is the final step in the complement pathway

• CD59, a naturally occurring protein, protects retinal cells from damage by MAC

• Hemera Biosciences has developed a gene therapy which produces soluble CD59 (sCD59) that blocks MAC

• A single intravitreal injection allows for long term protection from AMD progression

Hemera Biosciences is currently seeking funding to begin animal toxicology studies to get to a phase 1 study in humans.

Inquiries for further information should be made to: Elias Reichel, MD.

Gene Therapy in Ophthalmology Update 4: Table of Companies and Institutions Participating

2011-11-16T15:27:00.000-05:00

As a followup to the stem cells in ophthalmology table recently published, here is one tabulating the participants using gene therapy in ophthalmology.

When I first wrote about gene therapy in ophthalmology (Gene Therapy for RP and Dry AMD) in November 2010, I began collecting information about the various participants with the thought of writing a Primer, similar to the one I did on stem cells in ophthalmology. At that time, I was able to identify seven companies participating. Since then, and with the help of a few friends, I have now identified nearly thirty companies and institutions using gene therapy approaches to treat ophthalmic diseases. Since I believe access to knowledge is very important, here is the latest version of my table of companies and institutions using gene therapy approaches for treating ophthalmic diseases.

Please let me know of any corrections or omissions.

(An easier to read pdf file of this table is available from the author via email request.)

Stem Cells in Ophthalmology Update 12: Updated Table of Company Participants

2011-11-12T17:24:00.000-05:00

When I first wrote about stem cells in ophthalmology (Primer) in September 2010, I was able to identify six companies participating. Since then, and with the help of a few friends, I can now identify eleven companies using stem cells to treat ophthalmic diseases. Since I believe access to knowledge is very important, here is my revised table of companies using stem cells in treating ophthalmic diseases.

Please let me know of any corrections or omissions.

(An easier to read pdf file of this table is available from the author via email request.)

Iluvien Update 4: FDA Turns Down Alimera’s NDA for Approval of Iluvien Again

2011-11-11T13:27:00.001-05:00

Alimera again received bad news from the FDA on its application for approval of Iluvien. In a letter (a CRL or complete response letter), the FDA said that questions remained based on the data previously submitted, about the adverse reactions shown by Iluvien in the FAME Study (risk of cataracts and raised IOPs) and that these were not offset by the benefits demonstrated.

The FDA indicated that Alimera would need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.

Here is Alimera’s complete new release:

Alimera Sciences Receives Complete Response Letter From FDA for ILUVIEN(R)
Conference Call Scheduled for Monday, November 14 at 8 a.m. Eastern Time

ATLANTA, Nov 11, 2011 (GlobeNewswire via COMTEX) -- Alimera Sciences, Inc., ("Alimera"), a biopharmaceutical company that specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals, today announced that it has received a complete response letter (CRL) from the U.S. Food and Drug Administration (FDA) in response to the New Drug Application (NDA) for ILUVIEN(R) for the treatment of diabetic macular edema (DME) associated with diabetic retinopathy.

A CRL is issued by the FDA's Center for Drug Evaluation and Research when their review of an application is completed and questions remain that precludes the approval of the NDA in its current form.

The FDA stated that it was unable to approve the ILUVIEN NDA because the NDA did not provide sufficient data to support that ILUVIEN is safe and effective in the treatment of patients with DME. The FDA stated that the risks of adverse reactions shown for ILUVIEN in the FAME(R) Study were significant and were not offset by the benefits demonstrated by ILUVIEN in these clinical trials. The FDA has indicated that Alimera will need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.

The Company will be requesting a meeting with the FDA to clarify next steps.

ILUVIEN is Alimera's investigational, sustained drug delivery system that releases sub-microgram levels of fluocinolone acetonide (FAc) for the treatment of DME. In December 2010, the FDA issued a CRL to Alimera related to its June 2010 NDA for ILUVIEN, which included data through month 24 of the FAME(TM) Study. In that first CRL, the FDA asked for, among other things, analyses of the safety and efficacy data through month 36 of the FAME Study. Alimera submitted a response to the FDA on May 12, 2011, addressing the issues raised in the first CRL and including 36-month trial data. The FDA classified Alimera's response as a Class 2 resubmission, resulting in a six-month review period and a Prescription Drug User Fee Act, or PDUFA, date of November 12, 2011.

"We are surprised and disappointed with the FDA's decision on our application to market ILUVIEN in the U.S. to patients with this devastating disease. Based on extensive research with U.S. retinal physicians, we have learned that ILUVIEN's long-term sustained delivery treatment benefit is desired and that ILUVIEN has a manageable risk to benefit ratio. We continue to believe in ILUVIEN as a long-term effective treatment option for DME. We are committed to, and have the funds for, pursuing approval in Europe and for evaluating our options in the U.S.," said Dan Myers, president and chief executive officer of Alimera.

For Europe, Alimera expects to submit its formal response to the Preliminary Assessment Report to the Medicines and Healthcare products Regulatory Agency (MHRA) later this month. Based on this submission, the MHRA is expected to make a recommendation on the approvability of ILUVIEN to Alimera and the Concerned Member States (Austria, France, Germany, Italy, Portugal and Spain) by the end of this year, with a decision regarding the approval of ILUVIEN expected in the first half of 2012. The market opportunity in Europe is similar in size to the U.S. market opportunity.

Fighting Retinal Disease: The Promise of New Approaches

2011-11-09T16:29:00.001-05:00

Dr. Stephen Rose, the Chief Research Officer of the Foundation Fighting Blindness has just written an article about emerging treatments for retinal diseases, including the use of stem cells, gene therapy and new pharmaceutical approaches. I feel it is important for those of you on the front lines fighting these diseases and those of you who have them, to know that we are getting closer and closer to solving some of the questions about saving sight, and perhaps even bringing back lost sight.

Please take a look at Dr. Rose’s words and dig deeper into the resources available on the FFB website. (I have not included the links that were included with some of his remarks, but you can go to the original on the web and check them out for yourselves.)

What Emerging Treatment Will Work Best for Me?

Written by Stephen Rose, Ph.D., Chief Research Officer, Foundation Fighting Blindness

November 8, 2011 - Hope has never run higher in the fight against retinal degenerative diseases, thanks to clinical trials now underway for gene, stem cell and pharmaceutical therapies. As a result, people affected by these vision-robbing conditions are naturally eager to figure out what emerging treatment approach is going to work best for them.

While it is tempting for someone affected to focus on a "magic bullet" to stop or reverse their disease, I strongly encourage people to consider the Foundation's comprehensive portfolio of emerging treatments when thinking about the future of their vision. Here are three important reasons why:

We can't predict how future research will unfold

Science always has surprises. As an example, until a year or two ago, we believed that corrective gene therapy would be suitable only for treating early-stage disease when a person had a lot of photoreceptors left to save. But recently, Foundation-funded researchers from the University of California, Berkeley and other groups are using gene therapy to enable ganglion cells -- cells in the retina that survive long after photoreceptors are lost -- to provide vision. This research advance has now put gene therapy on the map for potentially reversing total blindness. Previously, we thought that only stem cells or artificial retinas could restore vision in advanced disease.

We need to have back-up plans

In the next couple of years, as we see a big increase in the number of clinical trials for inherited retinal diseases, some setbacks will be inevitable. We need to keep in mind that clinical trials are experiments and, invariably, will not always achieve optimal results. It is critical that we have multiple treatments available, or in the pipeline, for each disease, in case a promising course of action does not pan out. This is one reason pharmaceutical therapies are so important. Generally speaking, they can treat a broader range of conditions than, for example, a gene therapy directed at a specific genetic defect. I envision pharmaceuticals often serving as bridges, or as alternatives, to more targeted therapies.

Treatment decisions will be personal

Several factors will play a role in determining which treatments might work best for an individual, including his or her genetic profile, stage of disease, age and even tolerance for risk. Let's say in the future that a middle-aged person with retinitis pigmentosa has been taking a drug for many years that's done a good job preserving vision, and along comes a new gene or stem cell therapy. Does that person try a new treatment or stick with what is known to work? There is no right or wrong course of action. What's important is that we fund a diversified portfolio of research, so patients have options. Multiple treatment alternatives may seem like a luxury now, but we are working hard to make that day a reality as soon as possible.

Find out more about Foundation research

The Foundation currently funds 130 grants at 73 institutions around the world. Grants are selected through a rigorous review process conducted by the Foundation's Scientific Advisory Board, which is comprised of the world's top retinal researchers. A complete list of the Foundation's grants is at: www.FightBlindness.org/grants.

Gene Therapy in Ophthalmology Update 3: Genetic Testing of RP Patients Necessary in Order to Direct Treatment

2011-11-02T13:16:00.001-04:00

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations
Here is another of the presentations made during the Retina SubSpecialty Day Meeting.

Dr. Stephen Tsang presented on factors and the genetics of retinitis pigmentosa. His paper was based on the article previously published by he and his co-author, Kyle Wolpert, that appeared in the November 2010 issue of Retinal Physician.

The Genetics of Retinitis Pigmentosa
Knowing how the varieties of RP are transmitted can be half the battle of treatment.
Stephen H. Tsang, MD, PhD and Kyle Wolpert, BA

Published in Retinal Physician, November 2010
(Reprinted with permission of the authors)

Retinitis pigmentosa (RP) is a heterogeneous group of diseases characterized by progressive rod-cone dysfunction. Patients initially present with nyctalopia from rod photoreceptor loss, progress to tunnel vision and ultimately experience central vision loss. RP is also the most common form of inherited retinal degeneration, affecting one in 3,000 people.(1,2)

GENETICS BASICS

As a genetically heterogeneous set of disorders, the specific mutation involved in any given case of RP dictates the inheritance pattern and strongly influences the prognosis. As such, a careful family history is essential both for diagnosis and genetic counseling. When possible, the family members of a new RP patient should be examined in order to better define the inheritance pattern. Often, family members may be younger than the age at which the disease develops, which can make this process difficult.

Electroretinogram (ERG) testing, which provides a global assessment of rod and cone function, can measure electro-physiological disturbances long before photoreceptor loss occurs or changes can be seen on fundus examination.(1,3) Thus, ERG testing can help determine whether younger family members will present with the disease later in life, which is useful both for the construction of a pedigree and also for counseling purposes; for example, ERG screening may help a young patient identify plausible career paths.

Described inheritance patterns of RP include autosomal dominant (15% to 35% of cases), autosomal recessive (60%), X-linked recessive (5% to 18%), and mitochondrial. If no other family members are affected, the disease is likely the result of an autosomal recessive (AR) mutation. If the disease presents only in men and is transmitted maternally, then it is likely an X-linked recessive (XLR) mutation. Unlike the recessive modes of inheritance, autosomal dominant (AD) transmission is marked by disease occurrence in every generation and father-to-son transmission.

The rarest form of inheritance is X-linked dominance. These patients are almost always women, as such traits are generally lethal in men. It is possible that a sporadic case could represent a new autosomal dominant mutation, but this is rare. However, the possibility underscores the need for genetic testing to ensure an accurate diagnosis. Mitochondrial mutations are passed maternally and often present systemic problems. Identifying the inheritance pattern involved can help to determine the prognosis, both for the patient and the rest of his or her family.

AUTOSOMAL DOMINANT

Between 15% and 35% of all cases of RP follow an autosomal dominant inheritance pattern.(4,5) As stated previously, AD inheritance is marked by occurrence in each generation and father-to-son transmission of the disease. Compared to AR forms, the AD forms of the disease tend to be more mild, progress more slowly, and present later in life. Patients present with reduced visual acuity and loss of color vision in late adulthood and progress to legal blindness. In the first two decades of life, patients with autosomal dominant RP may be funduscopically indistinguishable from healthy patients. Mutations in rhodopsin, the visual pigment, are responsible for 30% of AD forms of RP. In patients with RP, autofluorescence imaging often shows a characteristic ring of hyperautofluorescence before abnormalities appear on fundus examination; as such, autofluorescence imaging can help to provide presymptomatic clinical evaluation of the patient and predict the course of the disease.(6-8)

Genetic counseling for patients with AD RP is relatively straightforward. Assuming that only one of the patient's parents is affected, each of the patient's children will have a 50% chance of inheriting the mutant allele and thus the disease. Furthermore, an affected patient's siblings each have a 50% chance of being affected. Siblings and children that do not have the allele (as determined by ERG testing) will not pass the disease on to their own children.

AUTOSOMAL RECESSIVE

Autosomal recessive forms of retinal degeneration tend to be more severe, progress more rapidly, and present earlier than the AD forms. As stated previously, the AR inheritance pattern is characterized by sporadic appearance and occurrence in both men and women.

Genetic counseling for patients with AR retinitis pigmentosa is more complicated than for the AD forms. If a patient is affected with an AR form of RP, then both of their parents must have been heterozygous carriers. This means that each of their siblings has a 25% chance of developing the disease and a 50% chance that they are asymptomatic carriers; thus, if a sibling does not have the disease, then there is still a 66% chance that they are carriers. The patient's children will not develop the disease, but each will be a heterozygous carrier, so it may reappear in later generations.

X-LINKED RECESSIVE

The X-linked recessive form of retinal degeneration is often the most severe. It has an early onset, with teenage men showing rod degeneration followed by cone degeneration. Female heterozygous carriers can show patchy areas of rod degeneration due to X-chromosome inactivation, and they present with a metallic, tapeto-like sheen apparent both in autofluorescent and color photographs.(9) The ERG in such carriers is typically affected by age 60.

Genetic counseling for those affected is nuanced due to the nature of the sex chromosomes. Sisters of affected men have a 50% chance of being heterozygous carriers, but they will not develop the disease. Brothers of affected men have a 50% chance of developing the disease, but if they do not, then they will not be heterozygous carriers. Sons of affected men will not be affected. Daughters will be heterozygous carriers, and as such, their own children will have a 50% chance of receiving the mutant allele.

GENETIC TESTING

It is essential that patients with retinitis pigmentosa submit to genetic testing, both for purposes of prognosis and for the improved understanding of the genetics of RP. There are 15 genes known to be associated with autosomal dominant RP, 17 genes associated with autosomal recessive RP, and two genes associated with X-linked RP.

There is currently a 30% chance that blood submitted for genetic testing will be matched with a known mutation within one year of submission. Knowing the inheritance pattern before submitting blood for genetic testing is important because there are different gene chips used when testing for RP genes: one with dominant mutations and one with recessive mutations.(10) This helps to streamline the process by avoiding the need for extraneous testing, making it more cost efficient.

Genetic tests can cost the patient hundreds of dollars, so reducing the price by narrowing the scope of the test is important. Genetic testing of all patients is important because the genotype-phenotype correlation can vary such that different members of a family express the disease differently or, alternatively, that different mutations manifest similar fundus alterations.(8)

Genetic testing for mitochondrial mutations is much more complicated than standard testing. In genetic testing of normal DNA, a blood sample is taken and submitted for testing, but mitochondrial testing requires a biopsy of the retina itself.

GENE THERAPY

For many years, cures for RP have been largely unavailable. However, recent developments point to the promise that, in some cases, gene therapy could arrest the progression of RP and perhaps even restore lost vision. Gene therapy can be difficult in most organ systems because the body's immune response causes a rejection of the introduced material. However, the eye is a rather immunoprivileged site, and as such, gene delivery using adeno-associated virus has been shown to be effective.

Several studies published in 2008 demonstrated the efficacy of gene therapy to help patients with an early-onset autosomal recessive form of retinal dystrophy, known as Leber's congenital amaurosis.(11-13) Gene therapy success can be measured noninvasively through the use of techniques such as ERG testing and autofluorescence imaging.

One major impediment to the development of gene therapies is that they are gene specific. This is why it is crucial that the database of known mutations be expanded. The inheritance pattern of a given mutation is also important for determining the relative likelihood of the development of successful gene therapies. Recessive genes are relatively easy to treat with "gene-replacement" therapy because the eye simply lacks a functional copy of the gene; if a functional copy is introduced, then results can be seen. Dominant genes are more complicated because they require "gene correction" in order to essentially override the deleterious effects of the mutant allele.

Cell replacement therapy using induced pluripotent stem cells is another treatment currently in development that may be an effective treatment for both AD and AR forms of RP.(14) Mitochondrial gene therapy is not currently a realistic possibility. However, stem-cell therapy has worked as a temporary treatment for the bone marrow in Pearson syndrome, so similar stem-cell therapy may someday be available for the retinal atrophy resulting from mitochondrial disorders.

SUMMARY

More treatments for retinitis pigmentosa are foreseeable in the coming decade, but genetic testing of RP patients is essential in order both to understand better the genetic associations of the disease and to direct efforts at developing treatments. However, even before implementing genetic testing, it is important to obtain, as much as possible, a complete family history in order to identify the inheritance pattern of the disease. The inheritance pattern has serious implications for the prognosis of the patient and is critical for genetic counseling for the patient and his or her family. RP

REFERENCES

1. Humphries P, Kenna P, Farrar J. On the molecular genetics of retinitis pigmentosa. Science. 1992;256:804-808.
2. McKusick VA, Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Vol CD-ROM. 12th ed. Baltimore, MD; The Johns Hopkins University Press; 1998.
3. Berson EL, Gouras P, Hoff M. Temporal aspects of the electroretinogram. Arch. Opthalmol. 1969;81:207-214.
4. Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH. Prevalence of retinitis pigmentosa in Maine. Am J of Opthalmol. 1984;97:357-365.
5. Ayuso C, Garcia-Sandoval B, Najera C, Valverde D, Carballo M, Antinolo G. Retinitis pigmentosa in Spain. The Spanish Multicentric and Multidisciplinary Group for Research into Retinitis Pigmentosa. Clin Genet. 1995;48:120-122.
6. Lima LH, Cella W, Greenstein VC, et al. Structural assessment of hyperautofluorescent ring in patients with retinitis pigmentosa. Retina. 2009; 29:1025-1031.
7. Tsang SH, Vaclavik V, Bird AC, Robson AG, Holder GE. Novel phenotypic and genotypic findings in X-linked retinoschisis. Arch Ophthalmol. 2007; 125:259-267.
8. Tsui I, Chou CL, Palmer N, Lin CS, Tsang SH. Phenotype-genotype correlations in autosomal dominant retinitis pigmentosa caused by RHO, D190N. Curr Eye Res. 2008;33:1014-1022.
9. Zeiss CJ, Ray K, Acland GM, Aguirre GD. Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3). Hum Mol Genet. 2000;9:531-537.
10. Tsang SH, Tsui I, Chou CL, et al. A novel mutation and phenotypes in phosphodiesterase 6 deficiency. Am J Ophthalmol. 2008;146:780-788.
11. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008;358:2231-2239.
12. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240-2248.
13. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008;105:15112-15117.
14. Gouras P, Kong J, Tsang SH. Retinal degeneration and RPE transplantation in Rpe65(-/-) mice. Invest Ophthalmol Vis Sci. Oct 2002;43:3307-3311.

Stephen H. Tsang, MD, PhD, is an ophthalmic geneticist and ERG attending at Columbia. Kyle Wolpert, BA, is a laboratory assistant at the Harkness Eye Institute of the Columbia University Medical Center. Neither author reports any financial interest in any products mentioned in this article. Dr. Tsang can be reached via e-mail at dr.stemcells@gmail.com.

Gene Therapy in Ophthalmology Update 2: Foundation Fighting Blindness Funds Six New Gene Therapy Projects

2011-10-31T16:39:00.001-04:00

In a news release that I found on the net, I learned that the FFB was going to put $8.25 million into six gene therapy projects, either already underway or about to start. The release contains good information about several projects that I knew about, and others that I did not.

Here, for your edification is their news release:

Foundation Fighting Blindness Invests $8.25 Million in 6 New Gene Therapy Research Projects
Foundation Fighting Blindness, 10/25/11

The Foundation Fighting Blindness, a national nonprofit dedicated to advancing sight-saving research, announces an $8.25 million investment in six new gene therapy research projects that are targeted to have treatments ready for clinical trials within three years. The grants focus on treating a broad range of retinal degenerative diseases and will be allocated through the Foundation's Translational Research Acceleration Program, which funds research efforts with strong, near-term clinical potential.

"The Foundation Fighting Blindness recognizes the great potential of gene therapy for saving and restoring vision, and we're eager to build on the clinical development of retinal gene therapies that has been accelerating at an incredible rate over the past few years," said Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "It was just three years ago that we reported groundbreaking results from our first gene therapy clinical trials that restored vision in children and young adults who were virtually blind from Leber congenital amaurosis (LCA). The success of those studies set the stage for this rapid expansion in gene therapy development."

As part of the new $8.25 million investment, one innovative project involves the use of gene therapy to resurrect and reactivate cone cells that are compromised by disease. In many inherited retinal conditions, including retinitis pigmentosa, cones stop working before they completely degenerate. The Institut de la Vision in Paris and the Friedrich Miescher Institute in Basel, Switzerland, are developing a gene therapy that revives degenerating cones, enabling them to regain their ability to respond to light and provide vision. The treatment also improves the health of cones and extends their lifespan significantly. This therapeutic approach holds the potential to benefit people affected by a range of conditions, because it works independently of the underlying disease-causing genetic defect. Resurrecting cones can improve an affected individual's well being, because these cells provide central, daytime and detailed vision that is critical for independent living.

The Foundation is also funding the Oklahoma University Health Sciences Center, which in collaboration with Copernicus Therapeutics, is developing a nanoparticle gene therapy system.
Nanoparticles are tiny manmade particles, 1/12,000th the diameter of a human hair, which can readily penetrate retinal cells, making them effective for delivery of therapeutic genes. They may provide advantages in certain cases over viral gene delivery technologies currently used in retinal disease therapies. Perhaps most beneficial is their ability to deliver large genes - genes that exceed the capacity of viral delivery systems - for treating some diseases.

Through a Foundation grant to Applied Genetic Technologies Corp. (AGTC), a clinical stage biotechnology company, funds will support researchers at Oregon Health & Science University's Casey Eye Institute and the University of Florida in their pre-clinical work to evaluate a gene therapy treatment for X-linked retinoschisis, a blinding disease that affects over 35,000 patients in the United States and Europe.

Portions of the Foundation's $8.25 million investment will also go toward research happening at the Massachusetts Eye and Ear Infirmary and the University of Florida for projects investigating gene therapy for two different LCA-causing genes. The final grant supports work at the University of Pennsylvania for choroideremia gene therapy led by Dr. Jean Bennett, who is also one of the lead investigators on the landmark LCA gene therapy clinical trial that has restored vision in more than 40 patients.

There are now human studies of gene therapy underway for Leber congenital amaurosis, wet age-related macular degeneration, and Stargardt disease, with clinical trials for Usher syndrome (the leading cause of deaf-blindness) type 1B and autosomal recessive retinitis pigmentosa scheduled to begin in late 2011 or early 2012. Currently supporting 30 other gene therapy efforts, including RDH12 and other genetic forms of LCA and RP, which are at various stages of development, the Foundation allocates funding toward basic research and investigation into a gene's role in disease, as well as projects poised for clinical trials.

Editor's Note: I have put together a matrix, that at the moment contains eight companies involved in Gene Therapy in Ophthalmology projects. Anyone wishing to obtain a copy of the matrix, please email me.

Stem Cells in Ophthalmology Update 11: Catheter Delivered Stem Cells to Treat Geographic Atrophy in Dry AMD

2011-10-27T22:10:00.001-04:00

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations

From afar (my home), I reviewed the program for the Retina SubSpecialty Program and decided to write about several of the presentations on the program. I was able to obtain a copy of the program abstracts (from a friend in attendance) and got in touch with each of the presenters of interest and requested an electronic copy of their presentations. The presentations of interest included the following:

The Genetics of Retinitis Pigmentosa by Stephen Tsang, MD;
Attacking Leber Congenital Amaurosi by Albert Maguire, MD;
Gene Testing and AMD: Are We Ready to Start? by Ivana Kim, MD;
Dry AMD Treatment: How Will We Define Sucess? by Phil Rosenfeld, MD;
Drug Delivery Implants for Geographic Atrophy by Baruch Kupperman, MD;
A Complement-Based Gene Therapy for AMD by Elias Reichel, MD; and,
The Promise of Stem Cells for AMD and Retinal Degenerations by Marco Zarbin, PhD.

In addition, in following the reporting by various sources of the meeting, I discovered that a paper by Dr. Michael Samuel about the delivery of stem cells to the macula via a specialized catheter was also presented (apparently in an update session). I was not familiar with either this approach or the program (even after writing A Primer on the Use of Stem Cells in Ophthalmology in September, last year), so I got in touch with Dr. Samuel (and his sponsor, iScience Interventional, the supplier of the special delivery catheter) and asked their permission to obtain an electronic copy of the presentation. After some back and forth, I learned that the actual sponsor of the clinical study that Dr. Samuel was reporting on, was the Centecor Division of Johnson & Johnson, from whom I would also need permission.

I attempted to get in touch with the appropriate people at Centecor/J&J and am still waiting to hear back from them.

In the meantime, after a little due diligence online, I discovered a couple of things. First, J&J’s Centecor was the sponsor of two ophthalmic clinical trials using its CNTO2476 stem cells, one for the treatment of retinitis pigmentosa (now terminated for business reasons – but no further explanation given) and the second for treating geographic atrophy in dry AMD.

I also came across a review article by Dr. Allen Ho on the GA program in the current (October) issue of Retina Today. Finally, I also discovered that EyeTube.net had a video online of Dr. Samuel presenting the results of the initial GA trial on the first set of twelve patients, apparently summarizing his presentation from the Retina SubSpecialty Day session.

So, armed with all of this new found information, I believe I can now tell the story of Centecor/J&J’s program to deliver stem cells to the macular in the hopes of treating geographic atrophy.

The other stories selected from the Retina SubSpecialty Day Program will be presented in other entries on this blog.

Novel Technique for Stem Cell Therapy to the Subretinal Space
Dr. Michael Samuel, and

Human Adult Umbilical Stem Cells: Potential Treatment for Atrophic AMD
Dr. Allen Ho

The Program

Treating Geographic Atrophy

As described by Dr. Ho, “Geographic atrophy (GA) is a slowly progressive pathology in nonexudative ("dry") age-related macular degeneration (AMD), for which there is currently no safe and effective treatment. Investigational strategies for treatment of atrophic AMD include oral nutraceutical formulations, vitamin A visual cycle modulators, and injectable molecular interventions with molecular targets such as complement system modulators to retard the progression of GA. The goals of these investigational interventions include preventing photoreceptor and retinal pigment epithelial (RPE) cell loss, reducing the load of toxic metabolites in these cells, and suppressing or modulating inflammation.

Another approach under investigation in relation to preventing photoreceptor and RPE cell loss in GA is cell-based therapy – the harvesting and transfer of stem cells to support or replace diseased cells. Traditional pharmaceutical agents work on a molecular level; cell-based therapies work on a cellular level to restore or preserve cellular function.

The main sources for the cells used in cell-based therapies include embryonic stem cells, which have been controversial, and adult stem cells. Sources for adult stem cells include bone, blood, umbilical cord, and, in the eye, the corneal limbus.”

The Approach

Again, as Dr. Ho has written, “Two approaches are used in stem-cell therapies: regenerative and trophic (Figure 1). In the regenerative approach, embryonic or adult stem cells are isolated, expanded (grown to larger number of cells), and differentiated into the stem-cell therapy product. That is, they are progressed to become another cell type: for example, corneal stem cells (or retinal pigment epithelial [RPE] cells). These functional cells are intended to replace lost or injured native cells to restore organ function. In the trophic approach, the stem cells are themselves the product. The adult cells are isolated, characterized, and expanded, but they remain differentiated, not progressed to become another cell type. In this approach, the role of the cells is to support or repair injured native tissue and preserve function by altering the microenvironment of the injured tissue, for example through cytokines or cell-to-cell interactions.

Figure 1. Regenerative (A) and trophic (B) stem-cell therapy. In the regenerative approach, embryonic or adult stem cells are isolated, expanded (grown to larger number of cells), and differentiated into the stem-cell therapy product. In the trophic approach, the stem cells are themselves the product.

In the regenerative approach, the stem cells are the precursor to the product. An example of regenerative stem-cell-based therapy is corneal limbal stem cell transplantation, in which autologous allogeneic adult corneal limbal stem cells from the palisades of Vogt are transplanted to help the corneal epithelium regenerate. The corneal limbal stem cells are transplanted onto the surface of the eye, repopulating the damaged cornea.

One example of trophic cell-based therapy is the NT-501 (Neurotech), an intraocular device that delivers ciliary neurotrophic factor (CNTF), a protein that has been investigated for the treatment of motor neuron disease, to the posterior segment. The implant contains human RPE cells that have been genetically modified to secrete CNTF. In a phase 2 clinical trial, NT-501 slowed the loss of vision in patients with GA due to dry AMD. Implanted in an OR-based procedure, the technology was superior to sham injection in stabilizing best corrected visual acuity (BCVA) at 12 months. No serious adverse events were reported, and the implant was well tolerated. Further study of this technology is ongoing.

