Thursday, March 15, 2012

Stem Cells in Ophthalmology Update 18: Stem Cells Inc. Demonstrates That its Human Neural Stem Cells Preserve Vision – Gets FDA Authorization to Initiate Clinical Trial for Dry AMD

On January 30, 2012, Stem Cells Inc. announced the publication of preclinical data demonstrating that its proprietary HuCNS-SCr cells (purified human neural stem cells) protect host photoreceptors and preserve vision in an animal model of retinal disease. The preclinical results are highly relevant to human disorders of vision loss, the most notable of which is dry age-related macular degeneration (AMD). The study is available online at and will be featured as the cover article in the February issue of the international peer-reviewed European Journal of Neuroscience.

This research was conducted in collaboration with a team of researchers led by Raymond Lund, Ph.D., Professor Emeritus of Ophthalmology, and Trevor McGill, Ph.D., Research Assistant Professor at the Casey Eye Institute, Oregon Health and Science University.

The results of the study show that photoreceptors, the key cells of the eye involved in vision, were protected from degeneration following transplantation of HuCNS-SC cells into the Royal College of Surgeons (RCS) rat. The RCS rat is a well-established model of retinal disease which has been used extensively to evaluate potential cell therapies. Moreover, the number of cone photoreceptors, which are responsible for central vision, remained constant over an extended period, consistent with the sustained visual acuity and light sensitivity observed in the study. In humans, degeneration of the cone photoreceptors account for the unique pattern of visual loss in dry AMD.

"These results are the most robust shown to date in this animal model," said Dr. Lund, one of the study's lead investigators. "One of the more striking findings is that the effect on vision was long-lasting and correlated with the survival of HuCNS-SC cells more than seven months after transplantation, which is substantially longer than other cell types transplanted into this same model. Also important, particularly for potential clinical application, was that the cells spread from the site of initial application to cover more of the retina over time. These data suggest that HuCNS-SC cells appear to be a well-suited candidate for cell therapy in retinal degenerative conditions."

Alexandra Capela, Ph.D., another of the study's investigators and a senior scientist at StemCells, commented, "This study showed that the HuCNS-SC cells persisted and migrated throughout the retina, with no evidence of abnormal cell formation, which supports our hypothesis of a single transplant therapeutic. With this research, then, we have shown that vision can be positively impacted with a simple approach that does not require replacing photoreceptors or the RPE cells. We look forward to investigating this promising approach in the clinic later this year."

Following the above announcement, the company, on February 2nd, announced that it received authorization from the U.S. Food and Drug Administration (FDA) for a Phase I/II clinical trial of the company's proprietary HuCNS-SCr product candidate (purified human neural stem cells) in dry age-related macular degeneration (AMD), the most common form of AMD.

AMD is the leading cause of vision loss and blindness in people over 55 years of age, and approximately 30 million people worldwide are afflicted with the disease. There are no approved treatments for dry AMD.

"With the approval of this trial, we have accomplished something truly unique in the stem cell field, which is the extension of clinical testing of our proprietary human neural stem cell platform to all three elements of the central nervous system: the brain, spinal cord and eye," said Martin McGlynn, President and CEO of StemCells, Inc. "The preclinical data supporting our IND is particularly compelling and we look forward to getting this trial underway."

The Phase I/II trial will evaluate the safety and preliminary efficacy of HuCNS-SC cells as a treatment for dry AMD. The trial will be an open-label, dose-escalation study, and is expected to enroll a total of 16 patients. The HuCNS-SC cells will be administered by a single injection into the space beneath the retina. Patients' vision will be evaluated using conventional methods of ophthalmological assessment at predetermined intervals over a one-year period. Patients will then be followed for an additional four years in a separate observational study.

Editor’s Notes: The company has not as yet disclosed where the clinical trial will be held. But, since the pre-clinical work was done at Casey Eye (OHSU), my guess is that that's where the clinical trial will be carried out. When the company does announce this information, I will pass it along to you.

When Stem Cells Inc. does begin its clinical trial, it will be joining two other companies that have approved clinical trials using stem cells underway to treat dry AMD: Advanced Cell Technology and Centecor/J&J. ACT has Phase I/II trials underway at two U.S. sites, while awaiting approval for a site in London, while Centecor also has a Phase I/II trial underway at two U.S. sites.

For more information on these and other stem cell clinical trials, request my table, Stem Cell Therapy in Ophthalmology by Application.

