Wednesday, May 25, 2011

Oraya IRay Update: Company Completes Enrollment in European Clinical Trial

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:

"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

Wednesday, May 18, 2011

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

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 -
for progressive keratoconus -

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
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.

Sunday, May 15, 2011

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

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


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


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.

Friday, May 13, 2011

Iluvien Update 3: Alimera Files Resubmission for Approval of Iluvien

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.

Saturday, May 07, 2011

Ellex 2RT Updated Clinical Results: ARVO 2011

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.


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.


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.


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.


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.

Friday, May 06, 2011

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

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.

Tuesday, May 03, 2011

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

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