Another example with a putative trophic mode of action is human adult umbilical stem cell rescue of photoreceptor cells. In the Royal College of Surgeons rat, in which most of the photoreceptors degrade before 100 days of age because of a defect in the RPE, both structure and function of the retina were preserved after transplantation of human umbilical-derived cells. Of 4 cell types evaluated, the umbilical-tissue derived cells demonstrated the best photoreceptor rescue.”

Editor’s Note: It must be noted that other companies besides Centecor/J&J are pursuing stem cells – and even gene therapy – approaches to treating the dry state of AMD. Advanced Cell Technology has an ongoing clinical study, using human embryonic stem cell derived RPE in treating dry AMD (as well as Stargardt’s disease). Retrosense – among others – using gene therapy, plans to study dry AMD after it gets its retinitis pigmentosa (RP) program underway, and Oxford BioMedica has just begun a clinical study to treat a form of RP associated with Usher’s Syndrome (type 1B) with gene therapy. (I have written about all three of these companies programs in this space.)

The Clinical Trial

As noted above, and also reported by Dr. Ho, Centecor/J&J has initiated a clinical study using their CNTO 2746 therapy in patients with geographic atrophy associated with the dry form of AMD. This clinical trial was initiated in October 2010. As stated in the clinical trial information sheet, the main purpose of the study is to assess the effects (good and bad) of the CNTO 2476 therapy for patients with age related macular degeneration. Patients will have CNTO 2476 injected by the surgeon into the subretinal space of the macula of one of their eyes. The patients will then be assessed over a period of at least one year by their surgeon.

CNTO 2476 is composed of human umbilical tissue-derived stem cells (hUTC) from Centocor, Inc.

Twelve patients were enrolled in the Phase I dose escalation and safety study at sites in Philadelphia and Los Angeles. In the Phase II study, an additional 56 patients will be enrolled at the two current and four additional study centers, and will be randomized to 1 of 2 optimal doses identified during Phase I.

Surgical Delivery

Again, as described by Dr. Ho, “CNTO 2476 is delivered to the subretinal space with the iTrack 275 microcatheter (iScience, Menlo Park, CA). The microcatheter is combined with a fiberoptic illuminator and a microcalibrated pump, which ensures rate-controlled delivery of the stem cell product.

The microcatheter is inserted through a sclerotomy and choroidal fistula. A wire-tipped cannula is used to inject sodium hyaluronate viscoelastic (Healon, Abbott Medical Optics) to create a peripheral retinal bleb; the retinal elevation allows subretinal cannulation of the probe. Ultrasound is used to visualize the creation of the bleb, and it can be directly visualized with an intraocular endoscope. The illuminated beacon tip of the microcatheter then can be visualized through the pupil to verify its position in the posterior pole, and CNTO 2476 is delivered to the subretinal space near the macular GA (Figure 2). The surgical procedure is challenging and continues to evolve.”

Figure 2. The iTrack is guided from the choroidotomy through the subretinal space to the macula.

Results to Date

(This is where I had hoped to report on Dr. Samuel’s presentation, given at the SubSpecialty session. But, since I have yet to receive it, I will relate what he said in his video on EyeTube, along with what has been reported by others who were at the meeting.)

From the OSNSupersite report:

Three serious adverse events were reported in a phase 1b study of 12 patients with advanced geographic atrophy undergoing a surgical technique that delivers mesenchymal stem cells via catheter to the macula.

"First and foremost, this was a safety study," Michael A. Samuel, MD, said, while delivering the "broad strokes" of the study's interim results at Retina Subspecialty Day preceding the annual meeting of the American Academy of Ophthalmology.

"The surgical procedure is difficult, and it's not something we're used to," he said, "...but we've learned many things, and we've refined the surgery."

The surgical technique employs a lighted catheter (iScience) that passes through a choroidotomy and delivers stem cells to the targeted area.

There was a clinical response in that half the patients in the study had "very substantial improvement in vision," he said.

Additional information derived from the EyeTube video:

The iTrack 275 catheter enabled delivery into the subretinal space below the macula.
In the last patient treated (at Wills Hospital in Philadelphia), visualization was done through an endoscope that enabled a much better look at where the catheter was delivering the stem cells and was considered a “quantum leap” forward in visualization.

Of the 12 patients treated, six had improved vision; four gained +4 lines, while 2 gained +6 lines. Of the remaining patients, 2 had retinal detachments and 1 lost vision because of macular pucker/loss of traction.

The Phase II study is expected to get underway in the next couple of months (see notes above in the Clinical Trial section).

Gene Therapy Update 1: First Clinical Trial for a Form of Retinitis Pigmentosa (RP) Approved to Begin

2011-10-18T16:58:00.001-04:00

In an announcement today, Oxford BioMedica said that it had gained approval from the FDA to begin a Phase I/IIa Clinical Trial for a form of Usher’s Syndrome, Type 1B, which leads to progressive retinitis pigmentosa combined with a congenital hearing defect.

Usher syndrome is the most common form of deaf-blindness which affects approximately 30,000-50,000 patients in the U.S. and Europe. One of the most common subtypes is Usher syndrome type 1B. The disease is caused by a mutation of the gene encoding myosin VIIA (MY07A).

The open label, dose escalation Phase I/IIa study will enrol up to 18 patients with Usher syndrome type 1B at the Oregon Health and Science University's Casey Eye Institute, Portland, Oregon. The study, led by Professor Richard Weleber, will evaluate three dose levels for safety, tolerability and aspects of biological activity and is expected to be initiated by the end of 2011.

Here is the complete news release from Oxford BioMedica:

Oxford BioMedica Announces US IND Approval for Novel Ocular Product in Usher Syndrome Type 1B

Third ocular product partnered with Sanofi approved to enter clinical development

Oxford BioMedica plc announced that the US Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application for the Phase I/IIa clinical development of UshStat, a novel gene-based treatment for Usher syndrome type 1B. UshStat was designed and developed by Oxford BioMedica using the company’s proprietary LentiVector platform technology and is the third program to enter clinical development under the Phase I/II ocular collaboration agreement signed with Sanofi in April 2009.

The approval of the IND follows the decision by the US Recombinant DNA Advisory Committee (RAC) to approve the UshStat Phase I/IIa protocol in May 2011. The open label, dose escalation Phase I/IIa study will enrol up to 18 patients with Usher syndrome type 1B at the Oregon Health and Science University's Casey Eye Institute, Portland, Oregon. The study, led by Professor Richard Weleber, will evaluate three dose levels for safety, tolerability and aspects of biological activity and is expected to be initiated by the end of 2011.

Usher syndrome is the most common form of deaf-blindness which affects approximately 30,000-50,000 patients in the US and Europe. One of the most common subtypes is Usher syndrome type 1B. The disease is caused by a mutation of the gene encoding myosin VIIA (MY07A), which leads to progressive retinitis pigmentosa combined with a congenital hearing defect. UshStat uses the company’s LentiVector platform technology to deliver a corrected version of the MYO7A gene to address the vision loss associated with the disease. On the basis of pre-clinical data, it is anticipated that a single application of UshStat to the retina could provide long-term or potentially permanent stabilization of vision. There are currently no approved treatments available for Usher syndrome type 1B. UshStat has received European and US Orphan Drug Designation which brings development, regulatory and commercial benefits.

John Dawson, Chief Executive Officer of Oxford BioMedica, said: "This is the third ocular IND approval that Oxford BioMedica has received from the US regulatory agencies over the last 12 months which represents an exceptional achievement for our R&D and regulatory teams. The continued progress of our ocular program partnered with Sanofi will further support the development path for other LentiVector platform products. With no approved treatment available for patients, we look forward to bringing UshStat into Phase I/IIa clinical development later this year."

Professor Richard Weleber, Principal Investigator at the Casey Eye Institute, commented: "We are delighted to be partnering with Oxford BioMedica in the design and conduct of this; the first trial of gene replacement for retinitis pigmentosa associated with myosin 7A-deficient type I Usher syndrome. As such, this trial represents a major milestone in the history of Usher syndrome. We conclude that the gene replacement therapy that will be evaluated in this trial has the potential to provide a substantial, durable benefit for the vision of these patients."

Dr Stephen Rose, Chief Research Officer of the Foundation Fighting Blindness, an early funding collaborator of Oxford BioMedica's pre-clinical ocular program, added: "The IND approval for UshStat is great news for people affected by a particularly devastating condition. UshStat will be the first vision treatment for any type of Usher syndrome to move into a human study and, as a corrective gene therapy, it holds potential to halt the disease in its tracks."

Editor’s Note: The other two programs involving gene therapy for ophthalmic applications that Oxford BioMedica is involved with, with Sanofi, are RetinoStat for treating the wet form of age-related macular degeneration, a Phase I study; and the treatment of Stargardt’s disease, using StarGen, a Phase I/II study.

If you have Usher Syndrome, Type 1B, or know someone who does, and would like more information about the study, please contact Maureen Toomey, Study Coordinator for the UshStat trial, at the Casey Eye Institute at toomeym@ohsu.edu.

Also, for additional background information on the use of gene therapy in the treatment of RP and dry AMD, please see my article: “The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD”.

INDEX/SEARCH

2011-10-09T06:00:00.000-04:00

INDEX/SEARCH

For your convenience, and because only the last ten posts are shown on the opening page, here is a means for finding all of my posts in an easy-to-use fashion.

Use the Blog Search box in the upper left-hand corner of the header above, enter "Menu" and click on "enter" and menus for all of my 200 or so postings will come up in an easy to search/find method (including short descriptions and live links.)

Avastin/Lucentis Update 51: And, the Dam Breaks!

2011-10-07T17:24:00.000-04:00

After reporting on the news out of England earlier this week (Update 50), I have been waiting for the “other shoe” to drop – and it just has, as reported by InPharm this morning (as tweeted by RetinaToday). Here is the story found on the InPharm website:

Novartis cuts Lucentis price amid growing pressure

Published on 10/07/11 at 10:15am
InPharm

Novartis has been forced to cut the Swiss price of its eye drug Lucentis by 30% after sharp negotiations with the government. The deal was negotiated by Switzerland's Health Minister Didier Burkhalter and could save the country hundreds of millions of francs over the next five years, according to local newspaper La Matin.

Lucentis (ranibizumab) is licensed in Europe to treat the eye disease wet age-related macular oedema, a leading cause of blindness in the over fifties. But ophthalmologists have been opting to treat patients with Roche's cancer drug Avastin (bevacizumab), which - though not licensed for wet AMD - is chemically similar to Lucentis and around 20 times cheaper.

Roche co-markets Lucentis with Novartis in the US, and has no plans to seek a new licence for Avastin for the eye disease because it would be undercutting its own drug. According to La Matin Burkhalter knew this, but still pressured Roche to conduct new trials for Avastin in wet AMD in order to persuade Novartis - whose head office is in Switzerland - to negotiate over the price of Lucentis.

The price cut could go even deeper. A ministry spokesman for the health ministry told La Matin: "We have been successful on this last point with a drop of 30%," but added that if nationwide sales of the drug exceed 108 million francs, then the price will have to drop again. This could have repercussions across other countries as Switzerland acts as a reference for many other markets, although many countries are already investigating using Avastin off-label without Roche's consent.

This is happening in the US where nationally-funded trials are ongoing to see if Avastin is as safe and effective as Lucentis in treating wet AMD. The main impetus is cost as analysts are projecting that switching treatments could save the US $1 billion over the next two years.

Both Roche and Novartis have fought against the use of Avastin in wet AMD, saying that patients are at risk of infections and other side effects from using Avastin off-label because it has not been studied for safety in wet AMD patients. But the Swiss price cut represents a realization that Lucentis must still compete with Avastin, even if it doesn't want to. This is especially true now that austerity measures start to take aim at healthcare budgets, with drugs like Lucentis representing an easy target for swift savings.

Ben Adams

Avastin/Lucentis Update 50: A Possible Break in the Dam?

2011-10-05T12:27:00.000-04:00

News has just come out of England that Novartis may discount the price of Lucentis to off-set the gains made by Avastin in the treatment of wet AMD. As Nick Smith of APM Health Europe wrote yesterday, Novartis is considering cutting the price of Lucentis because of the gains being made by doctors using Avastin to treat AMD.

Here is Nick’s story...and as we hear more, we will bring you the news:

Novartis UK may cut Lucentis price to compete with off-label Avastin in AMD
by Nick Smith, APM Health Europe

LONDON, Oct 4 (APM) - Novartis on Tuesday indicated it may discount Lucentis (ranibizumab) in age-related macular degeneration (AMD) to curb the off-label use of Roche's Avastin (bevacizumab) in the UK.

In a statement to APM following earlier press reports that Novartis may take such a step, the company said: "We recognize the cost pressure within the National Health Service" adding it was "working with the Department of Health and NICE ... exploring all options, to help make Lucentis available for as many as possible of the patients who could benefit from this treatment."

Novartis gave no further indication of what steps it might be prepared to take to boost sales volume but did highlight that NICE had found the drug cost-effective in AMD.

PATIENT ACCESS SCHEME

It did not mention the patient access scheme, then known as a 'risk-sharing' scheme, which was used to discount the drug to gain approval.

The company agreed to pay the cost of the drug beyond 14 injections in August 2008, (APMHE 12490) but this did not stop the UK government undermining the agreement by asking NICE if it could examine Avastin for cost-effectiveness in the indication, despite the fact it is not licensed for the use.

Early take up of Lucentis seemed slow, leading to some sales figures coming below analysts' expectations.

However, an ever-wider global market, ageing population and innovative pricing schemes has helped the company turn this around and second quarter sales reached the equivalent of 310 million euros.

ns/ra

Stem Cells in Ophthalmology Update 10: ACT Expands Trials for Embryonic Stem Cells for Stargardt’s to the UK

2011-09-22T15:49:00.000-04:00

In a news announcement today, Advanced Cell Technology said it had received approval to expand its stem cell treatment for Stargardt’s Macular Dystrophy to Moorfield’s Hospital in the UK.

As reported by the Guardian, “The Massachusetts-based company Advanced Cell Technology (ACT) announced the trial ... will run alongside a similar study that began in July at the Jules Stein Eye Institute at the University of California, Los Angeles.

Only one patient has been treated so far in the US trial for Stargardt's disease. The results from both studies are expected next year.”

Here is the company’s announcement:

ACT Receives Approval for First Human Embryonic Stem Cell Trial in Europe

Moorfields Eye Hospital in London is Site for Phase 1/2 Trial to Treat Stargardt's Macular Dystrophy

MARLBOROUGH, Mass. - Sept. 22, 2011 - Advanced Cell Technology, Inc., a leader in the field of regenerative medicine, announced today that it has received clearance from the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to begin treating patients as part of a Phase 1/2 clinical trial for Stargardt's Macular Dystrophy (SMD) using retinal pigment epithelium (RPE) derived from human embryonic stem cells (hESCs). ACT received similar approval from the the Gene Therapy Advisory Committee (GTAC), which has responsibility for the ethical oversight of proposals to conduct clinical trials involving gene or stem cell therapies in the U.K. The European Medicines Agency (EMA) previously granted Orphan Drug designation for the company's RPE cell product for use in treating SMD.

"This is another important milestone for ACT and for the field of regenerative medicine," said Gary Rabin, chairman and CEO of ACT. "We are pleased that the Moorfields Eye Hospital in London has agreed to participate as a site for this study as we continue to assess the capabilities of hESC-derived RPE cells to repair the retina and reduce the impact of these devastating eye diseases. We recently announced the dosing of the first patients in our Phase 1/2 clinical trials for Stargardt's macular dystrophy and dry age-related macular degeneration (dry AMD) with hESC-derived RPE cells in the U.S., and both patients successfully underwent the outpatient transplantation surgeries. (Editors Note: See Updates 8 and Update 9) Clearance from the MHRA to begin an SMD trial in the U.K. is the first step in our European clinical trial program. Europe not only represents the world's second-largest pharmaceutical market, but it is also home to some of the best eye hospitals and surgeons in the world. Building international relationships around our clinical programs, such as with Professor James Bainbridge at Moorfields Eye Hospital is very important to our strategy of developing new regenerative medicine therapies."

Stargardt's Macular Dystrophy affects an estimated 80,000 to 100,000 patients in the U.S. and Europe, and causes progressive vision loss, usually starting in people between the ages of 10 to 20. Eventually, blindness results from photoreceptor loss associated with degeneration in the pigmented layer of the retina, the retinal pigment epithelium. The first patient to be treated in the U.S. with stem cell-derived RPE cells was a young woman who was already legally blind as a consequence of this disease. This newly-approved clinical trial in Europe will be a prospective, open-label study designed to determine the safety and tolerability of RPE cells derived from hESCs following sub-retinal transplantation to patients with advanced SMD, and it is similar in design to the FDA-cleared U.S. trial initiated in July.

"This is the first time an embryonic stem cell trial has ever been approved anywhere else in the world," said Robert Lanza, M.D., ACT's chief scientific officer. "Stargardt's disease is currently untreatable, and is one of the leading causes of juvenile blindness in the world. Collectively, degenerative eye diseases afflict over 25 million people in the U.S. and Europe alone. These diseases have a devastating impact on patients and their families, which has been a strong motivating factor for developing this new treatment. In Stargardt's disease, the loss of RPE cells in the patient's macula causes a loss of photoreceptors - the cones and rods with which we see - leading to blindness. We believe that transplanting new, healthy RPE cells may provide an effective treatment for SMD and perhaps other macular degenerative diseases such as dry AMD. We are excited to start these trials in Europe, and look forward to analyzing the data we continue to collect in our ongoing trials to determine the engraftment and function of the transplanted RPE cells."

The trial will be led by Professor James Bainbridge, consultant surgeon at Moorfields Eye Hospital and Chair of Retinal Studies at University College London.

"Stargardt's disease is a form of macular degeneration that causes disabling loss of sight in young people and is currently untreatable," said Professor Bainbridge. "There is real potential that people with blinding disorders of the retina including Stargardt's disease and age-related macular degeneration might benefit in the future from transplantation of retinal cells. The ability to generate retinal cells from stem cells in the laboratory has been a significant advance and the opportunity to help translate such technology into new treatments for patients is hugely exciting. Testing the safety of retinal cell transplantation in this clinical trial will be an important step towards achieving this aim."

About Macular Degeneration and SMD

Degenerative diseases of the retina are among the most common causes of untreatable blindness in the world. As many as 30 million people in the U.S. and Europe suffer from macular degeneration, which represents a $25-30 billion worldwide market that has yet to be effectively addressed.

Avastin/Lucentis Update 49: A Follow-up on Infections from Intravitreal Injections

2011-09-13T11:30:00.001-04:00

In my last posting (Avastin/Lucentis Update 48), I wrote about the problems with Avastin injections, that appeared to be caused by non-sterile/non-aseptic techniques during re-packaging Avastin from 4 ml bottles into much smaller doses (0.05ml) in tuberculin syringes.

A colleague, who is a compounding pharmacist, pointed out to me that other things can cause contamination of the eye during intravitreal injections besides using non-aseptic techniques during aliquoting and re-packaging of Avastin into injectable syringes.

He sent me a copy of a report from Medscape Medical News that was published online following a meeting of the American Academy of Ophthalmology and Middle East Africa Council of Ophthalmology 2010 Joint Annual Meeting, held during last year’s AAO Meeting.

Here are excerpts from that report:

Intravitreal Injections Expose Patients to Streptococcus More Often Than Eye Surgery

Kathleen Louden
October 20, 2010
Medscape Medical News

Streptococcus is isolated much more frequently from endophthalmitis cultures after intravitreal injection (IVI) of antivascular endothelial growth-factor agents than after ocular surgery, results of a meta-analysis show.

Ophthalmologists should consider using additional sterile techniques during these injections to prevent exposing patients to the sight-threatening complication of streptococcal endophthalmitis, said study author Colin McCannel, MD, associate professor of ophthalmology from the Jules Stein Eye Institute at the University of California at Los Angeles.

"If we can prevent some of the worst cases of endophthalmitis, I think it's worth the effort," Dr. McCannel told Medscape Medical News.

To confirm his impression that reports of Streptococcus organisms seemed more frequent than should be expected after IVI, Dr. McCannel analyzed the American medical literature from 2005 through 2009. He found 16 articles that reported the causative organism in post-IVI endophthalmitis. As expected, endophthalmitis was rare, occurring in 54 of 105,531 injections. Only 26 were culture-positive, according to the abstract. Most of the causative organisms were coagulase-negative Staphylococcus, he said.

However, cultures yielded Streptococcus organisms 30.8% of the time (8 of 26), which Dr. McCannel said is "3- or 4-fold higher" than the incidence reported in the literature for acute postoperative endophthalmitis. The postoperative incidence of streptococcal endophthalmitis ranges from 0% after vitrectomy to 8.2% to 9% after cataract surgery, he reported.

Likely Source of Infection

This finding led him, he said during an interview, to do "some detective work" to try to find the possible source of these streptococcal infections. He found several studies in the anesthesia literature reporting streptococcal meningitis after dural puncture, a procedure that, according to Dr. McCannel, has a working distance between physician and patient similar to that of IVI. Analysis found that the causative organisms in most of those cases came from the treating physician's oral flora, which was aerosolized during talking.

Consequently, the Centers for Disease Control and Prevention in Atlanta, Georgia, recommended in 2007 that spinal procedure operators wear a surgical mask during the procedure (MMWR Morb Mortal Wkly Rep. 2010;59:65-69).

Ophthalmologists "often have to give directions to the patient during injections, and sometimes there is small talk," Dr. McCannel said. "The patient's eye is probably being showered with these microscopic droplets. We may be contaminating the injection field or the needle."

Recommendations

If other studies validate his findings, the ophthalmic community should decide whether to recommend wearing a surgical mask during IVI, he said. He told the audience that he does not wear a mask because "it would be burdensome to take it on and off" during the brief injections.

Another precautionary strategy that Dr. McCannel suggested was to avoid talking, coughing, or sneezing during the injections. He said he asks his ophthalmic technicians to instruct the patient before the procedure that "the injection is not the time to ask questions" and to refrain from talking. If he needs to instruct the patient, he said he speaks away from the patient.

A panelist at the session who did not participate in the study, Joan W. Miller, MD, said in an interview that the study findings have the potential to change clinical practice. Dr. Miller, professor and chair of ophthalmology at Harvard Medical School in Boston, Massachusetts, said she will consider changing her IVI techniques to try to prevent the spread of Streptococcus.

"Not talking on the [injection] field is probably sufficient precaution," she told Medscape Medical News.

My friend, the compounding pharmacist, went on to say, “I wish we had more visibility into what [really] happened in TN and FL and the pharmacies that prepared those compounds. It is even more critical that physicians look to do their diligence when choosing a pharmacy to provide these sterile compounds to patients. Because of our strict quality control and assurance procedures we have created an environment that focuses on quality.”

“As you may be aware OMIC, the ophthalmology insurance carrier, has been recommending to physicians that the best practice is to seek out compounding pharmacies that have been accredited by PCAB, the Pharmacy Compounding Accreditation Board. Being accredited by PCAB gives confidence to physicians and consumers that products are prepared in accordance with the United States Pharmacopeial Convention's standards. Chapter 797 of the USP clearly outlines the facility, environment and testing necessary to provide sterile compounded products. Without an accreditation body like PCAB, there is no reliable third-party verification that a pharmacy meets the USP 797 standard.”

Avastin/Lucentis Update 48: Contaminated Re-Packaged Avastin Causes Severe Eye Problems

2011-08-31T12:12:00.000-04:00

The inevitable was bound to happen. A pharmacy in Hollywood, FL repackaged Avastin into single-use syringes and in the process contaminated the drug that was then sold to several clinics for the treatment of wet AMD, causing severe eye damage, including complete vision loss in a few patients.

The FDA issued an alert on August 30th, warning health care professionals that repackaged intravitreal injections of Avastin (bevacizumab) have caused a cluster of serious eye infections in the Miami, Florida area.

According to Andrew Pollack writing in the NY Times, “At least 16 people in Florida and Tennessee have suffered serious eye infections, and some were blinded, after being injected with Avastin. And regulators and the manufacturer say the injuries underscore the risks associated with the unapproved use of the drug, which some doctors reach for when treating the wet form of age-related macular degeneration.

The FDA yesterday issued an alert at least 12 patients who were treated at three clinics in Miami developed infections. While all had some impaired eyesight in the first place, some lost all remaining vision in the treated eye due to endophthalmitis. The episode was traced to a single lot of Avastin that was repackaged and distributed by a pharmacy in Hollywood, Flordia.

And, in Tennessee, four patients received shots contaminated by bacteria, according to a statement provided to The Tennessean newspaper by the Tennessee Valley Healthcare System, part of the United States Department of Veterans Affairs. The Avastin doses were prepared in the pharmacy of the V.A. hospital in Nashville.

In his report, Pollack noted that, “The Florida patients received their injections last month and were apparently infected with endophthalmitis. Last week, the FDA announced a recall of syringes containing Avastin from Chroniscript, a unit of Walgreens, in Miami. A Walgreens spokesman tells the Times the syringes were supplied to "a limited number of physician offices in Miami-Dade and Broward counties."

To counterbalance this story, Pollack also interviewed Dr. Phillip Rosenfeld, the retinal specialist at the University of Miami who pioneered the use of Avastin for macular degeneration, who said the recent incidents apparently stemmed from careless procedures by pharmacies and should not discourage the use of the drug.

"It took six years for something like this to happen," he said, noting that there have been more than two million injections of Avastin into eyes in the United States alone since the practice began in 2005.

Stem Cells in Ophthalmology Update 9: First Patients Treated

2011-07-14T20:26:00.002-04:00

As I reported back on June 16th, Advanced Cell Technology had enrolled the first two patients in its Phase I/II clinical trials using retinal pigment epithelial (RPE) cells derived from embryonic stem cells (hESCs) for treating Stargardt’s Macular Dystrophy (SMD) and for the treatment of the dry form of age-related macular degeneration (Dry AMD). The company announced today that these first patients had now successfully received their first dose of the stem cells.

(Editors note: Please also see the addendum attached at the end of this piece.)

Here is the announcement:

ACT Announces First Patients Undergo Embryonic Stem Cell Transplantation Treatment for Stargardt's Disease and Macular Degeneration at UCLA's Jules Stein Eye Institute

MARLBOROUGH, Mass., July 14, 2011 /PRNewswire/ -- Advanced Cell Technology, Inc., today announced the dosing of the first patients in each of its two Phase 1/2 clinical trials for Stargardt's macular dystrophy and dry age-related macular degeneration (dry AMD) using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs). The patients were treated Tuesday (July 12) by Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute. Robert Lanza, M.D., chief scientific officer of ACT, attended the procedures. Both patients successfully underwent the outpatient transplantation surgeries and are recovering uneventfully.

Both the Stargardt's trial and the dry AMD trial will enroll 12 patients each, with cohorts of three patients each in an ascending dosage format. Both trials are prospective, open-label studies designed to determine the safety and tolerability of hESC-derived RPE cells following sub-retinal transplantation into patients with Stargardt's and dry AMD at 12 months, the studies' primary endpoint.

"This first treatment milestone is welcomed by scientists, stem cell advocates and patients hoping for cures," said Gary Rabin, interim chairman and chief executive officer of ACT. "The two trials could not have started any smoother, and we are very pleased to announce that the procedures went well. The dosing of the first patients represents an important milestone for ACT and opens the doors to a potentially significant new therapeutic approach to treating the many forms of macular degeneration. We believe that these procedures represent a key step forward in therapeutic stem cell research, and the capacity to treat a variety of devastating diseases."

Dr. Schwartz, the studies' principal investigator, explained, "One patient in each clinical trial, the Stargardt's trial and the dry AMD trial, has undergone surgical transplantation of a relatively small dose (50,000 cells) of fully-differentiated retinal pigment epithelial (RPE) cells derived from human embryonic stem cells. Early indications are that the patients tolerated the surgical procedures well. The primary objective of these Phase 1/2 studies is to assess the safety and tolerability of these stem cell-derived transplants. We will be carefully monitoring our patients over the course of the trials. We are privileged to be collaborating with ACT and honored to be working with these pioneering patients."

Dry AMD, the most common form of macular degeneration, Stargardt's and other forms of atrophy-related macular degeneration are usually untreatable. Safe and effective therapies are greatly needed for the treatment of these common forms of blindness. Disease progression of both Stargardt's and dry AMD includes thinning of the layer of RPE cells in the patient's macula, the central portion of the retina and the anatomic location of central vision. With RPE cell death comes the loss of macular photoreceptors and loss of central vision. Currently both conditions are untreatable and often lead to legal blindness over a multi-year course. ACT's Stargardt's and dry AMD therapies treat these conditions by transplanting RPE cells in the patient's eyes before the RPE population is lost.

"Today -13 years after the discovery of human embryonic stem cells - the great promise of these cells is finally being put to the test," said Dr. Lanza. "The initiation of these two clinical trials marks an important turning point for the field. While we will continue writing research papers and carrying out more research, it's time to start moving these exciting new stem cell therapies out of the laboratory and into the clinic. Tens of thousands of people continue to die every day from diseases that could potentially be treated using stem cells. In the meantime, we intend to accelerate our efforts to translate new embryonic stem cell (ES) and induced pluripotent stem (iPS) cell therapies into the clinic. It has taken years of extensive research to get to this point. Our research and preclinical studies have demonstrated the safety and effectiveness of such therapies. We hope these cells may provide a treatment option not only for degenerative eye diseases, but for a wide spectrum of other debilitating conditions, ranging from diabetes to vascular and autoimmune diseases. Our team remains committed to moving the field of regenerative medicine forward from bench to bedside."

Addendum: Along with the news from the company and UCLA shown in the press release above, the Los Angeles Times covered the story and presented some interesting additional information. I have attached the LA Times writeup as an addendum to this piece.

Stem cell clinical trials to treat eye diseases begin at UCLA

By Daniela Hernandez,
Los Angeles Times/For the Booster Shots blog
July 14, 2011, 2:01 p.m.

After more than 20 years of research, doctors at UCLA's Jules Stein Eye Institute have begun treating the first patients in clinical trials for two progressive eye diseases that cause blindness: dry age-related macular degeration and Stargardt's macular dystrophy.

The patients were given an injection of specialized eye cells that were derived from embryonic stem cells. Dr. Steven Schwartz, who is leading the trial at UCLA, performed both stem cell transplant surgeries Tuesday. The two patients are said to be recovering without complications.

According to Dr. Robert Lanza, chief scientific officer at Advanced Cell Technologies Inc., which developed the cells and is sponsoring the trials, "you could feel the excitement in the air and that history was being made."

Surgery began for the first of two patients, a 77-year old woman with dry macular degeneration, around 9:30 a.m. Tuesday and took about half an hour. In the afternoon, a 27-year old woman with Stardgart's macular dystrophy underwent the same procedure. Both patients are legally blind.

Doctors will monitor these two patients over the coming weeks. Another set of surgeries is scheduled to start in August.

Schwartz explained how these trials will help patients and what they mean for regenerative medicine. His comments were edited for space and clarity.

What are dry age-related macular degeneration and Stargardt's macular dystrophy?

Twenty percent of age-related macular degeneration is wet macular degeneration and it is treatable. The other 80% of people have an untreatable, progressive visual loss leading to legal blindness called dry, or atrophic, macular degeneration.

The retinal cells, the rods and cones, and the underlying retinal pigment epithelium atrophy. As they atrophy, there is a long period of time when they are compromised and then they're gone.

Stargardt's is a genetic disorder and it strikes earlier in life. Patients start to notice visual changes as early as their teens and as late as their forties. There are a number of known genetic abnormalities in the photoreceptors that are toxic over time.

In this trial, what cells in the eye are you replacing with stem cells?
Advanced Cell Technologies Inc. has been able to take [embryonic] stem cells and differentiate them into highly functional retinal pigment epithelium that do everything they're supposed to do. Our strategy of giving the eye brand-new, ready-to-go retinal pigment epithelium is designed for areas that are compromised, not for the areas that are gone. So we need to catch it early enough for this treatment to work.

Will the patients regain vision?

The patients' central vision is already gone. Not rescuable. So the patients we're enrolling in this trial know they will not be getting their central vision back.

If not to restore vision, what is the goal?
This is a safety trial. It's not designed to improve vision. It may; and if we see a signal, that would be great news and we're hoping we will. It's plausible biologically, but that's not what we're looking for.

What results are you hoping to see?

I hope what happens is that we find this is safe and that we can optimize the dosing, and that allows us to move into eyes that are earlier in disease. That could have a real visual upside.

How long is the surgery?

Under an hour. It's an outpatient procedure done with local anesthesia. It's a surgery that we've done before - not with the injection of these stem cells, but we've accessed the eye before, and that's one of the things that I've had a lot to do with surgically.

What does this trial mean for medicine?

We're super-privileged to be taking this first step. It's the unknown. These patients are doing a service for mankind. It's inspirational.

Avastin/Lucentis Update 47: Should the UK’s NICE Consider Adding Avastin to It’s Approved Drugs?

2011-06-30T11:51:00.000-04:00

In a blog, appearing on the BMJ (British Medical Journal) Group Blogs, James Raftery, a health economist with several decades' experience with the National Health Service (NHS) and a professor of health technology assessment at Southampton University, regularly writes about NICE (the UK’s National Institute for Health and Clinical Excellence). He is a keen "NICE-watcher," and has provided economic input to technical assessment reports for NICE.

In this blog entry, he discusses the case to be made for including Avastin in the approved drug registry for treating AMD and DMO (or DME, as we know it).

Avastin, Lucentis, and NICE
By: James Raftery

28 Jun, 11 | BMJ Group Blogs

A useful update was provided at a meeting this week sponsored by the Royal National Institute for the Blind (RNIB) and Patients Involved in NICE (the National Institute for Health and Clinical Excellence). As the proceedings are to be written up and published, I focus here on the key points that emerged for me.

The stakes in the Avastin/Lucentis (bevacizumab/ranibizumab) contest have been raised as the target condition has enlarged from macular degeneration to include diabetic macular oedema (DMO). This matters hugely because NICE is currently appraising Lucentis for this condition and has had to rule out consideration of Avastin because it is unlicensed. The potential patient population for DMO is put at 3% of people with diabetes, or around 100,000 patients each year. By contrast the estimates for wet age-related macular degeneration (AMD) are 20,000-25,000. NICE's appraisal consultation does not recommend use of Lucentis for DMO. Avastin, it notes, is already being used off label to treat DMO in the NHS. This draft guidance, if it remains unchanged, will increase this use. By not recommending Lucentis for DMO, off-label Avastin will be the only option available. The draft guidance seems unlikely to change since the appraisal committee considered that "a model that relied on a combined set of plausible assumptions would be certain to produce ICERs [incremental cost-effectiveness ratios] that substantially exceed the range it could consider to represent an effective use of NHS resources" (para 4.26).

The meeting heard that Avastin is being widely used in the private sector to treat AMD. Some primary care trusts (PCTs) have offered patients the choice of immediate treatment in private clinics using Avastin or waiting for NHS treatment with Lucentis.

The reasons private clinics are using Avastin are unknown but plausibly relate to its price (£85 pre VAT per injection supplied by Moorfields pharmacy compared with £740 for Lucentis). Extraordinarily, it seems that some ophthalmologists may be using Avastin in private practice but, depending on the local PCT, they may be required to use Lucentis in their NHS practice. The extent to which NHS use is split between Avastin and Lucentis for AMD is unknown. However, a recent US study showed that 64% of all AMD Medicare patients received Avastin.

What is clear is that UK ophthalmologists are using Avastin off-label to treat AMD and DMO and that this use is likely to increase, particularly in DMO. Legally it was suggested that ophthalmologists are covered by their host NHS trusts via the NHS Litigation Authority. GPs, it was suggested, might not be so likely to do so, but GP commissioning groups might well be happy to contract for off-label use of Avastin by their providers.

In any legal challenge to off-label Avastin prescribing the guidance to doctors from the General Medical Council (GMC) would be hugely important. The meeting received an update on the GMC consultation on changing its 2008 guidance Good Practice in Prescribing Medicines. The consultation proposed to change the requirement that off-label prescribing be "better" to "as good as." The 2008 guidance specified that the prescriber had to "be satisfied that it would better serve the patient's needs than an appropriately licensed alternative." The 2011 update proposed off-label prescribing if: "There was no appropriately licensed alternative available or you are satisfied on the basis of authoritative clinical guidance that is as safe and effective as an appropriately licensed alternative."

The GMC, it appears, has been lobbied particularly by ophthalmologists on this issue and the consultation, the results of which are being analysed, seems likely to support change. Acceptance of the proposed change would require clarification of "authoritative clinical guidance". Authoritative clinical guidance cited elsewhere by the GMC included that from NICE, royal colleges, the US Food and Drugs Agency (FDA), British National Formulary (BNF), or local prescribing committees. The meeting considered the possibility that a guideline, particularly if issued by a competent authority such as NICE, might also count.

Could a NICE guideline include off-label use of Avastin? Someone from NICE explained that although NICE cannot consider unlicensed drugs (or off-label use of licensed drugs) within the remit for technology appraisals, it can and has included such uses in its clinical guidelines. Almost all guidelines to do with children have to include off label use of licensed drugs. Which sparks the thought of what would happen if a NICE clinical guideline for either AMD or DMO included Avastin.

Could off-label Avastin be referred by the secretary of state for health to the Medicines and Healthcare products Regulatory Agency (MHRA) for "market approval"? Yes, is the answer, based on the precedent of such referrals of blood products and vaccines, which were noted at the meeting. NICE was asked if it could assess Avastin for AMD. The unsurprising answer was yes. "The next step is for the Department of Health to decide whether or not to refer bevacizumab (Avastin) to NICE for consideration as part of its technology appraisal process." That was NICE's view in December 2010.

I came away from the meeting thinking that the ophthalmologists are voting with their syringes and that some of the NHS is finding ways to follow their lead.

A Potential Breakthrough in the Treatment of Glaucoma

2011-06-20T00:22:00.000-04:00

Three related news items caught my attention last week. They had to do with the medical treatment of glaucoma.

The first item noted that patients don’t properly use their prescription eyedrops in treating elevated intraocular pressure (IOP). Dr. Ari Weitzer, writing in his Eye Doc News Blog, noted that a retrospective hospital study in a recent issue of the Archives of Ophthalmology said that after 1 year, only 22% of patients were adhering to their glaucoma treatment regimen and putting drops in their eyes – and this dropped to 11% after 3 years. It turned out that this was a study done in Singapore on an Asian population, but similar studies done in the U.S. show similar patterns.

So, compliance with putting drops in the eye is a major ongoing concern. In an editorial, also in the Archives of Ophthalmology, Drs. Kelly Muir and Paul Lee noted that many patients (only 31%) were able to correctly install a single eyedrop. Approximately 20% of patients depend on another person to install their eyedrops.

The second item that caught my attention was that the cost of glaucoma treatment drugs has gone up strongly over the past six years, with spending on glaucoma medications increasing 25% over the period 2001 to 2006. Part of this is due to a change to newer, more expensive medications such as the prostaglandin analogs, which are now the most prescribed and popular drugs in use, compared to older types like the beta blockers. Also, the prevalence of glaucoma is rising as the U.S. population ages (and people live longer). By 2020, it is estimated that 3.4 million people are expected to be affected. Currently, some 2.2 million Americans aged 40 or older have primary open angle glaucoma and the annual direct medical cost is estimated to be $2.8 billion.

But, the third item that caught my eye may be the saving grace. In a news release on June 14th, pSivida announced the commencement of a Phase I/II clinical trial to study a new bioerodible drug delivery implant for the treatment of glaucoma and hypertension. The implant is designed to provide long-term sustained release of latanoprost, one of the new class of prostaglandin analogs. The drug delivery implant, based on the company’s Durasert technology system, will be injected into the subconjunctival space in the eye (between the sclera and the lower lid), be bioerodible and is expected to deliver its drug for a period of months.

If successful, this implant would solve the problems of non-compliance, the inability to administer the drops and, depending on its price, perhaps address the increasing cost issues.

The new dose-escalating study is designed to assess the safety and efficacy of the implant in patients with elevated intraocular pressure and with hypertension. If successful, pSivida plans to advance the product into a multicenter Phase II study.

A Little Background Information

The Treatment of Glaucoma

I first wrote about glaucoma in the fall of 2001. At that time I prepared a comprehensive overview of what glaucoma is, how it is diagnosed/detected, and both the medical and surgical treatment options available or under development at that time. I even included some information on the U.S. market sizes for both treatment and equipment. To read this report, Advances in the Treatment of Glaucoma, published by OptiStock, please follow this link.

Sustained Release Drug Delivery Systems

I have also, more recently, written an extensive overview of ophthalmic drug delivery systems in my article titled, Iluvien and the Future of Ophthalmic Drug Delivery Systems. This report describes the development of Alimera Science’s Iluvien which delivers a corticosteroid (fluocinolone acetonide – FA) to the retina for treating macular edema for up to three years. It is based on a drug delivery system developed by pSivida and licensed to Alimera for this application.

The report also discusses both FDA-approved sustained delivery drug systems as well as those still in development. One of the systems mentioned as under development was a latanoprost coated punctal plug to treat open-angle glaucoma, that was being developed by QLT Therapeutics. It was supposed to stay implanted and deliver its drug for up to three months. Apparently, the plug did not stay in place well and did not demonstrate efficacy and, to my knowledge, is no longer being evaluated.

The pSivida Latanoprost Implant

Some Background Information

In their press release, pSivida stated that this was a joint development with Pfizer Inc. Pfizer and pSivida have been working together on drug delivery technology since 2007, with Pfizer investing in the company and helping to fund research and development.

According to the press release, the insert is being developed under the recently amended Research and Collaboration Agreement with Pfizer Inc. Under the revised agreement, Pfizer will make an initial payment of $2.3 million. pSivida will, with technical assistance from Pfizer, have the right to develop the glaucoma product candidate through Phase II clinical trials. At that point, Pfizer may exercise its option for an exclusive, worldwide license to develop and commercialize the product candidate in return for a $20 million payment, double-digit royalty payments on any sales of the product and additional development, regulatory and sales performance milestone payments of up to $146.5 million. If Pfizer does not exercise its option, pSivida will retain the right to develop and commercialize the glaucoma product on its own or with a partner. As part of the amended agreement, pSivida regains all rights to its intellectual property in ophthalmic applications previously included in the original Research and Collaboration Agreement other than that required for the latanoprost implant.

Latanoprost, which was approved for use in the eye in 1996, is now off-patent and low-cost generic forms of the drug are available.

Officials from both companies commented on both the new agreement and on the proposed new application of the implant to treat glaucoma and hypertension:

"Pfizer is an excellent partner, and we are pleased to be entering into this new stage of our relationship involving development of a potentially enhanced glaucoma product," said Dr. Paul Ashton, President and CEO of pSivida. "The $2.3 million payment from Pfizer comes on top of the approximately $7.0 million in R&D support we have already received from Pfizer since we first started our partnership in 2007. We believe that regaining rights to intellectual property in the ophthalmic arena outside the scope of the amended agreement is a key step for our company."

Yvonne Greenstreet, Senior Vice President and Head of the Medicines Development Group for Pfizer's Specialty Care Business Unit, added, "Latanoprost is the most commonly prescribed drug for reduction of intraocular pressure in the treatment of ocular hypertension and glaucoma. If successfully developed and approved by regulatory authorities, using pSivida's unique drug-delivery technology to deliver latanoprost could play a significant role in addressing compliance issues associated with a daily eye drop regimen for the treatment of glaucoma."

The Technology: How the Implant Will Work

The Durasert latanoprost implant (see Figure 1), is a tiny translucent cylindrical polymer tube, between 3 to 4 mm in length and about 0.4 mm in diameter, that contains a small amount of latanoprost (supplied by Pfizer). It is about the size of a grain of rice, and is designed to provide a low daily dose of latanoprost, which has a good history of treating open-angle glaucoma and hypertension.

Figure 1. The pSivida Durasert latanaprost implant.

The implant will be injected into the subconjunctival space of a patient's eye (between the sclera and the lower lid – see Figure 2) using a proprietary insertion device. The implant is bioerodible and is expected to deliver an appropriate dosage of latanoprost for about three months and, depending on the results of the Phase I/II dosing study, might last as long as six months. Since the implant is bioerodible, it will be absorbed by the eye and will not have to be surgically removed.

Figure 2. Illustration showing conjunctival space where implant will be placed.

Latanoprost, now off-patent and available in generic form, is one of the class of prostaglandin analogs which reduce pressure in the eye by increasing the outward flow of fluid from the eye. They generally work by relaxing muscles in the eye’s interior structure to allow better outflow of fluids, thus reducing buildup of eye pressure. According to glaucoma specialists, the prostaglandins have taken the lead in recent years as a first-line therapy for treating open-angle glaucoma.

Side effects may include eye redness or irritation, a change in eye color (mostly in hazel or green eyes), increase in thickness and number or eyelashes, and joint aches or flu-like symptoms.

The Phase I/II dose-escalating study is currently underway at the University of Kentucky.

Stem Cells in Ophthalmology Update 8: ...and So It Begins

2011-06-16T15:24:00.002-04:00

Advanced Cell Technology announced today that it had enrolled the first patients in its two Phase I/II clinical trials, using retinal pigment epithelial (RPE) cells derived from embryonic stem cells (hESCs) for treating Stargardt’s Macular Dystropyy (SMD) and for the treatment of the dry form of age-related macular degeneration (Dry AMD). The first of twelve patients in each trial were enrolled at the Jules Stein Eye Institute at the University of California, Los Angeles (UCLA).

The two patients will be treated with immunosupressants for about a week before the RPE cells will be implanted.

Here is the full announcement:

ACT Announces First Patients Enrolled in Two Clinical Trials Using Embryonic Stem Cells to Treat Stargardt's Disease and Dry Age-Related Macular Degeneration

Patients for Phase 1/2 Trials Enrolled at UCLA

MARLBOROUGH, Mass. - June 16, 2011 - Advanced Cell Technology, Inc. ("ACT"; OTCBB: ACTC), a leader in the field of regenerative medicine, announced today the enrollment of the first patients in its two Phase 1/2 clinical trials for Stargardt's Macular Dystrophy (SMD) and Dry Age-Related Macular Degeneration (Dry AMD) using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs). The patients were enrolled at the Jules Stein Eye Institute at the University of California, Los Angeles (UCLA).

The Phase 1/2 trials are prospective, open-label studies primarily designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation into patients with SMD and Dry AMD. Each study will enroll 12 patients with cohorts of three patients in an ascending dosage format. The primary endpoint of both studies is to determine the safety and tolerability of hESC-derived RPE cells at 12 months.

"The enrollment of the first patients in our two clinical trials marks an important step forward for the field of regenerative medicine," said Gary Rabin, interim chairman and CEO of ACT. "We are very pleased with the progress that has been made toward bringing this ground-breaking technology to the patients who need it most. If these therapies work as we hope they will, particularly with small volumes of cells, then we should be in an excellent position to take advantage of our patented techniques for manufacturing large numbers of doses of RPE cells that can be conveniently stored and shipped to clinicians following the basic manufacturing and distribution systems already familiar to pharmaceutical and biotech companies."

Principal investigator Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at the Jules Stein Eye Institute at UCLA, said, "These trials mark a significant step toward addressing what is one of the largest unmet medical needs of our time -- treatments for otherwise untreatable and common forms of legal blindness, Dry AMD, SMD and other forms of atrophic macular degeneration. Dry AMD is the most common form of macular degeneration. It is the leading cause of blindness in the developed world, and is the leading cause of blindness in people over the age of 55. The incidence of Dry AMD is expected to double over the next 20 years as the population ages. This trial will begin the process of understanding whether stem cell-derived RPE cells have the potential to be a safe and effective treatment for these debilitating diseases. We are looking forward to evaluating the safety and tolerability data of these Phase 1/2 trials, and hope that these early trials will also produce key information relating to engraftment and function of the transplanted RPE cells."

The progress of disease in both SMD and Dry AMD includes atrophy or thinning of the layer of RPE cells in the patient's macula at the center of the retina, the region specialized for high acuity vision. With the loss of RPE cells in the macula comes the eventual loss of photoreceptors. Over time, the progressive loss of RPE cells and concomitant loss of photoreceptors can cause severe central visual deterioration and even blindness as the macula becomes less functional and central vision is gradually lost. ACT's SMD and Dry AMD therapeutic programs utilize transplanted RPE cells to treat these conditions by replacing RPE cells in the patient's eyes before all RPE function is lost.

"Initiating these two clinical trials represents an important milestone for embryonic stem cell research," said Robert Lanza, M.D., chief scientific officer of ACT. "After a decade of extensive research and preclinical studies, it is very satisfying to finally be moving into the clinic. We hope that these cells will, in the future, provide a treatment not only for these two untreatable diseases ‘Stargardt's disease and macular degeneration’ but for patients suffering from a range other debilitating eye diseases."

In addition to the Jules Stein Eye Institute at UCLA, the Casey Eye Institute (CEI) at Oregon Health & Science University (OHSU) in Portland, OR, is also open for enrollment of patients with SMD. As additional sites are ready to enroll patients with SMD and dry AMD, they will be listed on the Clinical Trials page on ACT's Web site and on www.clinicaltrials.gov.

Further information about patient eligibility for the SMD and the Dry AMD studies are also available on www.clinicaltrials.gov.

AMD Update 15: Visualization of Living Rods and Cones

2011-06-10T12:57:00.000-04:00

Back in February 2009, I first wrote about David Williams and his research group at the Institute of Optics at the University of Rochester, and their announcement that they had used adaptive optics to image RPE cells in vivo. That report, AMD Update 4: Does Visualizing RPE Cells Hold the Key to Understanding AMD? gave us a first look at how adaptive optics could image some of the retinal cells in the back of the eye in helping to understand how the effect of new drugs and treatments could be visualized in the living eye, providing a diagnostic mechanism to see changes in RPE cells, possibly when applying some of the new retinal treatment techniques.

Well, another group of researchers at the same Institute of Optics at the University of Rochester, along with colleagues from several other research institutions have done it again. This time using their knowledge of applying adaptive optics to visualizing the much smaller photoreceptor rod cells present in the living eye.

This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative retinal eye disorders sooner, leading to quicker intervention and more effective treatments.

Here is the complete press release from the OSA, describing the two papers recently published:

Historic First Images Of Rod Photoreceptors In The Living Human Eye

Adaptive optics technology likely to spur sight-saving interventions, usher in new era of eye disease research, diagnosis and treatment

08 Jun 2011

Scientists today reported that the tiny light-sensing cells known as rods have been clearly and directly imaged in the living eye for the first time. Using adaptive optics (AO), the same technology astronomers use to study distant stars and galaxies, scientists can see through the murky distortion of the outer eye, revealing the eye's cellular structure with unprecedented detail. This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative eye disorders sooner, leading to quicker intervention and more effective treatments.

"While therapies are only emerging, the ability to see the cells you are trying to rescue represents a critical first step in the process of restoring sight," says researcher Alfredo Dubra of the University of Rochester in New York, who led the team of researchers from Rochester, Marquette University, and the Medical College of Wisconsin (MCW), Milwaukee. "It's impossible to overemphasize how important early detection is to eye disease."

"One of the major hurdles in detecting retinal disease is that by the time it can be perceived by the patient or detected with clinical tools, significant cellular damage has often already occurred," adds team member Joseph Carroll of MCW.

The breakthrough that is ushering in a new era of eye disease research, diagnosis, and treatment is an improved design of a non-invasive adaptive optics imaging system. Dubra and his colleagues were able to push the device's resolution to its optical limits of nearly 2 microns (a micron is 1/1,000 of a millimeter), or the approximate diameter of a single rod in the human eye.

Rods are much more numerous than cones and are vastly more sensitive to light. With the optical design method successfully demonstrated by Dubra's team, even the smallest cone cells at the center of the retina, known as the foveal center, can be seen very clearly. Rods can be seen clearly in a less central retinal location.

"This is a really exciting breakthrough," says Steve Burns, a professor in the School of Optometry at Indiana University, who is not involved in the Biomedical Optics Express research. "Imaging contiguous rod mosaics will allow us to study the impact of a whole new class of blinding disorders on the retina. Since many of the eye diseases most amenable to intervention affect the rods, this should become a major tool for determining what treatments work best for those disorders."

De-twinkling Stars, Visualizing Rods

In astronomy, adaptive optics is able to correct for the blurring effect of Earth's atmosphere, effectively removing the "twinkling" from starlight and rendering cosmic objects as very sharp points of light. To achieve this correction, the AO system requires a reference point-either a bright, nearby star or an artificial "guide star" produced in the upper atmosphere by lasers mounted on a telescope. By monitoring that reference point, AO systems use a deformable mirror to create the exact but opposite distortion that is happening in the atmosphere. The result is a clearer image with much greater resolution.

Just as light passing through the atmosphere becomes bent and distorted, so too does light passing through the front part of the eye. This distortion is inconsequential on the scale of human vision, but poses a significant barrier in the microscopic realm of medical imaging.

In 1997, David Williams of the University of Rochester led the group that first demonstrated using AO technology to study the interior of the human eye. In this system, called an adaptive optics ophthalmoscope, a laser creates a reference point that is used to correct the blurring of the image obtained with a fundus camera. Today the fundus camera is commonly replaced by a second laser for imaging, which is known as an adaptive optics scanning laser ophthalmoscope. By moving the laser point across the retina and correcting the distortion along the way, line-by-line an accurate image emerges, in much the same way that a CRT monitor renders an image.

Though earlier AO systems could effectively image cones and have become a mainstay of high-resolution retinal imaging research, the smaller rods, which outnumber cones 20 to 1 in the retina, have eluded clear and contiguous observation in the living eye.

Breakthrough Design

The breakthrough in the design of the AO instrument that led to clearly visualizing rods was, according to Dubra, "embarrassingly simple, and relied on well-known equations and concepts." By simply folding the spherical mirrors that act as lenses in the instrument into a three-dimensional structure, the image quality of the retina was improved sufficiently to clearly resolve the contiguous rod mosaic, as well as the entire cone mosaic at the foveal center.

"By combining careful optical engineering, excellent adaptive optics control, and knowledge of the visual system the authors have made a major advancement in both biomedical imaging and vision science," says Burns.

Improving Patient Care

According to the researchers, their next step is to develop a clinical model that could be widely available. A related task is simplifying and teaching the art of interpreting AO images to guide clinical decisions about diagnosis and treatment.

When that occurs, hopefully in the next 5 to 10 years, doctors will likely be able to routinely peer into a living human eye with such precision and clarity that they will be able to see and evaluate individual rods-and do three things never before possible: accurately describe the physical presentation of specific rod disorders-the "phenotype" of a disease, intervene with early treatment at the first sign of disease, and even determine how individual cells are responding to a specific treatment.

"That's what's really exciting about this imaging device: it can really make a difference in a patient's life," says Carroll. "The ability to now resolve these cells opens up new possibilities for improving care that researchers have been anticipating for a long time-such as using the information in these retinal images to aid in targeting, delivering, and evaluating therapies."

Paper: "Non-invasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 7, pp. 1864-1876.

Abstract:

The rod photoreceptors are implicated in a number of devastating retinal diseases. However, routine imaging of these cells has remained elusive, even with the advent of adaptive optics imaging. Here, we present the first in vivo images of the contiguous rod photoreceptor mosaic in nine healthy human subjects. The images were collected with three different confocal adaptive optics scanning ophthalmoscopes at two different institutions, using 680 and 775 nm superluminescent diodes for illumination. Estimates of photoreceptor density and rod:cone ratios in the 5°-15° retinal eccentricity range are consistent with histological findings, confirming our ability to resolve the rod mosaic by averaging multiple registered images, without the need for additional image processing. In one subject, we were able to identify the emergence of the first rods at approximately 190 μm from the foveal center, in agreement with previous histological studies. The rod and cone photoreceptor mosaics appear in focus at different retinal depths, with the rod mosaic best focus (i.e., brightest and sharpest) being at least 10 μm shallower than the cones at retinal eccentricities larger than 8°. This study represents an important step in bringing high-resolution imaging to bear on the study of rod disorders.

Paper: "Reflective afocal broadband adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 6, pp. 1757-1768.

Abstract:

A broadband adaptive optics scanning ophthalmoscope (BAOSO) consisting of four afocal telescopes, formed by pairs of off-axis spherical mirrors in a non-planar arrangement, is presented. The non-planar folding of the telescopes is used to simultaneously reduce pupil and image plane astigmatism. The former improves the adaptive optics performance by reducing the root-mean-square (RMS) of the wavefront and the beam wandering due to optical scanning. The latter provides diffraction limited performance over a 3 diopter (D) vergence range. This vergence range allows for the use of any broadband light source(s) in the 450-850 nm wavelength range to simultaneously image any combination of retinal layers. Imaging modalities that could benefit from such a large vergence range are optical coherence tomography (OCT), multi- and hyper-spectral imaging, single- and multi-photon fluorescence. The benefits of the non-planar telescopes in the BAOSO are illustrated by resolving the human foveal photoreceptor mosaic in reflectance using two different superluminescent diodes with 680 and 796 nm peak wavelengths, reaching the eye with a vergence of 0.76 D relative to each other.

The papers appear as part of a special feature issue of Biomedical Optics Express on "Cellular Imaging of the Retina."

Menu 19: Updates for March 2011 - May 2011

2011-06-05T13:34:00.000-04:00

A lot of interesting news was made over the past few months that I posted online. This update covers the period from March through May of 2011, including extensive coverage of developments from the recent ARVO Meeting held the beginning of May, and several other items.

I would like to start with my coverage of developments announced either just prior to or during the ARVO Meeting.

ARVO Highlights – Synopses and Links:

I have posted several items to my online Journal, based on what I learned was presented at ARVO 2011. Here are a few short briefs of what I’ve put online, along with the links to each posting.

CATT Study Updates

CATT Study Update 13: A First Peek (April 27, 2011)

The day prior to the release of the NEJM writeup about the CATT Study results, Andrew Pollack of the NY Times broke the story after speaking with two of the researchers involved in the study (and who presumably had access to the study results), Pollack basically said that the study will be interpreted in many ways, as some complicating factors may indicate that Lucentis is safer to use than Avastin, but essentially the two drugs showed equivalent results.

CATT Study Update 14: One-Year Study Results Show Equivalency Between Avastin and Lucentis (April 28, 2011)

Probably the biggest news from this year’s ARVO Meeting was the presentation of results of the one-year results of the CATT Study, along with its publication in the NEJM.

In this posting I summarized the results from the NEJM that showed equivalency of Avastin and Lucentis, but with the latter having a 40x larger price tag.

CATT Update 15: Preliminary Two-Year Safety Data Presented at ARVO (May 3, 2011)

During the presentation at ARVO, the study co-authors presented on some of the preliminary safety data that they had collected, but not yet published. This was, perhaps, to refute the charges made by Genentech later in the week that a retrospective study that they had had conducted by a researcher from Johns Hopkins showed that Lucentis was apparently safer than Avastin (surprise!). In the data presented by Drs. Martin and McGovern, there were no major differences in safety.

Other Updates Announced During ARVO:

Iluvien Sustained Release for Treating Diabetic Macula Edema

Iluvien Update 2: New Safety and Efficacy Data Presented at ARVO (May 6, 2011)

Alimera presented on a subset of their FAME Study using Iluvien to treat DME. In this study, the subset data showed that 34% of patients treated with the low dosage of Iluvien that had had DME for three or more years before treatment, gained three lines of vision after therapy.

This subset of data will be provided to the FDA in response to the CRL letter issued by the FDA in December 2010, in response to the New Drug Application filed last summer.

New Results on 2RT for Treating Dry AMD

Ellex 2RT Updated Clinical Results: ARVO 2011 (May 7, 2011)

I have been closely following the exciting news about the Ellex 2RT laser treatment for stopping the progression of dry AMD. Based on the 12-month data presented at ARVO, it appears that we may have a non-invasive treatment that might be able to stop dry AMD in its tracks and prevent the progression into the vision-losing forms of this disease.

And, the Rest of the Recent Postings:

The Development of Femtosecond Lasers for Cataract Surgery (March 27, 2011)

Several years ago, I wrote about my history with intrastromal lasers. That became “Intrastromal Ablation: A Technology Whose Time Has Come?” In that article, I wrote about Automated Laser Systems; its successor, Phoenix Laser Systems; another company working on ISA at the time, Intelligent Surgical Lasers; and, finally, the followup of ISL’s work with picosecond lasers that became the laser development work done at the University of Michigan’s Ultrafast Laser Center, that spawned IntraLase, and its femtosecond (FS) laser.

That is where my history of the development of femtosecond lasers stopped – although I did mention the FS lasers were being developed by Technolas Perfect Vision. Carl Zeiss Meditec, and Ziemer Ophthalmic Systems, and the then startup LenSx, begun by former Intralase founders. In addition, I also wrote about the work being done by Dr. Luis Ruiz, using the Technolas FS laser in treating presbyopia.

Then, recently, Stephen Daily, news editor for CRST, wrote about what happened to the FS laser companies in the several years after my story. His story, “The Origins of Laser Cataract Surgery: Three companies' pathways from development to commercialization” picks up where my story ended.

A Golden Retriever Named Trevor and Retinitis Pigmentosa (April 6, 2011)

Katie McCormick recently learned about a genetic defect in her dog that has its counterpart in humans. The dog defect, photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA) is genetically similar to retinitis pigmentosa (RP) in humans. There is extensive research being done on RP, but little on PRA in dogs.

To read about Trevor, a golden retriever diagnosed with PRA as a puppy, and its owners search for a cure, perhaps due to RP research, please see my writeup about Trevor.

Drug Eluting Device Slows Vision Loss in Geographic Atrophy Brought on by Dry AMD

AMD Update 14: Neurotech Pharmaceuticals NT-501 Implant Shown to Slow Vision Loss in Patients with Geographical Atrophy Associated with Dry AMD (April 8, 2011)

A new study, recently published in the Proceedings of the National Academy of Sciences (PNAS) shows that a potential treatment for the advanced stage of dry AMD, geographic atrophy (GA), can be used to slow vision loss in this blinding condition that affects more than a million people.

Neurotech Pharmaceuticals’ NT-501 drug eluting device can be placed in the vitreous of those suffering from GA and will deliver a neuroprotective agent, ciliary neurotrophic factor (CNTF), for up to a year and should result in preservation of vision. NT-501 is not yet FDA approved, as further testing will be required before marketing can occur.

Some Further Updates:
Iluvien Update 3: Alimera Files Resubmission for Approval of Iluvien (May 13, 2011)

Alimera Sciences Inc. filed a resubmission of its New Drug Application (NDA) for the use of Iluvien in treating diabetic macular edema (DME). This resubmission addresses the questions raised in the Complete Response Letter (CRL) received in December 2010. (See Iluvien Update: FDA Marketing Approval Delayed)

Stem Cells in Ophthalmology Update 7: Research Studies with Induced Pluripotent Stem Cells Suggest Opposite Results (May 15, 2011)

Two research studies were recently published about the use of induced pluripotent stem cells (iPSCs) in treating retinal problems, but with opposing results.

In one study, published in Nature, Dr.Yang Xu and his colleagues at the University of California, San Diego, found that iPSCs made from mouse skin cells were rejected by genetically identical mice. (Similar studies with iPSCs, also published in Nature earlier this year, also showed problems, including genetic and epigenectic abnormalities. See Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells.)

In the second study, Dr. Budd Tucker and his colleagues at the Schepens Eye Research Institute used iPSCs derived from skin to regenerate large areas of damaged retinas and improve visual function in specially grown degenerative mice. This study was just published in PloS ONE.

Avedro Update: Company Completes U.S. Phase III Study of Microwave Treatment for Progressive Keratoconus and Ectasia after Refractive Surgery (May 18, 2011)

I have been following the progress of Avedro since I first learned about the formation of the company back in May 2009 (The Rebirth of Thermal Keratoplasty). I then wrote about the company a second time in February 2010 (Avedro Keraflex: Microwaves for Reshaping the Cornea).

Now the company has announced completion of the one-year follow up visits of patients enrolled in its two multi-center Phase III clinical studies, although, not releasing the data as yet, which is undergoing timely analysis.
Oraya IRay Update: Company Completes Enrollment in European Clinical Trial (May 25, 2011)

Since first writing about this company in November 2009 (Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report), I have been following its progress. As I wrote back then, its Phase III Clinical Trial, which planned to enroll approximately 450 patients at 15-20 sites in both the U.S. and Europe, was expected to initiate in mid-2010.

In January, 2010, I learned that the groundbreaking clinical trial, being conducted at seven European sites, and to include a minimum of 150 patients, with approximately one third of those receiving a sham exposure and the remainder receiving radiation dosing of either 16 or 24 Gray (GY), had been initiated.

Now the company has announced that it has completed enrollment in the European arm of the study, as reported in this update. I also asked company officials about the U.S. study arm and the company has responded with some information.

And, Finally, the Completion of my Trilogy About the Discovery of Avastin:

Avastin/Lucentis Update 46: Avastin — The Rest of the Story (April 18, 2011)

Early in April, I came across an important missing piece in the story behind the decision to try Avastin in the treatment of wet AMD. I learned of a story that had been written in November 2006 about how and why Dr. Phil Rosenfeld decided to try Avastin on his patients. I have posted this tidbit as, Avastin/Lucentis Update 46: Avastin — The Rest of the Story. I hope you enjoy this piece of history that might have changed the way that wet AMD is treated forever.

Oraya IRay Update: Company Completes Enrollment in European Clinical Trial

2011-05-25T19:22:00.001-04:00

Since first writing about this company in November 2009 (Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report), I have been following its progress. As I wrote back then, its Phase III Clinical Trial, which planned to enroll approximately 450 patients at 15-20 sites in both the U.S. and Europe, was expected to initiate in mid-2010.

In January, 2010, I learned that the groundbreaking clinical trial, being conducted at seven European sites, and to include a minimum of 150 patients, with approximately one third of those receiving a sham exposure and the remainder receiving radiation dosing of either 16 or 24 Gray (GY), had been initiated.

Now the company has announced that it has completed enrollment in the European arm of the study, as reported below.

I asked company officials about the U.S. study arm and the company has responded with the following information:

In early January 2010, before beginning the U.S. arm of the clinical trials, the company decided to expand the European arm of the study in order to be ready for accelerated commercialization outside of the U.S. The company also decided to hold off beginning the U.S. arm until after the CATT Study results were released (earlier this month) so it could assess the impact of those results, as well as those from Regeneron’s VEGF Trap-Eye studies, and integrate these new results into an optimal trial design for its Phase III clinical study in the U.S.

Oraya Therapeutics Completes Enrollment in Pioneering Sham-Controlled Study of Radiation Therapy for Wet AMD

Oraya Therapeutics, Inc. announced that it had completed enrollment of its INTREPID clinical trial in Europe. The study is the first sham-controlled, double-masked trial to evaluate the effectiveness and safety of radiation therapy in conjunction with standard of care anti-VEGF injections for the treatment of wet age-related macular degeneration (AMD). Oraya's proprietary IRay stereotactic radiotherapy system employs externally delivered robotically controlled low-energy X-rays. The IRay treatment is a one-time non-surgical procedure which may significantly reduce or eliminate the need for subsequent anti-VEGF injections, while maintaining or improving vision outcomes in treated patients. Total procedure time typically takes less than 15 minutes. One year efficacy results of INTREPID will be available in the second quarter of 2012.

Enrollment in the INTREPID trial was completed on April 15 with 226 subjects. One third of those subjects received a sham exposure, with the remainder receiving a radiation dose of either 16 or 24 Gray (Gy). This multi-national study includes sites in Austria, Czech Republic, Germany, Italy and the United Kingdom. The number of clinical investigators and the number of prospective enrollees increased rapidly over the later stages of trial enrollment. (For more information on this clinical trial, please see: http://clinicaltrials.gov/ct2/show/NCT01016873)

"We were very pleased with the high level of interest in participating in this trial on the part of both prospective patients and investigators and their clinical staffs," said Tariq Aslam, M.D., Chief Investigator and Consultant Ophthalmologist at the Manchester Royal Eye Hospital. "In fact, we had more sites and more prospective enrollees than we could accommodate. That suggests that wet AMD patients and their ophthalmologists are looking forward to the possibility of having a one-time therapy shown to maintain visual acuity while reducing or avoiding the need for chronic drug therapy with anti-VEGF injections."

"We at Oraya recognize that we were unable to accommodate all the patients who expressed a desire to participate in the INTREPID trial," said Jim Taylor, CEO of Oraya Therapeutics, "and we want them to know that we have plans to conduct a larger study in the UK and elsewhere beginning later this year. That will afford the opportunity to many more patients to participate in a clinical trial of this promising therapy. We also want patients and their families to know that we understand the cost and lifestyle burdens that the currently available drug therapy places on them, and we will continue to evaluate our IRay radiation therapy to assess its safety and efficacy in maintaining visual acuity while reducing or eliminating the need for regular injections." Information on future studies will be available on the company's web site.

Wet AMD is a major cause of vision loss in the elderly. The disease arises from a combination of factors that initiate inflammatory processes which lead to neovascularization, fluid leakage, scar formation, and/or atrophy of the retina. Oraya's device delivers a highly-localized dose of X-ray radiation to the macula using a proprietary positioning system, targeting algorithm, and special contact lens for eye stabilization and tracking. Radiation has been demonstrated to inhibit multiple inflammatory pathways, as well as to have a direct deterring effect on neovascular capillaries and scar formation, and thus holds considerable promise for the treatment of wet AMD.

The IRay is a CE marked medical device. In the United States, it is limited by U.S. Federal law to investigational use. For more information on the IRay, please visit www.orayainc.com.

Avedro Update: Company Completes U.S. Phase III Study of Microwave Treatment for Progressive Keratoconus and Ectasia after Refractive Surgery

2011-05-18T19:15:00.000-04:00

I have been following the progress of Avedro since I first learned about the formation of the company back in May 2009 (The Rebirth of Thermal Keratoplasty). I then wrote about the company a second time in February 2010 (Avedro Keraflex: Microwaves for Reshaping the Cornea).

Now the company has announced completion of the one-year follow up visits of patients enrolled in its two multi-center Phase III clinical studies, although, not releasing the data as yet, which is undergoing timely analysis.

When the analysis is completed, I will bring you the results.

Multi-Center US Phase III Studies for the Treatment of Progressive Keratoconus and Ectasia Following Refractive Surgery

Avedro, Inc. announced the completion of all one-year follow-up visits for patients enrolled in its two multi-center Phase III studies evaluating the safety and efficacy of corneal collagen cross-linking for the treatment of progressive keratoconus and ectasia following refractive surgery.

Keratoconus is a degenerative disease of the eye and is the leading cause of corneal transplants in the US today. Ectasia following refractive surgery is a complication following various types of surgery, including LASIK. Outside the US, Cross-linking has been deemed safe and effective and is approved for use in treating keratoconus and ectasia post-refractive surgery.

For more information about both clinical trials please see:
for ecstasia - http://clinicaltrials.gov/ct2/show/NCT00674661
for progressive keratoconus - http://clinicaltrials.gov/ct2/show/NCT00647699

Dr. Peter Hersh, a leading refractive surgeon and Medical Monitor for Avedro's clinical trial stated, "Avedro's efforts to make this clinically important treatment available to US patients is applauded by all US ophthalmologists who today lack any approved therapeutic treatment to halt the progression of these sight threatening conditions."

"I am extremely pleased that we have reached this important stage in the US clinical trials and our team is working diligently to accomplish a timely analysis of data," said David Muller, CEO of Avedro. "Outside the US, cross-linking has become the standard of care for treating weak and ectactic corneas. It is our hope to bring this technology to the US in the near future."

The company is also the sponsor of another clinical trial using its Keraflex KXL technique, which is expected to get underway in August 2011, Safety and Efficacy of the KXL System With Riboflavin 0.1% Ophthalmic Solution for Corneal Collagen Cross-Linking in Eyes With Keratoconus - http://clinicaltrials.gov/ct2/show/NCT01344187

The purpose of this study is to compare the efficacy of two treatment regimens for corneal collagen cross-linking for the treatment of keratoconus. The treatment is designed to help improve or slow the progression of keratoconus. The study treatment involves using an eyedrop containing riboflavin, also known as vitamin B2. Riboflavin increases your eye's sensitivity to light. The riboflavin eyedrops are placed in your affected eye at two-minute intervals for 10 minutes and then your affected cornea is exposed to ultraviolet light (UVA) from the KXL System (the UV light machine) for another 2 or 3 minute period, depending upon which treatment group subjects are assigned to. Subjects will be followed for twelve months to evaluate the safety and efficacy of the treatment.

Stem Cells in Ophthalmology Update 7: Research Studies with Induced Pluripotent Stem Cells Suggest Opposite Results

2011-05-15T18:10:00.002-04:00

Two research studies were published this week, about the use of induced pluripotent stem cells (iPSCs) in treating retinal problems, but with opposing results.

In one study, published in Nature, Dr.Yang Xu and his colleagues at the University of California, San Diego, found that iPSCs made from mouse skin cells were rejected by genetically identical mice. This study was just published in Nature. (Similar studies with iPSCs, also published in Nature earlier this year, also showed problems, including genetic and epigenectic abnormalities. See Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells.)

In the second study, Dr. Budd Tucker and his colleagues at the Schepens Eye Research Institute used iPSCs derived from skin to regenerate large areas of damaged retinas and improve visual function in specially grown degenerative mice. This study was just published in PloS ONE.

The difference may be in the way the stem cells were used in the experiments. In the first case, the iPSCs (along with embryonic stem cells (hESCs)) were directly introduced into the mice of the same strain from which they were created and the implanted iPSCs encountered an immune response, but not the implanted hESCs. In the Schepens study, the harvested iPSCs were forced to express transcription factors, and with additional chemical coaxing, developed into precursors of retinal cells. These latter cells were introduced into the mouse model eyes with retina degenerative disease. Within four to six weeks, the researchers observed that the transplanted cells had taken up residence in the appropriate retinal area (the photoreceptor layer) and had begun to integrate and assemble into healthy looking retinal tissue.

Another difference, as pointed out to me by an expert in the field in a private communication, is the extreme difference in transplant sites between the two studies. The eye, used in the Schepen’s study, is considered an immune privileged body, whereas the flank, where the teratomas were formed in the UC-SD study, is highly immunogenic. As for the immune rejection seen in the Nature paper it was far from complete, i.e., see the specific details of teratoma formation percentages. Nevertheless, the true importance of the Nature paper comes from the fact that everyone in the field just assumed that iPSCs would be unseen by the immune system, and that was not the case.

Here are highlights of both studies:

Immunogenicity of induced pluripotent stem cells

Tongbiao Zhao, Zhen-Ning Zhang, Zhili Rong & Yang Xu
University of California, San Diego

Nature (2011) doi:10.1038/nature10135
Received: 07 July 2010, Accepted 19 April 2011, Published online 13 May 2011

Abstract:

Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration.

In contrast to B6 ESCs, teratomas (tumors containing a chaotic jumble of cell types) formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice.

These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.

Basically, what the researchers found was that the immune system of one mouse could not recognize the cells derived from embryonic stem cells of the same strain of mice. But the experiments also showed that the immune system rejected cells derived from iPSCs reprogrammed from fibroblasts of the same strain of mice, mimicking the situation whereby a patient would be treated with cells derived from iPSCs reprogrammed from the patient's own cells. The scientists also found that the abnormal gene expression during the differentiation of iPSCs causes the immune responses.

As noted in his writeup about this study in the New York Times, Andrew Pollack said, “The initial creation of human iPS cells in 2007 (actually it was in 2006 by Shinya Yamanaka at Kyoto University in Japan) electrified scientists because the cells seemed to have two big advantages over embryonic stem cells. They were not controversial, because their creation did not entail the destruction of human embryos, and since the stem cells could be made from a particular patient's skin cells, they could be used to make tissues that presumably would not be rejected by that patient's immune system.

But that latter assumption was never really tested, until now. When Yang Xu, a biologist at the University of California, San Diego, and colleagues did so, they found that iPS cells made from mouse skin cells were nonetheless rejected by genetically identical mice.”

Dr. Xu, whose research was paid for by the National Institutes of Health and by California's stem cell program, created both embryonic stem cells and iPS cells from an inbred strain of mice and implanted those stem cells into other mice of the same strain. The mice did not have an immune response to the implanted embryonic stem cells. But their immune systems attacked the implanted iPS cells, and in some cases, were completely destroyed by the mice’s immune system.

Further experiments suggested that the reaction was caused by the abnormal activation of certain genes in the iPS cells, resulting in the production of proteins that seemed foreign to the immune systems of the mice. The degree of immune response depended on how the iPS cells were made. The strongest response was to cells made by incorporating genes for certain growth factors into the DNA of the skin cells. Cells made that way are not likely to be used for medical treatments anyway because at least one of the inserted genes can cause cancer.

As noted in a story about the study in The Guardian, Paul Fairchild, director of the Oxford Stem Cell Institute, said nobody would have anticipated the immune rejection problem, but added it was too soon to know the implications for medical therapies based on iPS cells.

"It does beg an important question as to whether the same would happen in humans, but it's premature to suggest it casts a cloud over the whole field. We have no idea if human cells would respond in the same way," he said.

Writing in the same issue of Nature, in the News Section, Erika Check Hayden wrote, “But Xu's study is not necessarily the dire news for the iPS field that it might seem. Researchers working with iPS-derived cells that have matured to an adult fate - for instance, neurons or heart cells - have been able to transplant them into mice without rejection, but these experiments have mostly looked at mice without functional immune systems. And scientists designing therapies are mostly proposing to transplant only one type of differentiated cell at a time made from patients' own skin cells back into their bodies, rather than the jumble of differentiated cells found in a teratoma.”

“Xu and other researchers don't yet know whether purified differentiated iPS-derived cells would be rejected, or whether the problem is specific to undifferentiated cells.”

Xu agrees. His group's next steps will be to examine which specific cells in the teratomas trigger immune rejection, and under what conditions. The team used two different methods to make the iPS cells, and they showed slightly different propensities to trigger immune rejection, so it may be that reprogramming methods can be fine-tuned to avoid the problem altogether.

"We propose that the technology to generate iPS cells needs to be improved in order to minimize the difference between iPS and embryonic stem cells, so that iPS cells can be more useful in human therapies," says Xu.

Transplantation of Adult Mouse iPS Cell-Derived Photoreceptor Precursors Restores Retinal Structure and Function in Degenerative Mice

Budd A. Tucker, In-Hyun Park, Sara D. Qi, Henry J. Klassen, Caihui Jiang, Jing Yao, Stephen Redenti, George Q. Daley, Michael J. Young

PLoS ONE 6(4): e18992. doi:10.1371/journal.pone.0018992
Received: October 22, 2010; Accepted: March 23, 2011; Published: April 29, 2011

Abstract

This study was designed to determine whether adult mouse induced pluripotent stem cells (iPSCs), could be used to produce retinal precursors and subsequently photoreceptor cells for retinal transplantation to restore retinal function in degenerative hosts. iPSCs were generated using adult dsRed mouse dermal fibroblasts via retroviral induction of the transcription factors Oct4, Sox2, KLF4 and c-Myc. As with normal mouse ES cells, adult dsRed iPSCs expressed the pluripotency genes SSEA1, Oct4, Sox2, KLF4, c-Myc and Nanog.

Following transplantation into the eye of immune-compromised retinal degenerative mice these cells proceeded to form teratomas containing tissue comprising all three germ layers. At 33 days post-differentiation a large proportion of the cells expressed the retinal progenitor cell marker Pax6 and went on to express the photoreceptor markers, CRX, recoverin, and rhodopsin. When tested using calcium imaging these cells were shown to exhibit characteristics of normal retinal physiology, responding to delivery of neurotransmitters.

Following subretinal transplantation into degenerative hosts differentiated iPSCs took up residence in the retinal outer nuclear layer and gave rise to increased electro retinal function as determined by ERG and functional anatomy. As such, adult fibroblast-derived iPSCs provide a viable source for the production of retinal precursors to be used for transplantation and treatment of retinal degenerative disease.

As noted in the press release from the Schepens Eye Research Institute, scientists from Schepens are the first to regenerate large areas of damaged retinas and improve visual function using iPS cells (induced pluripotent stem cells) derived from skin. The results of their study, which is published in PLoS ONE this month, holds great promise for future treatments and cures for diseases such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and other retinal diseases that affect millions worldwide.

“We are very excited about these results,” said Dr. Budd A. Tucker, the study’s prime author. “While other researchers have been successful in converting skin cells into induced pluripotent stem cells (iPSCs) and subsequently into retinal neurons, we believe that this is the first time that this degree of retinal reconstruction and restoration of visual function has been detected.” Tucker, who is currently an Assistant Professor of Ophthalmology at the University of Iowa, Carver College of Medicine, completed the study at Schepens Eye Research Institute in collaboration with Dr. Michael J. Young, the principle investigator of the study, who heads the Institute’s regenerative medicine center.

While Tucker, Young and other scientists were beginning to tap the potential of embryonic and adult stem cells early in this decade, the discovery that skin cells could be transformed into “pluripotent” cells, nearly identical to embryonic cells, stirred excitement in the vision research community. Since 2006 when researchers in Japan first used a set of four “transcription factors” to signal skin cells to become iPSCs, vision scientists have been exploring ways to use this new technology. Like embryonic stem cells, iPSCs have the ability to become any other cell in the body, but are not fraught with the ethical, emotional and political issues associated with the use of tissue from human embryos.

Tucker and Young harvested skin cells from the tails of red fluorescent mice. They used red mice, because the red tissue would be easy to track when transplanted into the eyes of non-fluorescent diseased mice. By forcing these cells to express the four Yamanaka transcription factors (named for their discoverer) the group generated red fluorescent iPSCs, and, with additional chemical coaxing, precursors of retinal cells. Precursor cells are immature photoreceptors that only mature in their natural habitat – the eye.

Within 33 days the cells were ready to be transplanted and were introduced into the eyes of a mouse model with retinal degenerative disease. Due to a genetic mutation, the retinas of these recipient mice quickly degenerate, the photoreceptor cells die and at the time of transplant electrical activity, as detected by ERG (electroretinography), was absent.

Within four to six weeks, the researchers observed that the transplanted “red cells” had taken up residence in the appropriate retinal area (photoreceptor layer) of the eye and had begun to integrate and assemble into healthily looking retinal tissue.

The team then retested the mice with ERG and found a significant increase in electrical activity in the newly reconstructed retinal tissue. In fact, the amount of electrical activity was approximately half of what would be expected in a normal retina. They also conducted a dark adaption test to see if connections were being made between the new photoreceptor cells and the rest of the retina. In brief, the group found that by stimulating the newly integrated photoreceptor cells with light they could detect a signal in the downstream neurons, which was absent in the other untreated eye.

Based on the results of this study, Tucker and Young believe that harvesting skin cells for use in retinal regeneration is and will continue to be a promising resource for the future. The two scientists say their next step will be to take this technology into large animal models of retinal degenerative disease and eventually toward human clinical trials.

Iluvien Update 3: Alimera Files Resubmission for Approval of Iluvien

2011-05-13T13:20:00.000-04:00

Following up the good news released at the recent ARVO Meeting (Iluvien Update 2: New Safety and Efficacy Data Presented at ARVO), Alimera Sciences Inc. filed a resubmission of its New Drug Application (NDA) for the use of Iluvien in treating diabetic macular edema (DME). This resubmission addresses the questions raised in the Complete Response Letter (CRL) received in December 2010. (See Iluvien Update: FDA Marketing Approval Delayed)

As noted by Alimera, according to the FDA's classification, this will be a Class 2 resubmission. Under the Prescription Drug User Fee Act (PDUFA), FDA review of a Class 2 resubmission is expected to be completed within a six-month period beginning on the date that the resubmission is received by the FDA.

This resubmission addresses the FDA's request for further analyses of the safety and efficacy data through month 36 of Alimera's FAME Study, and includes the data from the subgroup population that was presented last week at the ARVO Meeting. In addition, the resubmission includes further information regarding controls and specifications about the manufacturing, packaging and sterilization of Iluvien, which was requested by the FDA.

"We believe that the resubmission package sent to the FDA will demonstrate the safety and efficacy of Iluvien and address the FDA's additional issues," said Dan Myers, Alimera's president and CEO. "We look forward to working with the FDA for a prompt review and response."

In the CRL, the FDA also indicated that it had observed deficiencies in current good manufacturing practices (cGMP) during its facility inspections of two of Alimera's third-party manufacturers. Alimera believes the deficiencies have been resolved and no further action is required because the FDA has issued letters to both of these third-party manufacturers indicating that the inspections are now closed.

"We look forward to the FDA's response to Alimera's resubmission of the NDA for Iluvien for DME, which if approved, would be our third FDA-approved product," said Dr. Paul Ashton, President and Chief Executive Officer of pSivida. "We are also working on several earlier stage technologies including bioerodible systems to deliver proteins and small drug molecules for macular degeneration and glaucoma." (pSivida licenses the Iluvien delivery system to Alimera.)

Upon approval of Iluvien, pSivida is entitled to receive a $25 million milestone payment from Alimera and 20 percent of net profits, as defined, on sales of the drug made by Alimera.

Ellex 2RT Updated Clinical Results: ARVO 2011

2011-05-07T15:30:00.002-04:00

Last June, I reported on the six-month results of Professor Robyn Guymer’s pilot study of using nanosecond laser pulses to prevent vision loss from patients afflicted with early stages of dry AMD, the Ellex 2RT for Early AMD Study. The results were presented at ARVO 2010. (Ellex 2RT Updated Clinical Results: ARVO 2010).

This year, at ARVO 2011, Professor Guymer and her associates presented 12-month data from her study. This is one of the only treatments offered to prevent early stage dry AMD from progressing into vision loss stages.

Here are the details as provided by Ellex Medical Lasers Limited:

Positive Ellex 2RT Data Demonstrates Efficacy in Treatment of Early AMD

Ellex Medical Lasers Limited announced milestone clinical results for its breakthrough Retinal Regeneration Therapy (Ellex 2RT) for the treatment of Early Age-Related Macular Degeneration (AMD). Interim 12-month clinical trial results presented at the 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, demonstrated the ability of Ellex 2RT to sustain improved visual function and drusen reduction in high-risk Early AMD patients. This follows the presentation of interim 6-month results at the 2010 Annual Meeting of ARVO.

“Unlike other treatment options for AMD, which target the late-stage complications associated with the disease, Ellex 2RT offers the potential to treat AMD in its early stages,” said Tom Spurling, Ellex CEO. “This means that, for the first time, AMD can be treated before vision is lost.”

AMD is a progressive disease affecting the central area of the retina, the macula, and is the leading cause of blindness in the developed world. Globally, the early form of the disease accounts for up to 80% of all cases of AMD. To date, no treatment exists to halt the progression of AMD to its advanced stage, which is associated with severe vision loss.

“The fact that we have been able to maintain the positive effects of Ellex 2RT over a 12-month period provides further evidence that Ellex 2RT offers significant hope for the millions of people worldwide who suffer from AMD,” said Mr. Spurling. “These 12-month results provide a major step towards the market introduction of Ellex 2RT. Our next step is to secure key regulatory approvals during the 2011 calendar year, based on the positive clinical results achieved to date, and to expand the clinical trials across a larger and more diverse patient sampling in order to validate our clinical findings.”

AMD Clinical Trial Results

The interim 12-month results of 24 patients enrolled in the prospective clinical trial, Ellex 2RT for Early AMD, conducted in collaboration with Centre for Eye Research Australia (CERA) at the Royal Victorian Eye and Ear Hospital, demonstrate the clinical efficacy of Ellex 2RT in partially halting or reversing the degenerative processes which cause AMD.

At 12 months two-thirds of patients experienced an improvement in visual function and drusen reduction in the treated eye, with the majority of patients also noting an improvement in the fellow, untreated eye. Visual function improved predominately in the regions of greatest dysfunction, which ... are associated with the highest likelihood of progressing to the advanced stage of the disease.

Extensive laboratory research to date shows no evidence of laser damage to photoreceptor cells. “In the six months since first reporting our results we have observed a sustained improvement in the visual function in the majority of patients”, commented Professor Robyn Guymer, MB, BS, PhD, FRANZCO, Head of Macular Research at the CERA. “This is an extremely positive result. To date there has been no proven intervention in Early AMD that significantly halts or causes regression of the disease process.”

“Our research shows that application of 2RT treatment is safe and painless, and results in both improved visual function and drusen resolution.” A total of 50 patients are enrolled in the trial, with completion of the 12-month follow-up targeted for the end of December 2011. Preparations for a long-term, multi-centre randomised control trial are currently underway to demonstrate the ability of Ellex 2RT to reduce the progression rate to advanced AMD.

Here is the complete abstract from the 2011 ARVO program:

ARVO 2011 Abstract

Retinal Functional Improvement with Nano-Laser Treatment in High Risk Early Age-Related Macular Degeneration

Monday, May 02, 2011, 1:45 PM - 3:30 PM
Session Number: 259

Robyn H. Guymer(1), Kate Brassington(1), Peter N. Dimitrov(1), Mary Varsamidis(1), Galina Makeyeva(1), Khin Zaw Aung(1), Devinder Chauhan(2), Algis Vingrys(3), Chi Luu(1).

(1)Ctr for Eye Rsch - AU, University of Melbourne, East Melbourne, Australia; (2)Vision Retinal Institute, Box Hill Vic. 3128, Box Hill Vic. 3128, Australia; (3)University of Melbourne, Optometry & Vision Sciences, Carlton, Australia., Australia.

Purpose:

The aim of this pilot study was to show if a novel nanosecond laser (2RT) treatment could improve visual function and reduce drusen in high risk Early Age-Related Macular Degeneration (AMD), which may then lead to reduced risk of late stage AMD.

Methods:

Interim results out to12 months from a prospective pilot study (ACTRN12609001056280). Early AMD patients selected with high risk Early AMD but without choroidal neovascularization (CNV) or geographic atrophy (GA). Patients examined with visual field perimeter, optical coherence tomography (OCT), autofluorescence (AF) imaging, fundus photography, visual acuity.

Laser treatment consisted of 12 single laser pulses of 3ns duration, placed in “clock face” pattern around the mid-macular (5deg radius) of one eye using an energy range of 0.15mJ to 0.45mJ , spot diameter of 400μm, wavelength of 532nm. The patient’s eye with highest risk was treated and main follow-up was performed at 3, 6 and 12 months. Visual field results were used to determine the bilateral regions of greatest dysfunction.

Results:

13 of the 14 patients that have reached 12 month follow-up showed some level of visual function improvement or drusen reduction, in one or both eyes. The regions of greatest dysfunction in visual function improved significantly in 7 of these patients and the majority of improvement occurred in patients with the greatest pretreatment dysfunction. VA significantly improved (>5 letters) in 5 patients and some level of drusen reduction occurred in 13 of the patients in one or both eyes. No association was evident between the location of visual function improvements and the location of the laser treatment or the eye treated. Decreased function or other adverse events did not occur in the region of the laser spots.

Figure 1: The pre-treatment retina showing extensive drusen, i.e. yellowish spots that form in the retina which are an early sign of Dry AMD.

Figure 2: Post-treatment retina showing drusen reduction.

Conclusions:

Interim results from this pilot study show that the application of 12 extremely low energy, non thermal, 2RT laser pulses to the mid-macula resulted in visual function improvements in the regions of greatest pre-treatment dysfunction. These regions are likely to be at greatest risk of developing late stage AMD, providing circumstantial evidence that the progress of AMD is being slowed or partially reversed by this laser treatment.

The Way 2RT Works

Retinal Regeneration Therapy

Ellex 2RT is applied to the retinal pigment epithelium (RPE), targeting the melanin cells, and produces a regenerative healing effect. This process of cellular regeneration improves retinal function and reverses the degenerative processes which lead to retinal disease.

Iluvien Update 2: New Safety and Efficacy Data Presented at ARVO

2011-05-06T16:51:00.001-04:00

In July 2010, I wrote a comprehensive report about Iluvien and its potential in the treatment of diabetic macula edema (DME) (Iluvien and the Future of Ophthalmic Drug Delivery Systems). It was anticipated at that time that the company would obtain marketing approval for its sustained release treatment of DME by the end of that year. However, as I wrote in early January, the company received a CRL (complete response letter) from the FDA instead, that requested additional information before approval could be granted. (Iluvien Update: FDA Marketing Approval Delayed).

Earlier this week, Alimera Sciences and pSivida Corporation jointly announced that one of the FAME Study investigators had presented on a subset of the FAME Study data at the ARVO Meeting in Fort Lauderdale, and that the company (Alimera) plans to submit this new subgroup data to the FDA in support of its New Drug Application. Iluvien is licensed by pSivida to Alimera Sciences, Inc.

Here are the details:

Alimera's New 36-Month Safety and Efficacy Results From the Phase 3 Fame Study of Iluvien in Patients With Diabetic Macular Edema Presented at the 2011 Arvo Annual Meeting

Alimera Plans to Submit This New Data to the FDA in Support of Its Pending New Drug Application

Alimera Sciences, Inc. announced that positive new data from the completed FAME Study of Iluvien were presented at the 2011 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting. The new data showed that 33.6% of patients in Trial A (p<0.001) and 42.4% of patients in Trial B (p<0.001) were observed achieving best corrected visual acuity (BCVA) improvement of 15 letters or more from baseline at month 30 in the identifiable subgroup of patients diagnosed with diabetic macular edema (DME) for three years or more at baseline. The new data were presented by Dr. Andrew N. Antoszyk, one of the FAME investigators and a practicing retina specialist at Charlotte Eye, Ear, Nose and Throat Associates in Charlotte, N.C.

The new data, presented by Dr. Andrew N. Antoszyk, analyzed the subgroup of patients who had been diagnosed with DME for three or more years at entry of the FAME Study (which comprises over 50% of patients in the Study).

The FAME Study consisted of two three-year, Phase 3 pivotal clinical trials (Trial A and Trial B) to assess the safety and efficacy of Iluvien in the treatment of DME. The 956 patients in the trials were randomized to receive either high dose Iluvien, low dose Iluvien or control treatment. The primary endpoint for efficacy in the trials was the difference in the percentage of patients whose BCVA improved by 15 or more letters from baseline on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart at month 24 between the treatment and control groups.

As previously reported, the pre-specified primary endpoint for the FAME Study was met for the low dose Iluvien in both Trial A and Trial B. Based on these data, Alimera submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) on June 29, 2010 for approval of the low dose Iluvien. Therefore, only the low dose data is presented and discussed here.

In February 2011, Alimera presented positive results from the full patient population at month 36 of the FAME Study in Trial A (28.4%) and Trial B (29.0%) with demonstrated improvement in BCVA of 15 letters from baseline. Statistical significance was seen in both trials as late as month 33 with Trial A at 28.4% (p=0.042) and Trial B at 29.6% (p=0.046).

Dr. Antoszyk's ARVO presentation on May 3rd included additional data from a subgroup of study patients that was identifiable prior to administration of Iluvien. This subgroup reflected the duration of DME at baseline and across all patients randomized, with a median duration of DME at baseline of three years.

In the data reported for this subgroup at 36 months in Trial A, 31.8% of patients treated with Iluvien experienced an improvement in best corrected visual acuity (BCVA) of 15 or more letters from baseline compared with 13.6% of those in the control group (p=0.010), for a net benefit of Iluvien versus control of 18.2%. In Trial B, 36.4% of Iluvien patients in this subgroup experienced improvement of 15 or more letters compared to 13.2% of control patients (p= 0.004), for a net benefit of Iluvien versus control of 23.2%. On a combined basis for both Trials A and B, at three years the net benefit of Iluvien compared to control reported for patients in the subgroup was 20.6%, more than double that seen for the full patient population (9.8%).

In the subgroup, peak efficacy was seen at month 30, with 33.6% of Iluvien treated patients in Trial A gaining 15 or more letters in BCVA compared to 10.2 % of control (p < 0.001) and 42.4% of Iluvien treated patients in Trial B gaining 15 or more letters in BCVA Trial B compared to 11.3% of control (p< 0.001).

Consistent with the full patient population in the FAME Study, approximately 75% of the patients in this subgroup treated with Iluvien were reported to have received only one Iluvien insert over the 36 month study.

There was no statistically significant difference in BCVA improvement in the subgroup of patients with less than three years' duration of DME at entry compared to control.

"Throughout the FAME Study, Iluvien has shown significant potential for patients suffering with DME. This new data is particularly exciting with 34% of patients who've had DME for three years or more gaining three lines of vision after therapy," said Dr. Antoszyk. "If regulatory approval of Iluvien is obtained, we will be able to offer an additional option in the form of a long-term treatment to our patients who are dealing with this devastating disease."

Data for the subgroup was gathered from 536 patients who had been diagnosed with DME for three years or more and 416 patients who had been diagnosed with DME for less than three years. Alimera will provide these additional data in its response to the Complete Response Letter issued by the FDA in December 2010.

Safety was assessed among those patients within the subgroup who were treated with Iluvien in the study. Intraocular pressure (IOP) increases to 30 millimeters of mercury (mmHg) or greater at any time point were seen in 14.8% of these patients by month 36, compared to 18.3% in the full Iluvien treated patient population. By month 36, 5.3% of these patients had undergone an incisional surgical procedure to reduce elevated IOP, compared to 4.8% in the full patient population. The incidence of cataracts among patients with a natural lens in their eye at the start of the study was 86% at month 36, with 85% undergoing a cataract operation, compared to 80% and 74.9%, respectively, in the full patient population.

"We are pleased that this identifiable subgroup shows even greater benefit to risk than the full patient population through month 36 of the study, thereby further improving Iluvien's profile," said Dan Myers, Alimera's president and CEO. "This data spotlights the benefit that Iluvien, if approved, could bring to the patient population that retinal specialists are targeting for its use. We believe this data will be very valuable to the treatment of DME going forward."

Paul Ashton, president and chief executive officer of pSivida, said, "We are very pleased with the efficacy and safety results through month 36 in patients with chronic DME. This subgroup comprised a majority of patients in the FAME Study. We look forward to Alimera's filing of this data with the FDA in connection with the NDA for Iluvien."

About the FAME Study

Alimera conducted two 36-month, Phase 3 pivotal clinical trials (collectively known as the FAME Study) for Iluvien involving 956 patients in sites across the United States, Canada, Europe and India to assess the efficacy and safety of Iluvien with two doses of the corticosteroid fluocinolone acetonide (FAc), a high and low dose, for the treatment of DME. The primary efficacy endpoint for the FAME Study was the difference in the percentage of patients whose best corrected visual acuity improved by 15 or more letters from baseline on the ETDRS eye chart at month 24 between the treatment and control groups. The study concluded in September 2010 with the final patient visit at the three-year data point.

Following its NDA submission to the FDA, Alimera submitted a Marketing Authorization Application to the Medicines and Healthcare products Regulatory Agency in the United Kingdom. Applications have also been submitted to regulatory agencies in Austria, France, Germany, Italy, Portugal and Spain. Based upon the analysis of the FAME Study, all filings included the 24-month data. The FDA, in a December 2010 Complete Response Letter, requested further information including the month 36 data from the FAME Study.

About DME

DME, the primary cause of vision loss associated with diabetic retinopathy, is a disease affecting the macula, the part of the retina responsible for central vision. When the blood vessel leakage of diabetic retinopathy causes swelling in the macula, the condition is called DME. The onset of DME is painless and may go undetected by the patient until it manifests with the blurring of central vision or acute vision loss. The severity of this blurring may range from mild to profound loss of vision. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that over a 10-year period approximately 19% of people with diabetes studied were diagnosed with DME. As the population of people with diabetes increases, Alimera expects the annual incidence of diagnosed DME to increase, as well.

CATT Update 15: Preliminary Two-Year Safety Data Presented at ARVO

2011-05-03T17:18:00.000-04:00

Two of the authors of the CATT Study, that was published in the NEJM last Thursday (see CATT Update 14: One-Year Study Results Show Equivalency Between Avastin and Lucentis), Drs. Dan Martin and Maureen McGovern, presented additional information about the study at the opening day ARVO Meeting, to about 2000 eager attendees. As reported by MedPageToday, their presentation included preliminary two-year safety data from the landmark CATT trial.

Major adverse events during the trial's second year appeared to be about equal, in contrast with the one-year results which suggested that ranibizumab (Lucentis) might be somewhat safer than off-label bevacizumab (Avastin) for patients with wet age-related macular degeneration (AMD).

Nevertheless, when study co-leaders Daniel Martin, MD, of the Cleveland Clinic, and Maureen Maguire, PhD, of the University of Pennsylvania, took the podium at ARVO on Sunday afternoon, they surprised attendees with some data not included in the NEJM paper -- a glimpse of safety results in patients completing the study's second year of treatment.

They showed that rates of death, stroke, and all arteriothrombotic events were equal between the two drugs during the trial's second year:

    * All-cause mortality: ranibizumab 2.8%, bevacizumab 2.9% (P=1.00)
    * Arteriothrombotic events: ranibizumab 2.2%, bevacizumab 1.7% (P=0.68)
    * Stroke: ranibizumab 1.2%, bevacizumab 1.2% (P=1.00)

These data did not distinguish between the two treatment regimens that were tested in the four-arm trial, which was sponsored by the National Eye Institute. Patients received one of the two drugs by intravitreal injection either on a fixed monthly schedule or "as needed," based on whether fluid buildup was detected in retinal imaging conducted monthly.

According to the data reported in NEJM, serious systemic adverse events in aggregate during the first year were significantly more common with bevacizumab with a risk ratio of 1.29, at a 95% confidence interval, 1.01 to 1.66. (When the dosing regimen groups were combined, the proportions of patients with serious systemic adverse effects were 24.1% for bevacizumab and 19.0% for ranibizumab.)

Efficacy data from the second year of the CATT (Comparison of AMD Treatment Trials) study were not reported at the ARVO session. Those data are expected to be released at a later meeting.

Top-line efficacy results from the one-year data indicated that the two drugs were nearly equal to each other and that as-needed dosing was effective but slightly less so than the fixed monthly schedule.

During their presentation, Martin and Maguire highlighted five issues still to be answered in the full two-year data. Those include whether:

    * Visual acuity findings will change during the second year
    * Anatomical differences (favoring ranibizumab after one year) are related to long-term visual outcomes
    * As-needed dosing remains effective past the first year of treatment
    * Spectral-domain optical coherence tomography for retinal imaging increases fluid detection rates and therefore the number of injections under as-needed dosing
    * Patient genotype affects outcomes or dosing requirements

CATT Study Update 14: One-Year Study Results Show Equivalency Between Avastin and Lucentis

2011-04-28T18:32:00.001-04:00

The Comparison of AMD Treatment Trials (CATT Study) one-year results were released today in the New England Journal of Medicine (NEJM). As anticipated, the two anti-VEGF drugs, Avastin and Lucentis, both produced by Genentech, showed equivalent results in the four-arm head to head study. The 43-center, single-blind, noninferiority trial of 1208 patients with neovascular age-related macular degeneration, showed no significant difference either on a monthly injection schedule, or on an as needed injection schedule.

The National Eye Institute (NEI) launched the CATT Study in 2008 to compare Lucentis and Avastin for treatment of wet AMD. The study has now reported the one-year results for 1,185 patients treated at the 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or as needed, or Avastin monthly or as needed. Enrollment criteria required that study participants had active disease.

Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the as needed groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. As needed groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care did not know which study drug a patient was getting, to make sure that the data was not affected by how anyone felt about the treatment.

Change in visual acuity served as the primary outcome measure for CATT. Thus far, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on an as needed schedule, there also was no difference (within one letter) between drugs. As needed dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with as needed than with monthly treatment but overall visual results were still excellent.

In the monthly treatment arms, Avastin was equivalent to Lucentis, with 8.0 and 8.5 visual acuity letters gained, respectively, and in the as-needed arms, Avastin was equivalent to Lucentis with 5.9 and 6.8 letters gained.

Lucentis as needed was equivalent to monthly Lucentis treatments, although the comparison between Avastin as needed and monthly treatments was inconclusive. The mean decrease in central retinal thickness was greater in the Lucentis-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance).

Rates of death, myocardial infarction, and stroke were similar for patients receiving either Lucentis or Avastin (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Luentis (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.

It should be noted that the median age of patients in the CATT Study was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.

In conclusion, the CATT Research Group reported that at 1 year, Avastin and Lucentis had equivalent effects on visual acuity when administered according to the same schedule. Lucentis given as needed with monthly evaluation had effects on vision that were equivalent to those of Lucentis administered monthly. Differences in rates of serious adverse events require further study.

Or to put it another way, Avastin and Lucentis are equivalent in treating wet AMD, as needed dosing is nearly as effective as monthly injections and, there are no major safety differences between the two drugs.

I have chosen two graphics to illustrate the study results.

Graph 1 shows the changes in visual acuity over the course of the study and illustrates the equivalency of the four arms of the study.

Graph 1

The part of Table 2 that I have chosen, again shows how close the results were for the four arms of the study, and in addition, shows the number of treatments for each arm, as well as the average annual cost to the patients, with Lucentis costing as much as 40 times the cost of Avastin. This will have an important impact on national health care costs when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

Table 2

(By clicking on the table, an enlarged version will become visible.)

Another important observation was made concerning adverse effects. The CATT Research Group noted that "Clinical trials of intravenous Avastin in patients with cancer have identified associations with arteriothrombotic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications, and hypertension. With a limited statistical power to detect important adverse events, we found no significant differences between the two drugs in rates of death, arteriothrombotic events, or venous thrombotic events, findings that are consistent with the results of a study of Medicare claims involving more than 145,000 treated patients.However, in our study, the rate of serious systemic adverse events, primarily hospitalizations, was higher among Avastin-treated patients than among Lucentis-treated patients (24.1% vs. 19.0%, P=0.04). The excess numbers of these events were distributed over many different types of conditions, most of which were not identified in cancer trials involving patients who were receiving intravenous doses of Avastin that were 500 times those used in intravitreal injections. We also did not observe increased rates of adverse events with increased exposure to the study drugs; rates were higher for the two drugs when given as needed than when given monthly. The difference in rates may be attributable to chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk. Resolving this issue will require many more patients than were available for this study. Results from the second year of this study and from other comparative trials will provide more information regarding the relative risks of serious adverse events."

Dr. Philip Rosenfeld (the father of Avastin) provided an editorial to accompany the CATT Study results in the NEJM. Here is the full text of his editorial:

Editorial

Bevacizumab versus Ranibizumab - The Verdict

Philip J. Rosenfeld, M.D., Ph.D.

April 28, 2011 (10.1056/NEJMe1103334)

For 5 years, patients and clinicians have wrestled with the choice between two drugs for the treatment of neovascular age-related macular degeneration (AMD), a common cause of irreversible blindness among the elderly worldwide. Vision loss results from the abnormal growth and leakage of blood vessels in the macula, a specialized portion of the retina responsible for the best visual acuity. Without this macular vision, patients become legally blind. Vascular endothelial growth factor (VEGF), the cytokine primarily responsible for blood-vessel growth, is inhibited when anti-VEGF drugs are injected repeatedly into the eye, and blindness is prevented in most patients. The majority of treated patients go on to have some improvement in vision.

The two anti-VEGF drugs most commonly used are bevacizumab (Avastin) and ranibizumab (Lucentis), both developed by Genentech. Bevacizumab, a full-length humanized monoclonal antibody, has been approved by the Food and Drug Administration (FDA) for the systemic treatment of certain cancers. Ranibizumab, an antigen-binding fragment, is a smaller molecule that was specifically developed and approved to treat eye diseases and is derived from the same anti-VEGF mouse monoclonal antibody as bevacizumab. Both ranibizumab and bevacizumab bind VEGF at the same position; however, they differ in size, affinity for VEGF, speed of clearance from the eye, and cost. Ranibizumab, the FDA-approved treatment for neovascular AMD, costs approximately $2,000 per dose, whereas bevacizumab, the off-label treatment, costs approximately $50. This cost difference, along with the perceived clinical similarities between these two drugs, has led to the widespread use of bevacizumab in the absence of level I evidence.

Editors Note: According to various sources, approximately 65% of ophthalmologists in the U.S. currently use Avastin over Lucentis as their primary treatment for neovascular AMD.

In this issue of the Journal, Martin and colleagues provide such evidence in their findings from the first year of the Comparison of AMD Treatment Trials (CATT), a large, prospective, multicenter, randomized clinical trial comparing bevacizumab and ranibizumab. Despite formidable obstacles, the investigators successfully compared the two drugs and two different dosing regimens: a monthly regimen versus an as-needed regimen (i.e., drug administration only when signs of exudation are present). A monthly regimen is considered the standard for treatment. An as-needed regimen is used less frequently and relies on clinical judgment and imaging techniques to determine when to reinject the drug. The most common imaging method that is used is optical coherence tomography (OCT), a noninvasive technique that identifies fluid leakage from blood vessels. This VEGF-mediated exudate resolves after the injection of ranibizumab or bevacizumab. An OCT-guided as-needed regimen has been shown to result in improved visual acuity, but CATT is the first prospective approach to directly compare a monthly regimen with an as-needed regimen.

Martin et al. found that the monthly use of either bevacizumab or ranibizumab results in the same visual acuity outcome. This finding holds true for the mean visual acuity and the proportion of patients who gain 15 letters (which represents a doubling of the visual acuity), lose 15 letters, or remain stable. Critics will argue that the OCT outcomes suggest differences between these two drugs. Although the OCT retinal thickness measurements favor ranibizumab, this difference is not reflected in any of the visual-acuity or angiographic outcomes. Whether this difference is associated with changes in vision should become clear during the second year of follow-up.

In addition, Martin et al. observed equivalent visual-acuity outcomes with both the monthly and the as-needed regimens of ranibizumab. This result is particularly good news for patients. The success of the as-needed regimen in a multicenter clinical trial cannot be overstated, given the intrinsic difficulties associated with the training of investigators to agree on OCT interpretation and retreatment guidelines. Given deficiencies that were reported by the reading center, it is likely that visual acuity and anatomic outcomes would have been even better with improved investigator compliance. Other strategies to improve overall treatment outcomes might include the use of newer OCT techniques with improved image resolution to help with retreatment decisions and the use of three mandated monthly injections at the start of the study.

Although the as-needed regimen with bevacizumab appeared similar to the as-needed regimen with ranibizumab, the as-needed bevacizumab regimen compared less favorably with monthly regimens for either bevacizumab or ranibizumab. One possibility may be that bevacizumab has a less durable treatment effect in a subgroup of patients and thus more frequent administration may be required. If the frequency of administration were increased, then the outcomes in such patients should approach the outcomes observed with monthly treatments.

Although CATT addresses the question of efficacy, the study was insufficiently powered to identify differences in drug-related adverse events. Although bevacizumab persists longer than ranibizumab in the systemic circulation after an intravitreal injection, Martin et al. observed none of the expected adverse events associated with systemic anti-VEGF therapy. Although more patients receiving bevacizumab had multiple systemic serious adverse events and hospitalizations than those receiving ranibizumab, these events were not associated with organ systems typically identified with systemic anti-VEGF therapy. The results from the second year of CATT and from five other large, ongoing, multicenter comparative clinical trials in Europe should help to clarify whether these adverse events are related to intravitreal anti-VEGF therapy.

The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD. An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required. Health care providers and payers worldwide will now have to justify the cost of using ranibizumab. Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label, particularly when so many of their citizens cannot afford ranibizumab. The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab.

CATT Study Update 13: A First Peek

2011-04-27T16:24:00.000-04:00

As reported by Andrew Pollack of the NYTimes, in a column published earlier today, the first results of the 1200 patient CATT Study (Comparison of AMD Treatments Trials), whose first-year results are scheduled for release at ARVO on Sunday afternoon, indicate equivalency between Avastin and Lucentis.

Speaking to two of the researchers involved in the study (and who presumably had access to the study results), Pollack basically said that the study will be interpreted in many ways, as some complicating factors may indicate that Lucentis is safer to use than Avastin.

Here are Pollack’s comments:

Test of Eye Drug Is Said to Show Success in Elderly

By ANDREW POLLACK
NY Times Prescriptions Blog
April 27, 2011, 11:40 am

A far less expensive alternative proved roughly as effective as Genentech's costly drug Lucentis in preserving or improving vision in elderly people with a common eye disease, according to two people familiar with the results of a closely watched clinical trial.

A clear showing of equivalence between the two drugs could lead to greater use of the less expensive drug, Avastin, which is also made by Genentech, saving Medicare hundreds of millions of dollars a year or more. However, some researchers said, there are some complicating factors, both in the trial data and in other studies, that would favor Lucentis.

"The data is going to be interpreted many different ways,'' said one investigator in the trial, who spoke under condition of anonymity but would not provide any trial results. Revealing trial results before they are published or presented at a conference is considered a violation of scientific protocol.

Genentech developed Lucentis to treat the wet form of age-related macular degeneration, the most common cause of severe vision loss in the elderly. While Avastin, which is a cancer drug, has not been approved for use in treating macular degeneration, it has the same mechanism of action as Lucentis. And Avastin costs only about $50 per injection into the eye, compared to roughly $2,000 for Lucentis.

Many eye doctors already are using Avastin off-label to treat macular degeneration, and many say it appears to work just as well as Lucentis. But there has never been a definitive trial to compare the two drugs.

So the National Eye Institute, part of the National Institutes of Health, sponsored a randomized trial involving 1,200 patients. Results are scheduled to be presented Sunday at the annual meeting of the Association for Research in Vision and Ophthalmology in Fort Lauderdale, Fla. The results will also be published in The New England Journal of Medicine.

Some 1.6 million Americans have advanced forms of age-related macular degeneration and the number is expected to increase as baby boomers age. In 2008, Medicare paid for 480,000 injections of Avastin to treat macular degeneration and 337,000 injections of Lucentis, according to a study led by Dr. Philip Rosenfeld of the University of Miami. Yet Medicare paid only $20 million for the Avastin compared to $537 million for the smaller number of Lucentis injections.

Investigators in the National Eye Institute trial had a day-long meeting on Tuesday in Chicago to learn the results. But they were sworn to secrecy.

But two people familiar with the data, who spoke on condition of anonymity, said that injections of Lucentis and Avastin every four weeks resulted in vision changes after one year that were essentially the same.

The result was largely expected. Under the rules of the trial, patients treated with Avastin could read on average of up to five fewer letters on an eye chart than those treated with Lucentis and Avastin would still be considered "non-inferior." It is believed the results were closer than five letters, however.

Still, doctors will be looking closely at details of the data. One person said Avastin was less effective than Lucentis in decreasing the thickness of the retina, suggesting that Avastin might not prove as effective in preserving vision over a period beyond one year. Patients in the trial are being followed for a second year.

Safety of the two drugs will also be closely watched. However, experts say that with only 1,200 patients, the trial will be able to detect only major differences in safety.

Another part of the trial compared injecting the drugs as needed, depending on the course of the patient's disease, rather than on a strict monthly schedule. One source said Avastin was slightly inferior to Lucentis, but the other said the results of the two drugs were the same.

The trial comparing the two drugs is of the type known as a comparative effectiveness study. Such studies are being encouraged under the new health reform law, though this one started before the law was enacted.

Genentech, which is owned by Roche, has already mounted a pre-emptive counterattack aimed at nullifying any results of the federal trial that would shift more patients to Avastin.

The company sponsored a study looking at records of nearly 78,000 Medicare recipients with age-related macular degeneration. The study found that those who received Avastin had an 11 percent higher risk of dying and a 57 percent higher risk of hemorrhagic stroke than those getting Lucentis, according to an abstract of the study posted on the Web site of the upcoming ophthalmology conference, where the results will be presented.

Genentech arranged for the lead investigator of this study, Dr. Emily W. Gower of Johns Hopkins University, to brief Congressional staffers on the results on Tuesday.

If this finding is considered valid, it could render the results of the National Eye Institute trial somewhat moot by raising safety questions about Avastin.

"Once you plant that seed of doubt in patients' minds it's very difficult to overcome that,'' said one retina specialist, who spoke on condition of anonymity. "I would say it changes the landscape.''

However, experts have not been able to scrutinize the data of this study. One obvious potential flaw is that people who get the cheaper Avastin are more likely to be poor and uninsured and might therefore have worse health to begin with than those who get Lucentis. The study tried to correct for this but whether it did so adequately is a subject of debate.

Roche sells Lucentis in the United States and Novartis in other countries. Sales of the drug for each company were about $1.5 billion last year.

Avastin/Lucentis Update 46: Avastin — The Rest of the Story

2011-04-18T17:15:00.001-04:00

I decided to begin this online Journal for two reasons, the first was to put some of my published columns and reports online and make them available to ophthalmic researchers and historians, and the second was because I became interested in the potential for some of the new drugs I had been reading about to stop macular degeneration cold in its tracks. During the summer of 2005, I read a review by Lynne Peterson, of Trends-in-Medicine, of what had happened at the American Society of Retina Specialists (ASRS) Meeting held that summer in Montreal.

As I wrote in one of my first original pieces for this blog (Avastin: A New Hope for Treating AMD) in late January 2006, Lynne had reported about two drugs from Genentech – Lucentis and, for the first time, its sister drug, Avastin – and how they had the ability not only to stop the progression of AMD, but to actually improve vision for those afflicted with the disease.

As she wrote, “Word spread like a tsunami through the American Society of Retina Specialists (ASRS) meeting about the newly discovered benefits in wet age-related macular degeneration (AMD) from the off-label – and very inexpensive – use of a chemotherapy agent for colorectal cancer. At the beginning of the meeting, only a handful of doctors knew about intravitreal injections of Genentech’s Avastin (bevacizumab), but by the end of the meeting, most doctors questioned said they plan to go home and try it.”

“In fact, Avastin stole the show from Genentech’s Lucentis (ranibizumab), a fragment of the Avastin molecule that is being developed specifically as an intravitreal injection for AMD. The data presented on Lucentis was outstanding, but it did as much to convince doctors of the value of Avastin as to build anticipation for Lucentis. There have been no studies of Avastin, just case reports and personal experiences, but that was enough to make doctors want to use it – particularly in patients who have failed photodynamic therapy and/or Eyetech’s Macugen (pegaptanib).”

Well, the doctor that spread the word at that meeting and was the first to use Avastin in the eye was Dr. Philip Rosenfeld of Bascolm Palmer Eye Institute in Miami. That was the first part of the story.

In June 2010, I received a request from a university student, Wendy Bedale, for the background information for the above report, for a paper she was writing for a journalism course at the University of Wisconsin. After reading her finished paper, I asked for and received permission to reproduce it, as it described “the story behind the story” about the invention of Avastin and Lucentis at Genentech. This was Avastin/Lucentis Update 41: The Story Behind the Invention of Avastin and Lucentis, and was part two of the story.

Then last week, I heard from a colleague blogger, Dr. David Khorram (The Retina Blog), with a question. Did I recall a story about how Dr. Philip Rosenfeld had come up with the idea to try Avastin in his patients in the first place? I didn’t remember reading this story, but David found an online version, in of all places, a diabetes online forum. I knew that that wasn’t the origin of the story so I decided to ask Dr. Rosenfeld about this story and he was kind enough to send me a copy of the original. It had been written in November 2006 by Jacob Goldstein, then working for the Miami Herald. (Jacob went on to write the WSJ Health Blog, and is currently a blogger for NPR.)

As soon as I read the piece, I realized that this was the missing piece to complete the story that I had started in January 2006.

And, with the expected release of the first year results of the CATT Study – a controlled head to head study of Avastin and Lucentis – at the opening session of the ARVO Meeting on May 1st, I decided to request permission from both the Miami Herald and from Jacob Goldstein to reproduce the Avastin story here, or, as I ‘ve called it, “the rest of the story.”

(Editor’s note: I did find the story on the Miami Herald website, but it is behind a pay to view wall, so I have not provided a link.)

Two Drugs: How a Miami Doctor Found a Cheap Way to Save People’s Sight – and Got a Lesson in Medicine & Money

November 14, 2006
Jacob Goldstein, Miami Herald

Dr. Philip Rosenfeld had the epiphany that would save the vision of thousands of people -- and may save billions of dollars in healthcare costs -- one evening last year, as he drove home over the Rickenbacker Causeway. He realized that a cancer drug could be injected directly into the eye to fight wet macular degeneration, which leaves thousands of Americans legally blind every year.

'As soon as I got home, I said to my wife, `You're not going to believe this,' '' Rosenfeld says.

Rosenfeld, a retina specialist at the University of Miami's Bascom Palmer Eye Institute, may have guessed that night how effective the drug would be, and he had some sense of the possible cost savings. But he could not have foreseen that his idea would spread around the world in a matter of months, with eye doctors from Santa Barbara to Beirut launching their own studies; nor could he have predicted that a biotechnology company's reluctance to get involved would draw him into the quagmire of the rising cost of new drugs.

The story properly begins five years earlier, when the results began to come in from the first clinical studies of an experimental drug called Lucentis. At that time, there was no way to prevent a gradual loss of vision for the vast majority of patients with wet age-related macular degeneration, or wet AMD, which affects more than 100,000 Americans each year.

''We knew since 2000 that everything was going to change with Lucentis,'' says Rosenfeld, who was one of the leaders of the early trials. ``We saw dramatic effects -- effects we'd never seen before with any other drug.''

Lucentis, developed by the biotechnology giant Genentech, prevents the formation of new blood vessels associated with wet AMD. The drug is very similar to Genentech's cancer drug Avastin, which prevents the formation of new blood vessels associated with lung and colorectal cancer. Indeed, Lucentis is essentially a smaller version of the molecule used in Avastin; it was developed after early studies at Genentech suggested a molecule the size of Avastin would not penetrate the retina as well as a smaller molecule.

By 2004, Lucentis was in the final stage of clinical trials. But it would be two more years before the FDA approved the drug, and in the meantime only those patients lucky enough to be included in the Lucentis trials were able to get it. For other patients, doctors were limited to far less effective treatments which usually failed to stop the loss of vision.

That prompted Rosenfeld to try Avastin. At first, he gave the drug the same way it is given to cancer patients -- with an IV infusion into the patient's bloodstream. ''The results were spectacular,'' Rosenfeld says. But studies of Avastin in cancer patients showed it increased the risk of heart attack and stroke. And when Rosenfeld shared his Avastin results with other eye doctors in early 2005, it became clear they didn't like those risks.

Then Rosenfeld learned researchers had shown that a molecule similar to Avastin could penetrate the retina -- and as he drove home to Key Biscayne one night not long after, he realized that, by sheer coincidence, the liquid preparation of Avastin sold for cancer treatment was the perfect concentration to inject into the eyes of wet AMD patients. He also realized that the amount needed for an injection to the eye would be a tiny fraction of the amount given with an IV infusion to cancer patients. That would likely reduce not only the risk of heart attacks and stroke, but also the cost. Indeed, an Avastin injection would cost about $50 -- compared to $1,000 for Macugen, the main macular degeneration drug used before Lucentis. And when Lucentis was released, it would cost $2,000 per monthly dose.

''Whoa, wait a second,'' Rosenfeld thought. ``Another lesson in healthcare economics.''

The next day, Rosenfeld asked Serafin Gonzalez, Bascom Palmer's chief pharmacist, if he could transfer Avastin from the glass vials it came in into syringes suitable for injecting people in the eye.

By the end of the week, he had injected his first patient, who showed improvement within days. That was in May. At a conference in July, (the ASRS Meeting) he presented the successful results of his first few patients, and other doctors started using the technique on their own patients. The next month, an ophthalmology insurance company posted an Avastin consent form online.

''He just started a revolution,'' says Dr. Robert Avery, a Santa Barbara ophthalmologist who was one of the first to begin using Avastin. ``He did the lion's share of the work and had the guts to make the first injection.''

Not only did ophthalmologists around the world begin using Avastin within a matter of months; they also began studying it, trying to answer all the questions usually resolved by drug company research.
Doctors in Lebanon and Brazil launched clinical trials. An Israeli scientist used rabbits to test whether Avastin was toxic in the eye -- then FedExed a box of rabbit eyeballs to Avery, who showed that the drug did in fact penetrate the retina. The effort had the spirit of open-source software development, where new computer programs are created without the aid of software companies by programmers working in their spare time, each contributing a piece of the puzzle.

Early on, Rosenfeld had flown to Genentech's California headquarters to discuss his Avastin findings. Scientists there were impressed with his findings, he said, but the company never got involved in testing Avastin for the eye.

''We're not developing Avastin for ophthalmic use,'' said Genentech spokeswoman Dawn Kalmar. “We specifically designed and stand behind our decision to design Lucentis for use in the eye. . . Our mission is to meet unmet medical needs and we believe that Lucentis is doing that today.''

By the time Lucentis was approved in June of this year (2006), Medicare covered Avastin for wet AMD in more than 30 states, including Florida. The approval of Lucentis has presented doctors and patients with a choice: a $2,000 drug that has been thoroughly studied in the eye, or a $50 drug that has been studied in an ad-hoc fashion but has become widely used.

Both drugs seem to be similarly effective, slowing or stopping the loss of vision in many patients and improving the vision of some. Serious side effects appear to be very rare for both -- although long-term studies of the effects of Avastin in the eye have not yet been done. A head-to-head study of the two drugs, funded by the National Institutes of Health and Medicare and set to begin in the next few months, should provide a clearer picture of how they compare.

Meanwhile, Rosenfeld -- who is 49 and has spent his career in academia, largely sheltered from issues of healthcare costs -- can't stop thinking about drug prices. ''I'm a physician, a retina specialist, a molecular biologist, a geneticist. I'm not an expert in healthcare policy,'' he says. ``But certain things are becoming painfully obvious . . .

“I think people should be rewarded for developing remarkable, fabulous, miracle drugs. I'm not someone who believes in penalizing the industry, but I have become acutely aware of how these drugs appear to be excessively priced. “We need to strike a better balance between financial rewards and affordability. . . . It's percolated into my everyday life -- in how I treat patients, how I think about studies and how I pursue future treatments.''

AMD Update 14: Neurotech Pharmaceuticals NT-501 Implant Shown to Slow Vision Loss in Patients with Geographical Atrophy Associated with Dry AMD

2011-04-08T18:43:00.000-04:00

Back in December 2009, I reproduced Dr. Philip Rosenfeld’s excellent article that presented an overview of the drugs in development to treat dry AMD. At the time, and still today, there was no drug or treatment approved for the treatment of the dry stage of AMD, that represents about 90% of AMD sufferers.

Here is what I presented (from Dr. Rosenfeld’s article) about drugs to promote the survival of photoreceptors and retinal pigment epithelium (RPE) for the treatment of dry AMD:

“No matter what the underlying cause of AMD, drugs that can preserve viable photoreceptors and maintain the RPE should preserve vision. One strategy to promote survival of photoreceptors and the RPE is to protect cells against ischemia and improve the choroidal circulation in patients with dry AMD. Two studies are currently using this strategy. In Europe, an ongoing multicenter, randomized, placebo-controlled study is investigating the use of an offlabel, generic drug known as trimetazidine (Vastarel MR, 35 mg tablet), a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is considered to have cytoprotective effects in ischemic conditions. Other uses for this drug include the treatment of vertigo, tinnitus, and vision loss and visual field loss due to vascular causes. The primary goal of this study is to slow the conversion of dry AMD to wet AMD.”

“Another drug being investigated for its vasodilatory effect is Alprostadil, also known as prostaglandin E1 (PGE1). The presumed rationale is based on the belief that improved circulation would slow the progression of AMD. This multicenter, randomized, placebo-controlled study is ongoing in Europe.”

“Another strategy to preserve the macular function is to prevent apoptosis by using neuroprotective agents. Ciliary neurotrophic factor (CNTF), a potent neuroprotective agent, has been shown to inhibit photoreceptor apoptosis in an animal model of retinal degeneration and is being investigated as a treatment for dry AMD. Using encapsulated cell technology that permits CNTF-producing transfected cells to be implanted into the vitreous cavity, Neurotech Pharmaceuticals (Lincoln, RI) has developed a sustained-release platform that produces CNTF for a year or longer. The phase 2 study is completed and data analysis is currently under way. Other neuroprotective agents currently under investigation for dry AMD include a brimonidine tartrate intravitreal implant (Allergan, Irvine, CA) and topical tandospirone (Alcon, Fort Worth, TX).”

Well, this week, Neurotech Pharmaceuticals, Inc., announced that a report in the Proceedings of the National Academy of Sciences (PNAS) (published online March 28, 2011) showed that its product candidate NT-501, slowed progression of vision loss in patients with geographic atrophy (GA) associated with dry age-related macular degeneration (AMD) in a Phase 2 study.

The report, “Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration”, is the first to show the benefits of a therapy to slow the progression of vision loss from this disease. The results highlight the benefit of the use of a neotrophic factor to treat geographic atrophy and provides hope to the nearly one million sufferers of this vision loss disease.

NT-501 is an intraocular implant that consists of human cells genetically modified to secrete ciliary neurotrophic factor (CNTF) - a nerve growth factor capable of rescuing and protecting dying photoreceptors. GA is a condition that destroys sharp central vision, often resulting in serious vision loss to one or both eyes, for which there is no available treatment.

The Phase 2 study was a multi-center, double-masked, sham-controlled, dose-ranging study in 51 subjects with GA. Subjects were randomly assigned to receive either a high- or low-dose NT-501 implant or sham surgery. The primary study endpoint was change in best corrected visual acuity (BCVA) at 12 months. The study results demonstrated a dose-dependent increase in retinal thickness suggesting increased photoreceptor metabolic activity. This increase was followed by visual acuity stabilization (loss of fewer than three lines of vision, or 15 letters) of 96.3% in the high-dose group compared to 83.3% in the low-dose group and 75.0% in the sham group. In a sub-group analysis of subjects with better vision at base line (20/63 or better), 100% of the high-dose group (n = 10) maintained visual acuity stabilization compared to 55.6% (p = 0.033) in the combined low- and sham-treated groups (n = 9). In this sub-group analysis, there was a 0.8 mean letter gain in the high-dose group compared to a 9.7 mean letter loss in the combined low- and sham-treated groups. Overall, there were no serious adverse events reported and the surgical procedures were well tolerated. The proof of concept study results were originally reported by the company in March 2009.

Quoting from an earlier safety study, published in PNAS in March 2006, the authors then noted: “This trial indicates the safety and promising utility of encapsulated cell delivery as a mode of administration of protein therapeutics to the eye. The results raise the intriguing possibility that CNTF may improve visual acuity in some eyes with advanced RP and atrophic macular degeneration. At the end of the 6-month implantation duration, all explanted capsules contained viable cells that secreted CNTF at expected levels that were therapeutic in the rcd1 dog study. Because pharmacokinetic data on preclinical studies showed continued CNTF production out to 1 year and beyond, encapsulated cell implants may provide a longer-term therapeutic release that will facilitate efficacy studies in retinal and macular neurodegenerative diseases. These results, coupled with robust implant performance, provide the basis for considering the next stages of human trials of CNTF delivered by encapsulated cell implants.”

(Editors note: Whereas the earlier safety study indicated that NT-501 might improve visual acuity in some eyes with advanced RP and GA, the Phase 2 study results, the focus of this article, indicated that the device might slow vision loss.)

The current study's lead author and one of its clinical investigators was Dr. Kang Zhang, Professor of Ophthalmology & Human Genetics, Shiley Eye Center and Director of the Institute for Genomic Medicine, University of California, San Diego. He noted, "The study findings are very promising since both structural and functional improvements were demonstrated in a disease that is currently untreatable. These results support the initiation of larger confirmatory studies of NT-501 in patients with GA."

Paul Sieving, MD, PhD, Director of the National Eye Institute and Principal Investigator of Neurotech's Phase 1 study of NT-501 in retinitis pigmentosa, commented that, "The results of this Phase 2 study suggest that CNTF delivered by the ECT platform may be a useful approach to slow the progression of vision loss in GA patients, and warrant further study in a larger trial of patients exhibiting early onset of this condition."

Ted Danse, Chief Executive Officer of Neurotech stated, "These results in GA demonstrate the significant opportunity of NT-501 to fill a much needed treatment void for sight-robbing retinal degenerative diseases. The data also provide further validation of our proprietary ECT technology and strongly support the introduction of additional product candidates from the platform."

About Dry AMD/ Geographic Atrophy (GA)

Age-related macular degeneration (AMD) is a chronic progressive disease of the macula that results in the loss of central vision. It is the leading cause of blindness in elderly people in the developed world. There are two forms of AMD - dry and wet. Dry AMD is the most common form of AMD representing approximately 90% of all AMD cases. In its advanced stages dry AMD can lead to the degeneration of photoreceptors, those cells of the retina responsible for fine central and color vision, and retinal pigment epithelial cells, those cells responsible for nourishing photoreceptors, resulting in a chronic condition called geographic atrophy (GA). There are currently no approved GA therapies for the nearly 1 million individuals affected in the United States.

About NT-501

NT-501 is one of Neurotech's lead product candidates under development and consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). CNTF is a nerve growth factor capable of rescuing dying photoreceptors and protecting them from degeneration. NT-501 is designed to continually deliver a therapeutic dose of CNTF into the back of the eye in a controlled, continuous basis for up to twelve months, by means of the company's proprietary Encapsulated Cell Therapy (ECT) platform. Delivery via ECT bypasses the blood-retinal barrier and overcomes a major obstacle in the long-term treatment of retinal disease.

About Encapsulated Cell Therapy

Neurotech's core technology platform is Encapsulated Cell Therapy (ECT), a unique technology that allows for the long-term, sustained delivery of therapeutic factors to the back of the eye. ECT implants consist of human cells that have been genetically modified to produce a specific therapeutic protein and encapsulated in a semi-permeable hollow fiber membrane. The diffusive characteristics of the hollow fiber membrane are designed to promote long-term cell survival by allowing the influx of oxygen and nutrients while simultaneously preventing direct contact of the encapsulated cells with the cellular and molecular elements of the immune system. The cells continuously produce the therapeutic protein which diffuses out of the implant at the target site. ECT enables the controlled, continuous delivery of therapeutic factors directly to the retina, thereby bypassing the blood-retina barrier.

The ECT Implant

ECT implants consist of cells that have been genetically modified to produce a desired therapeutic factor that are encapsulated in a section of semi-permeable hollow fiber membrane. The implant has a suture loop at one end to anchor it to the sclera in the vitreo-retinal body inside the eye. The current product is 6 mm in length, roughly the size of a grain of rice.

ECT Device

ECT Placement

In contrast to gene therapy, ECT does not modify the host genome. The implant is surgically placed in the vitreous body of the eye as an out-patient procedure in about 15 to 20 minutes. The implant is sutured in a manner that allows for its retrieval when desired, providing an added level of safety as well as the ability to reverse or adjust therapy, if needed.


Placement in the eye

How it Delivers its Drug

The diffusive characteristics of the ECT hollow fiber membrane are designed to promote long-term cell survival by allowing the influx of oxygen and nutrients while simultaneously preventing direct contact of the encapsulated cells with the cellular and molecular elements of the immune system.

Delivery Action

ECT Applications

ECT-based products can be tailored to address the three main clinical manifestations of retinal diseases: degeneration of photoreceptors and/or ganglion cells in the neural retina, vascular proliferation and inflammation. A number of proteins have been discovered in the field of ophthalmology that possess powerful neurotrophic, anti-angiogenic and anti-inflammatory properties. These proteins have the potential to significantly slow, stabilize or halt disease processes in the eye. ECT represents a unique platform for the safe and effective delivery of many of these factors for the treatment of various chronic ophthalmic diseases as follows:

* Neurotrophic factors for the treatment of retinal degeneration in geographic atrophy (a serious condition associated with the atrophic (dry) form of age-related macular degeneration), retinitis pigmentosa, glaucoma and others.

* Anti-angiogenic factors for the treatment of the wet form of age-related macular degeneration, retinal vein occlusion, vascular proliferation in diabetic retinopathy and for the treatment of abnormal vascular permeability for various forms of macular edema.

* Anti-inflammatory factors for the treatment of ocular inflammations such as uveitis.

The graphic below shows the status of several of the company’s programs involving its encapsulated cell technology devices.

Neurotech Device Pipeline

About Neurotech Pharmaceuticals, Inc.

Neurotech is developing sight-saving therapeutics for the treatment of chronic retinal diseases. NT-501, one of the company's lead product candidates, is currently in late-stage clinical development for retinitis pigmentosa (RP) and advanced dry age-related macular degeneration (dry AMD). The company's portfolio of product candidates also includes treatments for wet AMD, including NT-503 that delivers a VEGF antagonist. All of Neurotech's development programs are based on the company's proprietary Encapsulated Cell Therapy (ECT). ECT uniquely enables the controlled, continuous delivery of biologics directly to the back of the eye, thereby overcoming a major obstacle in the treatment of retinal disease. To learn more, please visit our web site at www.neurotechusa.com.

A Golden Retriever Named Trevor and Retinitis Pigmentosa

2011-04-06T11:30:00.002-04:00

Trevor

Almost every day, I check on who is looking at my online Journal, where the referrals came from, and what articles are being read most frequently. (I can do this because I use Sitemeter as a visitor counter and for viewer statistics.)

Recently, I encountered a unique referral source, goldenretrevor/pra-research. This piqued my curiosity and I went to the site and took a look. It turns out that the site is run by the owner of a Golden Retriever, Trevor, and two sibling Labrador Retrievers. It seems that Trevor had been diagnosed with photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA). This was discovered when the dog was a puppy and the owner decided to look into this disease to see if there was anything that could be done to prevent him from going blind.

In doing extensive research, the owner, Katie McCormick, discovered that there was little research being done in the field of PRA in animals, but that PRA is genetically similar to retinitis pigmentosa (RP) in humans, as one study noted, "Identical mutation in a novel retinal gene causes progressive rod-cone degeneration (prcd) in dogs, and retinitis pigmentosa in man." And, there was lots of research being done on RP.

As she put it, “Because of this genetic connection, dogs are being used as proxies to study human retinal degeneration, and to test possible therapies. So that is the ultimate irony – whereas "no one cares about treating PRA" since the best way to eliminate it is through selective breeding, finding an effective treatment for retinitis pigmentosa is huge. And dogs are right in the middle of it.”

She continued, “My research about RP convinced me that even though PRA and RP are diseases of programmed cell death (also known as apoptosis), there were ways to delay the onset (update 8-19-09: see the conclusion in this article for a discussion of how photoreceptor cell death is different from classic apoptosis). But as always, the devil is in the details.”

“Should dog owners mimic what human RP patients do to delay onset? The answer turns out to be no, not necessarily. Contact me personally if you want more background on this.”

In her blog entry on PRA Research, Katie describes how she set up a “Google Alert” using the terms “progressive retinal atrophy” and “retinitis pigmentosa” – which is how she found my Journal article on The Use of Gene Therapy in Treating RP and Dry AMD.

In any event, I thought you might find this interesting. To read more about Trevor, his accomplishments, and how he is progressing with his PRA, take a look at Katie’s blogs about him by following these links: “Welcome to Trevor's Website! “, and “PRA Research”. Katie can be reached at Katie McCormick

Postscript:

Trevor had his annual eye exam at the end of November 2010, on the eve of his 4th birthday. Katie is happy to report that his eye vet said that his eyes still look perfectly normal

Katie and Trevor


A Blue Ribbon Winner

The Development of Femtosecond Lasers for Cataract Surgery

2011-03-27T20:50:00.000-04:00

Several years ago, in October 2008, I came across a writeup in Cataract & Refractive Surgery Today (CRST), about Technolas Perfect Vision announcing that the newly formed company would be using femtosecond laser technology to investigate laser-based treatments for presbyopia, including the use of intrastromal ablation (ISA). That statement piqued my interest, since I had been involved with the concept of ISA since my earliest involvement with ophthalmic lasers, beginning in the mid-1980s. I decided to write about my engagement with this technology and its history. That became “Intrastromal Ablation: A Technology Whose Time Has Come?”

In that article, I wrote about Automated Laser Systems; its successor, Phoenix Laser Systems; another company working on ISA at the time, Intelligent Surgical Lasers; and, finally, the followup of ISL’s work with picosecond lasers that became the laser development work done at the University of Michigan’s Ultrafast Laser Center, that spawned IntraLase, and its femtosecond (FS) laser.

That is where my history of the development of femtosecond lasers stopped – although I did mention the FS lasers being developed by Technolas Perfect Vision. Carl Zeiss Meditec, and Ziemer Ophthalmic Systems, and the then startup LenSx, begun by former Intralase founders. In addition, I also wrote about the work being done by Dr. Luis Ruiz, using the Technolas FS laser in treating presbyopia.

Then, this month, Stephen Daily, news editor for CRST, wrote about what happened to the FS laser companies in the several years after my story. His story, “The Origins of Laser Cataract Surgery: Three companies' pathways from development to commercialization” picks up where my story ended.

With the permission of Stephen and the publishers of CRST, I would like to reproduce his article, to bring the story of the development of femtosecond lasers up to date.

The Origins of Laser Cataract Surgery Three companies' pathways from development to commercialization.

Cataract & Refractive Surgery Today - March 2011

By Stephen Daily, News Editor

This year, the technology behind one of the most anticipated advances in years -- laser cataract surgery – begins its transition from testing laboratories to physicians' offices. The precision of femtosecond lasers in cataract surgery is expected to enhance outcomes in practically all areas of measurement, especially with premium IOLs, which depend on a well-centered capsulotomy. The three major players in the laser cataract surgery market are Alcon, Inc. (Hünenberg, Switzerland), which purchased LenSx Lasers, Inc.; LensAR, Inc. (Winter Park, FL); and OptiMedica Corp. (Santa Clara, CA). These companies plan to commercially launch their devices this year and will go down as the pioneers of the technology. The path each company took to make it to commercialization, however, was unique.

Intralase to LenSx

Similar to many other innovative devices in ophthalmology, femtosecond lasers were originally conceptualized and developed for use unrelated to their potential. The roots of laser cataract surgery can be traced to the work of Ron Kurtz, MD, and Tibor Juhasz, PhD, the founders of IntraLase Corp., who between 1995 and 1997 developed the IntraLase Femtosecond Laser at the University of Michigan in Ann Arbor. The new technology was built for corneal surgery. Knowing the potential to improve LASIK and corneal refractive procedures, Dr. Kurtz and Dr. Juhasz raised $1.4 million in seed money and then approached William Link, PhD, who previously founded American Medical Optics and Chiron Vision and was, at the time, a partner with Brentwood Venture Capital (Los Angeles, CA).

"When I decided to invest, I said to those guys, `I think to do this well, I need you to move to Southern California nearby where we can build a business together,'" Dr. Link said in an interview with Cataract & Refractive Surgery Today.

Dr. Kurtz and Dr. Juhasz made the move to Irvine, California, with the intention to build technology to improve LASIK and corneal refractive procedures, Dr. Link said. During the reduction-to-practice phase, they found in early 2000 that the intrastromal procedure did not work, (emphasis added by I.J. Arons) despite the investment of 5 years and $11.5 million. Dr. Link and the rest of the team decided to refocus their efforts on developing the best device for creating LASIK flaps and later for corneal transplants. They raised $95 million at the initial public offering. Dr. Link attributed the company's ultimate success to "a talented team, substantial capital, and ruthless focus."

In March 2007, IntraLase was acquired by Advanced Medical Optics, Inc., for $808 million in cash. Advanced Medical Optics was acquired by Abbott Laboratories in February 2009, and Abbott Medical Optics Inc. (AMO; Santa Ana, CA) became Abbott's eye care unit. The femtosecond laser developed by IntraLase and now owned by AMO is still trademarked under the name IntraLase.

Before IntraLase was sold to AMO, Dr. Kurtz left the company to pursue the use of femtosecond technology to improve cataract surgery. In 2008, he founded LenSx Lasers, Inc.

The venture capital backers of LenSx include Versant Ventures (Menlo Park, CA), SV Life Sciences (Boston, MA), Interwest Partners (Menlo Park, CA), and Venture Investors (Madison, WI). LenSx received FDA clearance for its laser to create anterior capsulotomies in August 2009, followed by clearance for the creation of corneal incisions in December 2009. In February 2010, Stephen G. Slade, MD, the medical director for LenSx, performed the first laser cataract surgery in the United States on 50 consecutive eyes.(1) Dr. Slade, chief medical editor of CRSToday, said that all of the patients he operated on saw 20/25 or better the first day after surgery, and all of the capsulotomies were perfectly centered and achieved a diametric accuracy of -0.25 mm. In July 2010, Alcon, Inc., announced its purchase of LenSx for a total deal consideration of $744 million, validating the value and interest of the new technology in the ophthalmic marketplace.

LensAR

The pathway to commercial viability for LensAR's femtosecond laser traces back to an original intention of presbyopic correction. Randy Frey was the founder and CEO of Autonomous Technologies Corp. (Orlando, FL), which later merged with Summit Technology (Waltham, MA) and was eventually acquired by Alcon. In 2004, he founded Lasersoft Vision, the predecessor of LensAR, and brought with him some of his partners from Autonomous. Throughout his career, Mr. Frey has been awarded dozens of patents in the area of excimer laser radar tracking, small-beam scanning, and wavefront-guided customized treatments. When he founded Lasersoft Vision, the idea was to research a laser in situ treatment for presbyopic correction, Monty Allen, chief financial officer of LensAR, told CRSToday.

Unlike LenSx, which had venture capital-backed money to help develop and test the technology from the beginning, when Lasersoft Vision started, it was angel funded. Mr. Frey lined up investors who knew of his skills, his capabilities, and his history in ophthalmology, Mr. Allen said. Even Mr. Frey himself was a significant investor in the early stages of the company.

In the course of studying laser techniques for presbyopia, medical advisors at Lasersoft Vision pointed out that the procedure would be ideal for ease of removal of lenticular material as a function of a cataract procedure, especially the lenses that surgeons have the most difficulty breaking up and removing such as higher-grade cataracts.

"In some of the work done in both porcine and human cadaver eyes initially, it was noticed how easily the lens extracted after these treatments, when you needed to extract the lens, for example, to run tests on it," Mr. Allen said. "Some of our physician consultants just simply said we should use this for cataracts. It would make extraction of the lenticular material so much easier, so much faster, and so much less traumatic in terms of the negative side effects from the pounding of the ultrasound energy that causes waves of energy to ripple through the globe. [Potentially] a major cause of anterior segment trauma and endothelial cell loss."

In 2007, after system software upgrades and successful animal trials, Mr. Frey turned his attention to cataract surgery. The company changed its name to LensAR and acquired venture capital. The new focus was to design and develop a highly integrated measurement technology within a three-dimensional scanning laser system. The result was the LensAR Laser System. The primary venture capital partner is Aisling Capital (New York, NY), which was also previously involved as an investment banker for Autonomous Technologies.

The focus on cataracts allowed LensAR to move toward 510(k) clearance, a shorter approval pathway than the full premarket approval the company seeks for its presbyopic indication. An analysis of clinical results with the LensAR Laser System showed a trend toward faster and better anterior capsulotomies with respect to centration and regularity. Also shown were speedy visual recovery, a much reduced use of ultrasound in high-grade cataracts, and the elimination of ultrasound in the lowest-grade nuclei during cataract surgery using laser lens fragmentation versus traditional techniques.(2) In May 2010, the company received FDA 510(k) clearance for use of the LensAR Laser System to create the anterior capsulotomy during cataract surgery. Clearance for laser fragmentation (chop and cylinder patterns) is under active review at the FDA. Other indications are being pursued as well, and the company expects to commercially launch the product in the second half of 2011. (See addendum for further update.)

OptiMedica

The development of femtosecond laser technology at OptiMedica occurred more behind the scenes.

The company was founded in 2004 by five entrepreneurs, including Mark Blumenkranz, MD, chair of ophthalmology at Stanford University. The other founders were George Marcellino, PhD, David Mordaunt, Dan Andersen, and Mike Wiltberger.

Mark Forchette, who has been the president and CEO of OptiMedica since 2007, said there were three areas of focus when the company began-retina, glaucoma, and in the background, in a really "stealthy way," laser cataract surgery.

"We kept it very quiet. Even in the original funding presentation, femtosecond laser cataract surgery was part of it," said Mr. Forchette, who spent 23 years at Alcon before moving to OptiMedica.

Mr. Forchette said the initial investors in the company saw the potential of a precisely controlled capsulotomy and the synergistic effect with the lens that could be there. Those investors include Kleiner Perkins Caufield & Byers (Menlo Park, CA), Alloy Ventures (Palo Alto, CA), DAG Ventures (Palo Alto, CA), and Blackrock Private Equity Partners (Plainsboro, NJ).

The prized possession of OptiMedica up until 2010 was the Pascal Photocoagulator-pattern-scanning laser technology used for retinal surgery. More than a million patients were treated with the Pascal system, according to OptiMedica, and more than 600 systems were sold in 40 markets all over the world.

In August 2010, OptiMedica sold its glaucoma and retina assets, including its proprietary Pascal photocoagulation system, to Topcon Corp. (Tokyo, Japan). The deal allowed OptiMedica to focus exclusively on the continued development and commercialization of its Catalys Precision Laser System. The sale also provided OptiMedica with significant funding for the global market launch of its laser cataract surgery system in 2011.

"The whole time, from the founding of the company until the acquisition last year, we were working on [laser] cataract surgery in the background quietly," Mr. Forchette said. "There's a lot of intellectual property that we filed early that was very forward-thinking, and it was all about image-guidance of femtosecond laser for cataract, capsulotomy, fragmentation, softening, corneal incisions, astigmatic correction, and so those things we've been thinking about since day 1."

Mr. Forchette said the company immediately involved physicians to collaborate with scientists and engineers in the research and development process at OptiMedica. For example, William W. Culbertson, MD, the chair of OptiMedica's Medical Advisory Board, was involved right from the beginning.

The Catalys Precision Laser System combines a femtosecond laser, integrated optical coherence tomography imaging, and OptiMedica's pattern-scanning technology. The platform helped surgeons achieve greater precision during several critical steps of cataract surgery when compared with manual techniques, according to a study published in Science Translational Medicine.(3) The system is not yet approved for sale in the United States, but Mr. Forchette expects it to launch worldwide this year like its competitors.

Technolas Perfect Vision

A fourth company, Technolas Perfect Vision GmbH (Munich, Germany), recently announced its plans to enter the laser cataract surgery market. At the 2010 European Society of Cataract and Refractive Surgeons meeting in Paris, Technolas introduced a customized lens module for cataract surgery. The company's laser, not yet available in the United States, is also able to perform refractive, intrastromal, and therapeutic procedures. (Again, for an update, see the addendum.)

Mr. Allen may be reached at (407) 641-4889; monty.allen@lensar.com

Mr. Forchette may be reached at (408) 850-7488; mforchette@optimedica.com.

Dr. Link may be reached at (949) 729-4500; bill@versantventures.com.

   1. Slade SG.First 50 accommodating IOLs with an image-guided femtosecond laser in cataract surgery.Paper presented at:Refractive Surgery Subspecialty Day,American Academy of Ophthalmology Annual Meeting;October 15,2010; Chicago,IL.
   2. Edwards KH,Frey RW,Naranjo-Tackman R,et al.Clinical outcomes following laser cataract surgery.Invest Ophthalmol Vis Sci.2010;51:5394.
    3. Palanker D,Blumenkranz M,Andersen D,et al.Femtosecond laser-assisted cataract surgery with integrated optical coherence tomography.Sci Transl Med.2010;2(58):58ra85.

Addendum:

Since the above article was written and published, several additional events have occurred:

LensAR

On March 22nd, LensAR, Inc., a developer of next-generation laser technology for refractive cataract surgery, announced that it had received 510(k) clearance from the FDA for use of the LensAR Laser System for anterior capsulotomy and lens fragmentation during cataract surgery.

“Receiving the additional FDA indication for lens fragmentation is a significant milestone achievement in getting our technology one step closer to commercialization. We are very pleased with the exceptional fragmentation data that was submitted to obtain the indication and the resulting FDA clearance,” said Randy Frey, founder and Chief Executive Officer of LensAR.

B&L and Technolas Perfect Vision

On March 25, 2011, Bausch & Lomb and Technolas Perfect Vision announced an agreement in principle to distribute the first femtosecond laser capable of performing both cataract and refractive surgery on a single platform

"Femtosecond laser technology for cataract procedures promises to be one of the most significant clinical advances in cataract surgery in 40 years," said Robert E. Grant, chief executive officer and president of Bausch & Lomb Surgical. "The TPV femtosecond laser platform, which uniquely supports refractive and cataract procedures, is a natural complement to our portfolio of cataract products. This is the first of many new technologies we are pursuing focused on enhancing a physician's ability to improve patient outcomes."

Commercialization is expected to begin in the second half of 2011. TPV previously announced that they had filed for 510(k) clearance in the United States.

Richard Lindstrom @ ASCRS

On March 26th, Richard L. Lindstrom, MD, spoke at Glaucoma Day preceding the American Society of Cataract and Refractive Surgery meeting in the Cataract/Cornea Crossover Topic. He said femtosecond laser platforms are clinically well-established for LASIK flap creation on five platforms.

"Advances will come in both the imaging and diagnostics technology that would allow us to have applications to other fields, and I firmly believe glaucoma will be one of those," he said. "We will have to sort out, certainly, and understand better the demand and the business model, but I firmly believe that the 78 million baby boomers will probably find this very, very attractive. And the early surgeons who have adopted this technology are not finding much difficulty generating significant interest from their patients as to this alternative, if you will, to manual surgery. So lots more to learn."

For laser refractive cataract surgery, four companies are developing platforms: Alcon LenSx, LensAR, OptiMedica and Technolas Perfect Vision. In addition, three companies, Abbott Medical Optics, Schwind and Carl Zeiss Meditec, are in undisclosed stages of development. The technology offers excellent precision, smaller incisions and enhanced IOL performance, Dr. Lindstrom said. It creates a safer, more predictable and reproducible procedure.

Editor’s Note:

In addition to the history of intrastromal ablation and the introduction of femtosecond lasers article mentioned in the Preface, I have posted four other articles dealing with femtosecond lasers: one describing the FLEx (Femtosecond Lenticle Extraction) method of correcting corneal error, using the Carl Zeiss Meditec VisuMax femtosecond laser (Another Approach to Intrastromal Ablation); two articles about using the femtosecond laser for cataract removal (Femtosecond Lasers Proposed for Use in Cataract Surgery and, Femtosecond Laser Cataract Removal: The Second Revolution? And, What is Laser Photolysis? – the latter describing the possibility of using FS lasers to bleach a cataractous lens to postpone the need for cataract surgery); and, finally, A Comparison of Commercially Available Femtosecond Lasers in Refractive Surgery – which compares the IntraLase IFS (Abbot), Femtec (Technolas), VisuMax (Carl Zeiss Meditec), LDV (Ziemer) and UltraFlap FS 200 (WaveLight/Alcon) systems.

Menu 18: Updates for October 2010 – March 2011

2011-03-22T13:12:00.000-04:00

I have been negligent in updating the menus for my online Journal. So, here is the update for the past six months.

This update contains a number of new writeups, including the first use of gene therapy in treating retinitis pigmentosa; an overview of what happened at the Second Ophthalmic Innovation Symposium (held last year just prior to the AAO Meeting), a couple of interviews conducted by my colleague in China during lat year’s APAO Meeting in Beijing, and an excellent writeup about how femtosecond lasers are being used in ophthalmology.

I have also included several updates on subjects I have been closely following, including the controversy between the use of Avastin or Lucentis in treating AMD; an AMD update; a CATT Study update; five updates on the use of stem cells in ophthalmology; and updates on the latest news from Iluvien and NeoVista.

Here are synopses and links for the recent postings:

Avastin/Lucentis Updates:
Avastin/Lucentis Update 42: One-Year Results of Controlled Comparison Study Published (Oct. 4, 2010)

Last October (2009), I came across the six-month results of one of the first blinded, double-masked comparison studies run between Avastin and Lucentis, sort of a mini-CATT Study. This study was done by researchers at the Boston University School of Medicine in cooperation with the VA Boston, and was published in the American Journal of Ophthalmology. I published their news release describing the study and the six-month results as Avastin/Lucentis Update 29.

This weekend, the same group announced the one-year results of this study, this time published in Eye, a peer-reviewed publication of The Royal College of Ophthalmologists in the UK.

Avastin/Lucentis Update 43: Secret Rebates Offered for Lucentis (Nov. 4, 2010)

First, Genentech refused to provide Lucentis for the CATT Study, being run by NEI/NIH to compare Avastin to Lucentis for AMD (Avastin/Lucentis Update 12); then they threatened to stop supplying Avastin to compounding pharmacies so that ophthalmologists could continue to obtain the drug for their patients (Avastin/Lucentis Update 18); then they decided to provide Lucentis free of charge for the study looking at the use of panretinal laser treatment plus anti-VEGF (Lucentis) in the treatment of diabetic macular edema – at the exclusion of Avastin, in that “pay to play” study (Avastin/ Lucentis Update 37); and now, the company is offering secret rebates to selected large users of Lucentis – obviously to blunt the potential expected to be offered by Avastin when the CATT Study results are released next Spring.

Here, as written by Andrew Pollack online yesterday and published in today’s NYTimes, is the latest story in the ongoing Avastin vs. Lucentis Controversy:

Avastin/Lucentis Update 44: United Kingdom Closer to Allowing Avastin for AMD (Dec. 8, 2010)

While the U.S. comes closer to showing the equivalency of Avastin to Lucentis for treating the wet form of age-related macular degeneration, when the CATT (Comparisons of Age-Related Macular Degeneration Treatments Trials) Study results become public, hopefully, some time this Spring, the UK’s health services are still fighting over whether or not they should study the two drugs to determine if Avastin would be appropriate for the Brits to use in their National Health Service.

Avastin/Lucentis Update 45: Avastin Drug Treatment for ROP Better than Laser (Feb. 26, 2011)

A new study, published earlier this month in the New England Journal of Medicine, describes the use of intravitreal Avastin to treat Retinopathy of Prematurity (ROP) in premature infants.

This study was widely covered by the press, but I would like to reproduce just a few of the presentations to provide you with the information necessary to best understand the results of this study.

AMD Update:

AMD Update 13: Retinal Procedures on the Rise (Oct. 13, 2010)

A new study, just published in the October issue of Archives of Ophthalmology and reported by Ophthalmology Web, MedPage Today, and Medscape Medical News, shows that among those in the Medicare population (age 65 plus), treatments for retinal conditions nearly doubled between 1997 and 2007 – and this trend is expected to continue with the aging of the population and seniors living longer.

CATT Study Update:
CATT Study Update 12: Status of WorldWide Studies (Jan. 6, 2011)

With the anticipated arrival of the one-year results of the CATT Study this Spring, I thought it would be appropriate to update where the other worldwide studies stand.

During the Retina Subspecialty Day sessions, held prior to the recent 2010 AAO Meeting in Chicago, Daniel Martin, MD provided an update on the various comparative studies underway around the world between Avastin and Lucentis. Here are Dr. Martin’s comments, as reported by the Market Scope team in the November issue of Ophthalmic Market Perspectives.

Stem Cells in Ophthalmology Updates:
Stem Cells in Ophthalmology Update 2: ACT Gets Go-Ahead to Treat Stargardt’s (Nov. 23, 2010)

As I noted in my September report on the Use of Stem Cells in Ophthalmology, it was anticipated that either the program at The London Project to Cure Blindness or Advanced Cell Technology’s program to treat Stargardt’s disease would be the first to get the go-ahead to begin approved human trials. I have not heard any news out of London, but earlier this week ACT received notification from the FDA that it was cleared to begin its human trials with human embryonic stem cells.

Stem Cells in Ophthalmology Update 3: ACT Files IND to Treat Dry AMD (Nov. 30, 2010)

Furthering its lead in stem cell research in ophthalmology, Advanced Cell Technology Inc., announced today that it had filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration, to initiate a Phase I/II multicenter study for the treatment of dry Age-Related Macular Degeneration (dry AMD) using human embryonic stem cell (hESC) derived retinal pigment epithelial (RPE) cells.

Stem Cells in Ophthalmology Update 4: ACT Receives Receives FDA Approval to Use hESCs to Treat Dry AMD (Jan. 3, 2011)

Advanced Cell Technology Inc., announced today that it had received approval from the FDA to commence its clinical trial using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) to treat the dry form of age-related macular degeneration. ACT is now permitted to initiate a Phase I/II multicenter clinical trial to treat patients with dry AMD, the most common form of macular degeneration in the world. There are currently no approved treatments available for this prevalent disease of an aging global population. Dry AMD, representing a substantial global market opportunity and afflicts between 10-15 million Americans, and a further 10 million Europeans.

Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells (Mar. 5, 2011)

As the senior editor, John Gever, of MedPage Today reported, following the publication of three studies about induced pluripotent stem cells in the March 3rd, issue of Nature, “The road to regenerative medicine based on induced pluripotent stem cells (iPSCs) may have developed a giant pothole, with new studies showing that the cells are prone to several types of genetic defects.”

The three studies showed that the reprogramming process and subsequent culture of pluripotent stem cells in vitro can induce genetic and epigenetic abnormalities in these cells. The authors of the studies and the editorialist said that the results raise concerns over the implications of such aberrations for future applications of pluripotent stem cells.

Stem Cells in Ophthalmology Update 6: Stemedica Paper Accepted for Presentation at ARVO (Mar. 19, 2011)

I recently received an update from my contact at Stemedica and would like to share the information with you.

A safety study on the use of stem cells in the eye, in a clinical study underway at the Fyodorov Federal Institution of Eye Microsurgery in Moscow, to treat diabetic retinopathy and diabetic optical neuropathy with stem cells derived from bone marrow, has been accepted for presentation as a poster at the upcoming ARVO Annual Meeting in Fort Lauderdale at the beginning of May. An abstract is shown below.

Iluvien Update:

Iluvien Update: FDA Marketing Approval Delayed (Jan. 5, 2011)

Last July, I wrote a comprehensive report about Iluvien and the status and promise of other sustained release drug delivery systems (Iluvien and the Future of Ophthalmic Drug Delivery Systems). At that time, Alimera Sciences, the company developing Iluvien (under license from pSivida) had filed a new drug application (NDA) to treat diabetic macula edema (DME). The company obtained priority review status for the NDA at the end of August, raising the expectation that an approvable letter might be obtained by the end of 2010.

However, instead of an approvable letter, Alimera Sciences received a “complete response letter” (CRL) from the FDA, communicating to the company that its NDA application “cannot be approved in its present form”.

NeoVista Update:

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 4 (Jan. 20, 2011)

NeoVista just released an update, discussing the first commercial utilization of its Epimacular Brachytherapy device in Germany. The Epi-Rad device, now renamed as the VIDION ANV (Anti Neo Vascular Therapy System) has been commercialized in Europe since November 2009. The first patients treated were in Pisa, Italy, quickly followed by patients treated in London, UK, also in November of 2009, and now in Hamburg, Germany this month.

And, here are the new writeups:
The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD by Retrosense (Nov. 6, 2010)

A short while ago, I received a message from someone I did not know, who said that he enjoyed the writeups on my online Journal and was wondering if I might be interested in writing about the use of gene therapy as an approach to vision restoration. Since I knew absolutely nothing about gene therapy, the writer got my attention.

After several discussions with Sean Ainsworth, the founder of RetroSense, and much online research, I think I have learned a little about what gene therapy is about, and its application in ophthalmology, especially in the possible restoration of vision in those who suffer from retinitis pigmentosa (RP). Thanks to Sean for whetting my appetite -- here is what I have learned.

The Second Ophthalmic Innovation Summit (Dec. 10, 2010)

Last October, the Second Ophthalmic Innovation Summit (OIS) was held just prior to the 2010 AAO Meeting in Chicago. As was the case last year, my old friend, Larry Haimovitch,an ophthalmic industry veteran, who attended the meeting and wrote about it for the sponsor’s website, Healthcare Syndicate has given me permission to reproduce his writeup in this space.

An Interview with Dr Ronald Krueger (Feb. 17, 2011)

With the permission of Lei Zang, the Managing Editor of Ophthalmology World Report, here is her interview with noted refractive surgeon Dr. Ronald Krueger of the Cleveland Clinic. As noted below, Dr. Krueger was recently in China to perform a corneal transplant on a Mongolian patient and while there, attended the APAO Meeting held last fall in Beijing, where Ms. Zang had the opportunity to interview him.

An Interview with Professor John Marshall (Feb. 17, 2011)

During the APAO (Asia Pacific Academy of Ophthalmology) Meeting held in Beijing in September, 2010, Lei Zang, the Managing Editor of Ophthalmology World Report, interviewed Professor John Marshall of St. Thomas Hospital in London and the principal behind the Ellex 2RT (retinal regeneration) program for Ellex Laser, and also an investigator (and inventor?) of the Avedro microwave corneal crosslinking program.

In this interview, Prof. Marshall discussed both his work on 2RT and on microwave crosslinking as well as several other topics that will be of interest to ophthalmic researchers.

A Comparison of Commercially Available Femtosecond Lasers for Refractive Surgery (Mar. 17, 2011)

Over the past several years, I have either written or posted other peoples accounts of the use of femtosecond lasers in ophthalmology. Starting with the history of their development in October 2008 (Intrastromal Ablation: A Technology Whose Time Has Come?); an article on the use of the femtosecond laser to treat presbyopia by Dr. Rupal Shah in June 2009 (Another Approach to Intrastromal Ablation); a writeup on the use of femtosecond lasers for performing cataract surgery by Larry Haimovitch, again in June 2009 (Femtosecond Lasers Proposed for Use in Cataract Surgery); and finally, Dr. Joseph Colin’s writeup about femtosecond laser cataract removal as a second revolution, and my addition about the possibility of using the femtosecond laser to “bleach” the natural lens to delay the onset of needing to remove catatacts, inAugust 2010 (Femtosecond Laser Cataract Removal: The Second Revolution? And, What is Laser Photolysis?).

Earlier this month, I came across an article written by Drs. Ronald Krueger and Glauco Reggiani-Mello, of the Cleveland Clinic, that does an excellent job of summarizing the latest developments in the use of femtosecond lasers in refractive surgery and other applications in ophthalmology. Since the article was written in a professional journal – Expert Review of Ophthalmology, with limited access, I asked the authors for permission to reproduce a significant part of their writeup, along with a link to the original for those that wish to read it in its entirety. Permission was granted, and here is my version of what was presented, along with most of their illustrations and their two tables.

Stem Cells in Ophthalmology Update 6: Stemedica Paper Accepted for Presentation at ARVO

2011-03-19T10:43:00.000-04:00

I recently received an update from my contact at Stemedica and would like to share the information with you.

A safety study on the use of stem cells in the eye, in a clinical study underway at the Fyodorov Federal Institution of Eye Microsurgery in Moscow, to treat diabetic retinopathy and diabetic optical neuropathy with stem cells derived from bone marrow, has been accepted for presentation as a poster at the upcoming ARVO Annual Meeting in Fort Lauderdale at the beginning of May. An abstract is shown below.

In addition, my contact told me that Stemedica has registered in Clinical Trials, to conduct a Phase I/II multicenter trial under the auspices of UC San Diego, using bone marrow derived stem cells on patients with post ischemic strokes. The next step for the company will be to get a “green light” from the FDA to treat patients in the U.S., using the same type of cells on patients with retinal disorders. Those trials will include studies both with and without the use of a laser, as explained in my report on the company in the Primer on the Use of Stem Cells in Ophthalmology.

Phase I Study: Injection of Allogeneic Bone Marrow Derived Mesenchymal Stem Cells in Patients with Diabetic Retinopathy and Diabetic Optical Neuropathy

Author Block: Natalia Gavrilova (1), Khristo Takhchidi (1), Irina Saburina (2), Nikolai Mironov (3), Marina Polyakova (1), Alexei Lukashev (4), Paul Tornambe (5).

(1) Ophthalmology, Fyodorov Federal Institution 'Eye Microsurgery', Moscow, Russian Federation; (2) Institute of General Pathology, Moscow, Russian Federation;
(3) Moscow Neurology Hospital, Moscow, Russian Federation;
(4) Stemedica Cell Technologies, San Diego, CA;
(5) Retina Consultants, San Diego, CA.

Abstract:

Purpose: Diabetic retinopathy (DP) and diabetic optical neuropathy (DON) are common complications of diabetes which are caused by abnormal development of retinal microvasculature. Initial case studies have been performed on human patients to assess the safety and efficacy of this type of cell therapy.

Methods: Six patients (4 female, 2 male, age 42-62) with early stages of diabetic retinopathy and diabetic optical neuropathy were injected intravenously with a single dose of 100M allogeneic bone marrow derived mesenchymal stem cells (BM MSC). The cells were manufactured under the guidelines of current good manufacturing practice (cGMP). All patients were examined prior to the injection and post injection on day 1, 14, 30, 2 month, 3 month, 6 month, one, two and three years. General examination included blood and urine panel, blood coagulation test and measurements of brain derived neurotrophic factor (BDNF) in blood plasma and tear fluid. Ophthalmic examination included visual acuity and ophtalmoscopic exam, perimetry test, optical coherent tomography(OCT), eletroretinography(ERG), electrooculography(EOG), Doppler ultrasound exam, optic disk color analysis.

Results: No adverse effects were observed or reported by all patients. During the whole period of follow up there were no changes in cardiovascular system, liver and kidney functionality. No infection growth, interstitial pneumonia or cancer was found in all patients. The positive changes in hemostatic dysfunctions and well as improvements in hemodynamic at systemic level were observed as early as two weeks after injection. Fovea sensitivity; functional activity of optic nerve, pigmented epithelium layer, outer and inner nuclear layers; BDNF content in blood plasma and tear fluids as well as optic disc inflammation were gradually improved during the first six months post injection and became stable during the whole period of follow up.

Conclusions: The results show safety of intravenous injection of BM MSC on patients with diabetic retinopathy and diabetic optical neuropathy. Positive changes of ophthalmic parameters should be further investigated in full scale clinical trails.

A Comparison of Commercially Available Femtosecond Lasers in Refractive Surgery

2011-03-17T17:32:00.001-04:00

Over the past several years, I have either written or posted other peoples accounts of the use of femtosecond lasers in ophthalmology. Starting with the history of their development in October 2008 (Intrastromal Ablation: A Technology Whose Time Has Come?); an article on the use of the femtosecond laser to treat presbyopia by Dr. Rupal Shah in June 2009 (Another Approach to Intrastromal Ablation); a writeup on the use of femtosecond lasers for performing cataract surgery by Larry Haimovitch, again in June 2009 (Femtosecond Lasers Proposed for Use in Cataract Surgery); and finally, Dr. Joseph Colin’s writeup about femtosecond laser cataract removal as a second revolution, and my addition about the possibility of using the femtosecond laser to “bleach” the natural lens to delay the onset of needing to remove catatacts, inAugust 2010 (Femtosecond Laser Cataract Removal: The Second Revolution? And, What is Laser Photolysis?).

Earlier this month, I came across an article written by Drs. Ronald Krueger and Glauco Reggiani-Mello, that does an excellent job of summarizing the latest developments in the use of femtosecond lasers in refractive surgery and other applications in ophthalmology. Since the article was written in a professional journal – Expert Review of Ophthalmology, I asked the authors for permission to reproduce a significant part of their writeup, along with a link to the original for those that wish to read it in its entirety. Permission was granted, and here is my version of what was presented, along with most of their illustrations and their two tables.

Comparison of Commercially Available Femtosecond Lasers in Refractive Surgery
Glauco Reggiani-Mello and Ronald R Krueger

Cole Eye Institute - Cleveland Clinic Foundation, 668 Euclid Avenue, Unit 506, Cleveland, OH 44114, USA

Published in: Expert Review of Ophthalmology
Posted online: 03/01/2011

Abstract:

Refractive surgery is a procedure that requires excellence. Nothing less than the best is acceptable for an elective procedure that must be precise, accurate and safe. Femtosecond lasers were developed to help fulfill these requirements and have changed the field. The capabilities of the technology include not only the creation of corneal flaps for laser-assisted in situ keratomileusis, but limitless corneal- and lens-based incisions, as well as glaucoma and retinal applications that can break old paradigms. Manipulating biomechanics to correct presbyopia with the IntraCor procedure, the 'femtosecond-only' femtosecond lenticule extraction or SmILE procedures, intrastromal astigmatic incisions and cataract surgery are among the next exciting applications to this technology. New fields in refractive surgery can be opened and others can be expanded, as in refractive lens exchange, where its indications may be greatly increased, considering the new safety and precision standards that the technology can deliver. The expectations are huge and future studies will show how far we can go with the technology.

Introduction:

Femtosecond lasers have changed refractive surgery in the last 9 years since the market release of the Intralase Femtosecond Laser (Abbott Medical Optics, IL, USA) in 2001. The bladeless flap creation rapidly gained popularity because of its promised increased safety, fast recovery and excellent results.[1] Nowadays, the majority of high-volume refractive surgery centers in the world uses a femtosecond laser to create the flap.

Technical Parameters

All commercially available devices use a near infrared femtosecond laser with a wavelength of approximately 1053 nm. Despite the fact that the neodymium-doped yttrium aluminum garnet and femtosecond lasers have very similar wavelengths (Table 1), the ultrashort duration of the pulses (10-9 vs 10-15) in the latter causes significantly less damage in the collateral tissue.[2] Varying the duration of the laser pulses and energy applied can generate different effects on the tissue (Figure 1). The main technical specifications that play a role in the femtosecond laser are the following:

    * Laser pulse repetition rate;
    * Spot size;
    * Pulse energy;
    * Pulse pattern.

Figure 1. Effects of the relationship between laser interaction time and energy intensity.

There is an inverse relationship between the laser pulse duration and the energy required in each pulse to generate the optical breakdown.[3] A shorter pulse (200-500 fs) needs lower energy to achieve the threshold of photodisruption than a longer pulse (500-1300 fs). The numerical aperture (NA) of the lens influences the laser spot in terms of diameter and volume. A higher NA focuses the beam with less dispersion and is the reason why higher NA devices use lower energy. It is also suggested that a higher NA increases the depth accuracy and overall precision of the lamellar cut.

After the optical breakdown occurs, plasma is created and a cavitation bubble formed. This bubble expands and cleaves the tissue. If a high-energy photodisruption is used, the bubble is larger and the pulses do not need to be placed close together. Low-energy systems create a very small bubble, with a greater number of pulses in an overlapping pattern being mandatory, since there is almost no tissue cleaving induced by the bubbles.

The first devices operated with a low KHz repetition rate (15 KHz - first Intralase model) and needed a higher energy to photodissection. Newer devices (even the newer high-energy devices such as IntraLase 150 KHz) intend to increase the repetition rate, which makes the procedure duration shorter and uses lower energy with an intention of diminishing the inflammation. In addition, the spot size and separation can be lowered in higher repetition rates to produce smoother surface cuts without increasing the time of the procedure.

In summary, the ideal device would include a high repetition rate, small spot size and low energy per pulse.

The geometry of the cuts performed is theoretically limitless. Vertical, horizontal and every imaginable geometrical pattern can be applied. However, limitations in cutting placement vary among devices, with newer ones tending to offer a more customizable cutting. To perform precise incisions in cataract surgery, an imaging system (optical coherence tomography and 3D-confocal-structured imaging technology are under research) is required, since the position of intraocular structures change and must be accurately localized after docking.

Two main pulse patterns are used in commercially available corneal cutting devices: raster and spiral. The first involves pulses that are applied in a linear pattern, starting at the hinge area, passing through the center of the cornea and finally extending to the opposite edge. The spiral pattern is applied when the laser pulses begin centrally and expand centrifugally out to the periphery (centripetally can also be used). Most devices use the raster pattern, which was found to produce a smoother stromal bed in the Intralase machine. Visumax (Carl Zeiss Meditec AG, Jena, Germany) uses the spiral pattern.[4]

Furthermore, the method for fixating the eye, including the suction ring and docking system, varies among the devices. The amount of induced pressure is higher in devices that applanate the cornea, such as the Abbott Medical Optics IntraLase, WaveLight Ultraflap and LDV (Ziemer Ophthalmic Systems, Port, Switzerland), and lower in devices with a curved applanation docking interface, as found in the Visumax and Perfect Vision Femtec 20/10 lasers (Technolas Perfect Vision, Heidelberg, Germany).

Commercially Available Devices

Following the introduction of this new field by IntraLase, three additional systems have become commercially available in the last few years: Femtec, Visumax and LDV. The newest device to be released is the UltraFlap FS 200 from Alcon (Figure 2).

Figure 2. Commercially available femtosecond lasers for refractive surgery.

The success achieved by IntraLase inspired the other companies to research different approaches and applications of the promising femtosecond technology. New refinements are being systematically released with improvements in pulse rate, spot size, pulse energy and customized approaches for the use of the laser.

This competition has compelled the further development of this technology. The Femtec laser works with a similar pulse rate and energy as the IntraLase, but uses a curved applanation docking system, which promises less intraocular pressure (IOP) increase in a more physiologic interface between the eye and the laser. In addition, a new procedure for presbyopia called IntraCor[5] is being studied with this platform.

Visumax has a curved docking system, such as the Technolas laser, but uses a limbal suction mechanism compared with the standard conjunctival suction (Figure 3). The company has recently upgraded its laser to a 500-KHz pulse rate to be used together with a lower pulse energy profile, in the submicrojoule range. Furthermore, the company is investigating femtosecond-only refractive surgical procedures, femtosecond lenticular extraction (FLEx) and small-incision lenticular extraction (SmILE) in which a lenticule of stromal tissue is cut with the laser and pulled out manually. The first results are promising.[6,7]

Figure 3. Visumax and Femtec curved docking systems. (A) Visumax and (B) Femtec curved docking systems. Note the limbal suction in the Visumax device.

The LDV from Ziemer is a smaller, portable device with some uniquely different characteristics. It operates at a very high pulse rate (in the MHz range) with very low pulse energy (in the nanojoules range), which, according to the manufacturer, produces a smoother bed with considerably less bubble formation (Figure 4). However, there are no vertical side cuts with this system, so the flap-making approach is similar to a microkeratome with a tapered flap edge. Other limitations of this system are that the procedure is not directly visible during the application of pulses, and there is a need for an interface fluid (viscoelastic substance). Since there is no vertical cut when using this device, the nonapplanated periphery establishes a tapered edge to the horizontally cut flap, which can be irregular if air is present.

Figure 4. Different cutting profiles between high-energy and lower energy devices.

The new WaveLight FS200 UltraFlap laser from Alcon is newly available for evaluation, and its technical specifications show similarities to the IntraLase system. Initial studies show similar IOP rise pattern compared with IntraLase, with a flat applanation docking system.[8] Less opaque bubble layer (OBL) formation is expected owing to a new laser profile that creates specific cutting geometries (externalized channels) in the cornea to allow the gas bubbles to diffuse out of the relevant regions of the cornea. This can allow an immediate excimer ablation after femtosecond flap creation in the majority of cases.

IntraLase has also progressively refined its system, releasing new updates on a regular basis, being now in the fifth generation. There have been changes in the laser pulse rate (from 15-30 to 60-150 KHz), allowing faster procedures, an increase in side cut angle (>90°, allowing inverted bevel-in edge), increased geometry of cuts (allowing intrastromal corneal ring placement and shaped corneal transplants) and additional small changes in laser parameters.[101] Despite these changes, the same successful core structure of the device was maintained and its main characteristics were never lost.

Advantages of Using a Femtosecond Laser for Flap Creation

The growing success of flap creation with a femtosecond laser over that of a microkeratome is due to several distinct advantages. The literature shows a better contrast sensitivity,[1] increased safety,[8] faster uncorrected visual acuity recovery,[9] less induced aberrations[10,11] and less IOP variation[12] in the femtosecond-created flaps.

Dry eye is the most common side effect of laser-assisted in situ keratomileusis (LASIK), with up to 90% of patients having some sign or symptom.[13-15] Femtosecond laser flaps have a lower incidence of dry eyes.[16] This is probably owing to the thinner, more uniform flap geometry[15,16] (with greater predictability and lower standard deviation) in the femtosecond laser-treated eyes compared with the microkeratome.

In addition to the technical advantages, the perceived safety and accuracy of a laser is preferred by patients, who may fear the use of a bladed device.

Table 2 shows the technical features of femtosecond lasers useful for creating flaps during LASIK.

Complications

Aside from the technical benefits that came along with femtosecond lasers, there were new side effects that arose with the technology that are now better understood.

The formation of a bubble layer occurs along the cutting plane, which in some cases leads to an escape of some bubbles into deeper stroma with the formation of an OBL. These deeper bubbles may take a few hours to disappear, and if severe, may impair the aim of the eye tracker during surgery. This is less common with a softer docking (applanation) pressure, lower energy and faster repetition rate devices.[17] Gentle scraping of the surface with a spatula may lessen the density of the OBL prior to laser treatment.

Interface haze is also a possible complication, with an increased risk when making very thin flaps (<100 μm)

Transient light-sensitivity syndrome is characterized by photophobia and mild pain that can appear days after surgery and can persist for weeks.[18] Rainbow glare is an optical effect due to light scattering from the perfect array of laser spots remaining on the back surface of the flap. It can create a spectral pattern whose visual impact is clinically inconsequential in the majority of patients. Both of these situations are predominately related to earlier, femtosecond laser devices with higher raster energy and lower numerical aperture optics.[19,20]

Expert Commentary

Different Concepts to Approach the Same Technology

The main commercially available femtosecond devices have different concepts and applications on how the technology should be used. The IntraLase was the first device and set the standards regarding energy delivered and geometry of cuts. The IntraLase had the strategic advantage of being the first, and achieved a significant market penetration, so that it is number one in the marketshare.

The LDV from Ziemer has implemented a different concept. It is a device entirely focused on flap creation (even though intrastromal ring channels and lamellar keratoplasty can be performed), with the lowest pulse energy, fastest pulse rate and negligible, if any, OBL formation. The device is portable and can be used by different lasers centers, optimizing cost. However, the vertical cut is not available and changes in the geometry of the intrastromal cut are very limited. It is touted as being the simplest and cheapest way to replace the microkeratome for a laser.

The Technolas Femtec laser and Carl Zeiss Visumax initially followed the same standards for flap creation set by IntraLase, yet their features offer newer approaches and applications, which help to differentiate them. Both systems have a curved docking interface (more physiologic and less IOP rise during applanation). The customizable features in Technolas are similar to IntraLase; however, the Femtec laser has been used to first perform and popularize intrastromal cutting to induce a biomechanical effect in the IntraCor procedure. The Carl Zeiss Visumax is the largest and most complex (and expensive) of the devices. The technical specifications of the laser beam lies somewhere between IntraLase and LDV, with relatively low pulse energy and fast repetition rate. It has the most customizable software and is focused on the development of 'femtosecond-only' refractive tissue removal with the FLEx and SmILE procedures.

The new Wavelight FS200 from Alcon follows the same successful path of IntraLase in its basic concept, being similar in technical specifications. However, it addresses some of the early issues found in the IntraLase device, promising a faster procedure with the 200-KHz rate and less OBL formation.

Femtosecond laser-assisted cataract surgery devices are expected to be released during 2011. The first generations are expected to be 'cataract only' devices, and it is possible that future versions will have the ability to combine cataract and refractive surgical applications (i.e., flaps, ring channels, and so on). This could consolidate femtosecond laser technology into a versatile workstation for cataract, refractive and corneal surgeries.

What concept will prove to be the best has not yet been determined, but it is possible that a variety of concepts will be successful. For example, the portability, simplicity and low cost of Ziemer LDV may be best for lower volume centers, while more complex and expensive devices may be chosen in the larger corporate and academic centers.

Five-year View

Femtosecond laser technology has evolved considerably over the past 5 years, and further advances are expected. This technology will probably guide the major surgical changes in ophthalmologic care over the next 5 years. In addition to expected changes in refractive, corneal and cataract surgery, this technology can introduce and refine the treatment options for newer procedures such as keratolimbal grafts,[21] glaucoma[22] and retina[23] surgeries (to cut vitreous traction fibers - (Figure 5).

Figure 5. Retinal traction fibers could theoretically be cut with the femtosecond laser technology.

Refractive Surgery

In refractive surgery, a promising treatment modality using only the femtosecond laser (no excimer laser involved) is called FLEx.[6] In this procedure, the femtosecond laser is used to cut a lenticule of corneal stroma, instead of an excimer laser ablating this same tissue (Figure 6). The refractive outcomes are still not as good as the excimer laser treatments, but there is room for improvement. The theoretical advantage over the standard procedure is that it is faster, has no need of two different lasers and less energy is applied. In addition, in excimer laser ablation we observe a reduction in laser efficiency in the periphery of the cornea, yielding results that differ from that expected with wavefront-guided and optimized treatments. This would not be a problem with the femtosecond laser-cut lenticules, with the first results showing a large prolate treatment zone, and with less induction of high-order aberrations.[24] The development of faster, more advanced femtosecond laser systems, such as the Zeiss Visumax, allows for a more accurate placement of laser pulses, making this modality a potentially competitive treatment to excimer laser ablation. This feature, present in the Visumax, is not yet available in the USA.

Figure 6. Flex procedure: a lenticule of stroma is cut at the same time as the flap is created, then the flap is lifted and the lenticule removed.

Manipulating Corneal Biomechanics

One of the promising new applications using the femtosecond laser in refractive surgery is the IntraCor procedure,[5,25] which is based on a controlled biomechanical manipulation.

In this procedure, femtosecond laser pulses are used to perform corneal 'intrastromal-only' incisions in a cylindrical shape pattern (Figure 7). The only device to date that has this software available is the Technolas Femtec. The incisions heal fast, since there is no damage to the epithelium. The incisions biomechanically induce a hyperprolate, negatively aspheric corneal shape, and aberrated refractive profile with both negative spherical aberration and positive secondary spherical aberration.[5] First results demonstrate an increased depth of focus and refractive corneal stability over the first year with no patients showing loss of best-corrected visual acuity.

Figure 7. Intracor procedure. (A) Intrastromal-only cuts. (B) It is possible to visualize the incisions in the slit-lamp.

Our knowledge regarding cornea biomechanics has been increasing in the last decade with the development of new diagnostic tools and crosslinking procedures. However, the fear of biomechanical disasters,[26,27] resulting in corneal instability and ectasia (that occurred in procedures such as hexagonal keratotomy, automated lamellar keratoplasty and radial keratotomy), are still fresh in our minds and long-term results are needed to prove safety and stability.

Cataract Surgery

The main objectives within the surgical management of cataracts has always been in the treatment of disease. Residual refractive errors, delayed recovery, and even complications were accepted and expected by patients and physicians. With the development of intraocular lenses and small-incision surgical technique, patients and doctors became less tolerant to an imperfect and unexpected result. Modern-day cataract surgery is becoming part of refractive surgery, and despite the excellent results obtained with the current technology, perfection is demanded. In the years ahead, patients' expectations with cataract surgery will probably be the same as among LASIK patients. Femtosecond laser technology is bringing these two procedures even closer.

Currently, four companies (LensAR, LenSx Lasers Inc. [CA, USA], OptiMedica Corporation [CA, USA] and Technolas) are researching the use of femtosecond technology to make primary incisions, paracentesis, capsulotomy, lens fragmentation and limbal-relaxing incisions.

The femtosecond laser devices for cataract surgery are more complex than those for flap creation. They require very precise imaging systems and a docking system that preserves the anatomy of intraocular structures. The LenSx laser (LenSx Lasers Inc.) and the OptiMedica laser (OptiMedica Corporation) use a real-time high-resolution optical coherence tomography. The docking system specifications have not been disclosed by the companies. The LensAR laser system uses a high-resolution 3D confocal structured illumination, a form of infrared-based imaging used together with a no-touch, non-applanating suction fixation device (an automatically filled miniature water chamber). The device from Technolas is able to do cataract surgery and flaps for refractive surgery. It uses the same curved applanation plate used in the current femtosecond laser device for flap creation. More data regarding the differences among the devices are expected after they become commercially available.

The precision involved in these lasers promises a safer and more predictable cataract surgery, and could be responsible for the most important evolution since the transition to phacoemulsification. The first results show a more reproducible and stronger capsulotomy, excellent incision architecture (less leakage and less potential endophthalmitis) and less energy used (less potential endothelial damage).[28,29]

The enhanced safety and predictability can improve outcomes, especially with premium IOLs, which depend on a regular, well-centered capsulotomy and minimum residual corneal astigmatism. These can lead to an expansion of the indications of refractive lens exchange and limbal-relaxing incisions, bringing the revolution not only to cataract surgery but also to the refractive surgery area.

Astigmatic Correction

An area that has been undergoing research in refractive surgery and has been a hot topic in the past few years is astigmatism correction. It is more challenging to correct astigmatism than myopia and extra precision is required. Four main options currently in the treatment of astigmatism include: excimer laser photoablation, manual limbal relaxing incisions, astigmatic keratotomy and toric IOLs.

The results of excimer laser photoablation to correct astigmatism are usually accurate, but is not as good as with myopic treatments. In cataract surgery, excimer photoablation of residual astigmatism would require a separately performed procedure. In addition, nonorthogonal astigmatism cannot be treated with astigmatic excimer laser photoablation and topographic customization is not currently available.

Toric IOLs have been the subject of intense research in refractive cataract surgery, and the technology has evolved into being the first option for correcting astigmatism when facing a patient that is undergoing to cataract surgery. More accurate visual results are found when compared with manual limbal relaxing incisions.[30] However, the placement of a toric IOL is not possible when using a multifocal or accommodative implant and it cannot be used in the absence of cataract surgery.

Manual limbal-relaxing incisions have been used mainly to correct low-grade astigmatism (<3 diopters) during cataract surgery with good results.[31] However, when dealing with manual incisions we must be aware of the lack of length, depth and orientation precision during incision placement, as the reproducibility of outcomes would probably be enhanced with imaging-based laser incisions.

Astigmatic keratotomy has been widely performed during the radial keratotomy era, but because of irregular astigmatism, instability and imprecision, it was essentially abandoned, except for high postkeratoplasty astigmatism, although excimer laser vision correction may be needed to correct the residual astigmatism.[32]

Early studies of femtosecond laser-assisted astigmatism correction have begun with good results.[33,34] In higher degree astigmatism (postkeratoplasty and high naturally occurring astigmatism) laser astigmatic keratotomy is effective, while among lower astigmatic eyes, limbal-relaxing incisions seem to be most effective. The results for high postkeratoplasty astigmatism show greater accuracy and less complication compared with manual techniques.[35]

In addition, femtosecond lasers can create intrastromal-only astigmatic incisions. Although these are expected to be less effective, they would also be safer and more stable, but these facts need to be verified in further studies.

The precision of femtosecond laser technology in creating incisions still needs to be matched with better nomograms for an accurate correction. In addition, a precise imaging system and flexible geometric cutting profile are required for a better placement of the incisions.[36] This technology is still evolving and advanced refinements are currently being developed in the newer generation femtosecond laser devices.

Presbyopia Correction

Presbyopia is one of the last major challenges in ocular surgery. Many different surgical techniques have been studied to correct this huge problem, yet the simplest solution, reading glasses, are still the most utilized, because other solutions are still potentially compromising. The prevalence of presbyopia is increasing in the world owing to aging of the population, and is expected to be approximately 1.8 billion in 2020.[37] The main pathology of this disease is the increasing stiffness of the crystalline lens related to aging, for which there is currently no restorative solution.

Although the IntraCor procedure uses femtosecond lasers in the cornea to increase the depth of focus for spectacle independence in presbyopia, intralenticular femtosecond laser pulses could also be noninvasively applied for accommodation restoration at the level of the crystalline lens.

The concept of using low-energy femtosecond pulses inside the crystalline lens is currently being studied. This would allow increased flexibility and sliding of lens fibers that could partially restore the accommodative loss of the lens with aging.[38-40]

The main fear of this approach is the potential in causing cataracts and a loss of best-corrected visual acuity. The studies thus far show the development of pinpoint opacities at the site of laser interaction but no progressive cataract formation in preclinical[41] and clinical studies. When comparing this novel method with other presbyopia-correcting options and their complications, the minimal invasiveness of this technique makes it a potentially attractive potential remedy. The risk of infection is negligible since no exterior wound is created, and the possibility of presbyopia correction involving lens exchange could still be performed without concern if unsatisfactory results with femtosecond laser correction are experienced. An undesirable outcome within the crystalline lens would be much easier to treat than an undesirable outcome secondary to a corneal procedure. Studies in animals have shown promise,[41] and human trials are underway to show the real potential for efficacy and safety in performing this technique.

Nonrefractive Corneal Applications

In corneal procedures, the potential of femtosecond laser technology has not yet been fully achieved, although its initial uses for shaped penetrating corneal transplantation have been reported successfully in the last years (Figure 8). In addition, femtosecond laser-created keratolimbal autografts have been easily prepared with very positive results.[21]

    Figure 8. Shaped edges can be created for a better wound architecture.

The laser cutting of Descemet's stripping automated endothelial keratoplasty (DSAEK) grafts and anterior lamellar keratoplasty are hot topics with this technology.[42-44] The current standard procedure for cutting DSAEK grafts utilizes a microkeratome. Femtosecond lasers promise thinner and more reproductible DSAEK grafts.[45] However, a real benefit compared with microkeratome would depend on the use of a curved applanation system (to maintain the posterior stroma and endothelium in a physiologic, unfolded position) and on a cutting plane reference along the posterior surface, rather than the anterior as it is today (since cornea's posterior curvature is steeper than anterior, a cut based on an anterior curvature will leave the graft thicker in the periphery). How close to the endothelium we can go without inducing damage is still to be determined. In deeper cuts, there is an increase in laser scattering, resulting in an irregular cut. Very similar challenges are found when using the laser with deep anterior lamellar keratoplasty.

There are many more advances to be explored in this field, and future studies will determine whether or not there is any benefit to using a Femtosecond device in these situations.

Key Issues

●   Refractive surgery is rapidly evolving; relevant advances to the area are expected in the next few years.
●    Femtosecond laser technology is safe, precise and reliable. Results show better outcomes when compared with using a microkeratome in laser-assisted in situkeratomileusis flap creation.
●   The technology also introduced new complications such as opaque bubble layer, transient light-sensitivity syndrome and rainbow glare, which must be known and understood by the refractive surgeons that are changing from a microkeratome to a femtosecond laser.
●   The full potential of femtosecond laser technology has not yet been achieved. New forms of treatment such as IntraCor, FLEx and femtosecond laser-assisted cataract surgery are expected to play a relevant and significant role.
●   Despite the initial focus on refractive surgery, femtosecond laser technology can bring advances to nonrefractive surgery procedures, such as glaucoma, retina and corneal surgery.
●   Femtosecond-assisted cataract surgery can bring cataract and lens-based surgery closer to that of refractive surgery with its precision, safety and reproducibility.
●   New forms of presbyopia correction and accommodation restoration will become the major focus of investigation in refractive surgery, considering its huge impact on quality of life in an aging population.

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Website
101. Intralase IFS Advanced Femtosecond Laser (2010) (Accessed 17 July 2010)

Editor’s Note: All of the original text is included, but certain figures illustrating some of the text has been eliminated for space reasons. Please see the original version for the removed figures.

The Authors:

Ronal R. Krueger, MD

Ronald Krueger, MD is Medical Director of Refractive Surgery and Professor of Ophthalmology at the Cleveland Clinic. He has performed over fifteen thousand refractive surgery procedures, and has authored more than 150 peer-reviewed manuscripts and many more abstracts, book chapters and trade journal articles. He has 27 years of experience in excimer laser research, including the first physical descriptions of the effects of the excimer lasers on corneal tissue and many more developments. He is also an early pioneer of ocular wavefront customized laser vision correction, having coauthored the first book on the subject, and cohosted an international “wavefront congress” each year since 2000. He also has more than 15 years of research experience in pico and femtosecond laser photodisruption of ocular tissue, and is involved in research investigating the correction of presbyopia and restoration of accommodation.

Glauco Reggiani-Mello, MD

Glauco Reggiani Mello, MD, is a fellow in cornea, cataract and refractive surgery at the Cole Eye Institute of the Cleveland Clinic Foundation.

The authors can be reached at the following email addresses:

Glauco Reggiani-Mello

Ronal R. Krueger

Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells

2011-03-05T16:56:00.001-05:00

As the senior editor, John Gever, of MedPage Today reported, following the publication of three studies about induced pluripotent stem cells in the March 3rd, issue of Nature, “The road to regenerative medicine based on induced pluripotent stem cells (iPSCs) may have developed a giant pothole, with new studies showing that the cells are prone to several types of genetic defects.”

The three studies showed that the reprogramming process and subsequent culture of pluripotent stem cells in vitro can induce genetic and epigenetic abnormalities in these cells. The authors of the studies and the editorialist said that the results raise concerns over the implications of such aberrations for future applications of pluripotent stem cells.

Point mutations, copy number variations, and abnormal DNA methylation patterns all appear to crop up during generation of iPSCs. The frequency of such defects significantly exceeds what is normally found in human embryonic stem cells or in fibroblasts, the somatic cells from which iPSCs are usually derived.

"The studies raise concerns over the implications of such aberrations for future applications of iPSCs," wrote Martin F. Pera, PhD, of the University of Southern California in Los Angeles, in an accompanying editorial commentary. But he noted that it remains unknown whether the genetic "reprogramming" undertaken to generate iPSCs from fibroblasts is itself responsible for the genetic defects. Perhaps, Pera indicated, such defects "would be common to any experimental situation in which a cultured cell is subjected to strong selection and replication pressures in vitro."

Each of the three studies focused on a different type of genomic defect.

Kun Zhang, PhD, of the University of California San Diego, and colleagues from several other institutions looked at rates of point mutations in 22 iPSC lines and in the fibroblasts from which they were generated. The average number of mutations in protein-encoding genomic regions in each cell line was close to six. "Every single stem cell line we looked at had mutations. Based on our best knowledge, we expected to see 10 times fewer mutations than we actually observed," Zhang said.

All of the 22 iPSC lines had at least one "nonsilent" mutation that affected the resulting protein. One line showed 12 such alterations leading to mutated proteins. The mutations took different forms, the researchers reported, including splice variants and nonsense mutations.

In addition, they wrote, the abnormalities "were enriched in genes mutated or having causative effects in cancers."

Another of the Nature papers, by investigators from the Samuel Lunenfeld Research Institute in Toronto and elsewhere, examined gene copy-number variations that arise in iPSCs. Samer Hussein, PhD, of the Lunenfeld Institute, and colleagues found that these variations -- which included deletions as well as multiple copies -- were present in 37% of the iPSC lines they analyzed. Such variations were present in just 15% of fibroblasts and 25% of human embryonic stem cells (ESCs). The defects may be less significant in practical applications, however, relative to the point mutations. Hussein and colleagues reported that the highest rates of copy-number variations in iPSCs were seen in early-passage cells, whereas rates dropped with additional passages.

"Most of these novel CNVs rendered the affected cells at a selective disadvantage," the researchers explained. "Expansion of human iPSCs in culture selects rapidly against mutated cells, driving the lines towards a genetic state resembling human ESCs."

The third paper investigated what authors Joseph Ecker, PhD, of the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues called "aberrant epigenomic reprogramming."

DNA methylation patterns help regulate gene expression and are variable during life as well as transmissible during reproduction. Ideally, causing an adult cell to revert to a stem-cell state would also involve reestablishing stem cell-like methylation patterns. Ecker and colleagues therefore generated whole-genome methylation profiles of five iPSC lines along with undifferentiated human ESCs, somatic cells, and differentiated iPSCs and ESCs.

They found that the reprogramming of methylation patterns in iPSCs was generally successful when looked at across the entire genome. "Overall, this process generates an iPSC methylome that, in general, is very similar to that of ESCs," they wrote. But in their base-by-base analysis, Ecker and colleagues discovered hundreds of differentially methylated regions compared with ESCs. Some of these were on the megabase scale, which apparently were "repeatedly resistant to reprogramming."

There were detectable differences in cell appearance or function as a result, the researchers noted. Moreover, whereas cells with copy-number variations failed to survive multiple passages, the abnormal methylation patterns did not appear to affect cell survival, as differentiated iPSCs retained the abnormal patterns.

That these aberrations "cannot be erased by passaging and are frequently transmitted through cellular differentiation has immediate consequences for the derivation and use of iPSCs," Ecker and colleagues warned.

In his "News and Views" commentary, Pera pointed out that these are not the first studies to warn of genomic irregularities in iPSCs. Two previous analyses, one published in 2010 and another earlier this year, also documented abnormal chromosome numbers and gene copy-number variations in the cells. These and the new Nature studies raise a number of questions about the future of iPSC research, Pera contended. Perhaps the most important, he wrote, "is the biological significance of the changes."

He indicated that missing or duplicated chromosomes would clearly disqualify cells from use in therapy, as would a high frequency of mutations in genes associated with cancer or known genetic disorders. "However, the many subchromosomal changes, copy-number variations, or point mutations that are not obviously associated with known disease-related genetic abnormalities pose challenges to interpretation," Pera argued.

He suggested that high-throughput functional genomics may be the best approach to resolving the problems -- which need to be addressed before iPSCs can become a basis for human disease treatments.

All three studies were supported by government and foundation grants. No commercial funding was reported.

The three studies are:

Gore A, et al, "Somatic coding mutations in human induced pluripotent stem cells" Nature 2011; 471: 63-67.

Hussein S, et al, "Copy number variation and selection during reprogramming to pluripotency" Nature 2011; 471: 58-62.

Lister R, et al, "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells" Nature 2011; 471: 68-73.

And the accompanying editorial:

Pera M, "The dark side of induced pluripotency" Nature 2011; 471: 46-47

Source:
MedPage Today, John Gever, Senior Editor
March 2, 2011

In addition, Healthzone Canada published a lengthy review of the Toronto study: “Toronto Scientists Report Roadblock in Stem Cell Field”; and a press release from the UC San Diego Health System“Mutations Found In Human Induced Pluripotent Stem Cells”, reported in depth on the study from the scientists and colleagues from the University of California, San Diego:

For more on “induced pluripotent stem cells “(iPSCs) and the three other types – "embryonic stem cells" (embryonic SCs, or human embryonic stem cells hESCs), "adult stem cells" (adult SCs) and "parthenogenetic stem cells" (hpSCs), please see my Primer on the Use of Stem Cells in Ophthalmology.