Wednesday, March 14, 2012

Gene Therapy in Ophthalmology Update 10: Gene Therapy Research in Dogs Cures X-Linked Retinitis Pigmentosa – Paves the Way for Similar Treatment in Humans

Researchers at several universities and laboratories collaborated to treat dogs afflicted with the x-linked form of retinitis pigmentosa, to deliver the therapeutic RPGR gene specifically to the diseased rods and cones, which led to functional and structural recovery. This is the first proof that this condition is treatable in an animal model and the researchers feel the results are promising and relevant for translation to humans afflicted with this disease.

The results have been published in the journal, Proceedings of the National Academy of Sciences.

Here are twin news releases from the University of Pennsylvania and the University of Florida, that participated in the study:

January 23, 2012

Members of a University of Pennsylvania research team have shown that they can prevent, or even reverse, a blinding retinal disease, X-linked Retinitis Pigmentosa, or XLRP, in dogs.

The disease in humans and dogs is caused by defects in the RPGR gene and results in early, severe and progressive vision loss. It is one of the most common inherited forms of retinal degeneration in man.

"Every single abnormal feature that defines the disease in the dogs was corrected following treatment," said lead author William Beltran, assistant professor of ophthalmology at Penn's School of Veterinary Medicine.

"We were thrilled," said senior author Gustavo Aguirre, professor of medical genetics and ophthalmology at Penn Vet. "The treated cells were completely normal, and this effect resulted from introducing the normal version of the human gene into the diseased photoreceptor cells."

The similarities between humans and dogs, in terms of both eye anatomy, physiology, disease characteristics and positive response to this gene therapy, raise hope for a clear path to human therapies.

Beltran and Aguirre collaborated with Artur Cideciyan and Samuel Jacobson at the Scheie Eye Institute, part of the University of Pennsylvania's Perelman School of Medicine. This achievement results from more than 10 years of close collaboration between the scientists at Penn's Veterinary and Medical Schools and the University of Florida.

In addition to others at Penn Vet, Scheie, and Florida, researchers at the Universities of Michigan and Massachusetts and the National Eye Institute at the National Institutes of Health contributed to the research.

The study was published in the journal Proceedings of the National Academy of Sciences.

The gene therapy approach used takes advantage of a viral vector - a genetically modified virus that doesn't cause disease and is unable to divide -- to deliver the therapeutic RPGR gene specifically to diseased rods and cones. In the absence of treatment, these cells malfunction and progressively die.

The research team has previously successfully applied a similar approach to two other heritable vision disorders that occur in both humans and dogs: Leber congenital amaurosis (LCA) and achromatopsia. The present study was more challenging, as it was necessary to target both main classes of photoreceptor cells.

While the exact disease mechanism of the RPGR form of XLRP is still unknown, the researchers were able to successfully treat dogs with two different RPGR mutations. The mutations disrupt photoreceptors in different ways, but both ultimately cause them to become useless for vision. While this form of blindness is rare in dogs, it is common in humans. Patients with XLRP usually begin to lose night vision as children and become almost totally blind by middle age.

This is the first proof that this condition is treatable in an animal model; a single subretinal injection administered to the diseased dogs led to functional and structural recovery. The dogs' recovery was assessed using a variety of methods that are used clinically in patients, such as electroretinography and optical coherence tomography.

The researchers feel the results are promising and relevant for translation to the clinic.

"We are intervening to treat both classes of photoreceptor cells, rods and cones, and that has never been done before in a large animal model," Beltran said. "And not only can we prevent the disease onset but also restore the remaining photoreceptors cells to normal once the disease is ongoing."

While the ability to repair both rods and cones was itself a first, the research team went further, showing that its treatment also repaired the photoreceptor connections to other retinal neurons that eventually send visual signals to the brain, another first.

"This not only provides hope for reversing XLRP but potentially for any form of photoreceptor degeneration," Aguirre said. "Altered inner retinal wiring is a common feature for these diseases that has been considered irreversible.

"The study required a combination of genetic tools and surgical technique to make sure the therapy targeted only the diseased cells. The viral vector had to be injected in the sub-retinal space so as to be in close proximity to the photoreceptors. Likewise, you need to ultimately deliver the therapy to the right location of the retina," Aguirre said.

"In the human disease, careful characterization of the areas of the retina that need to be treated is going to be critical for therapy to succeed in the clinic," Cideciyan said.

The genetic aspect of the viral vector used in this study involved a double safeguard. The first safety feature was to use a viral vector that is known to predominantly target both rods and cones but not other cells. The second safeguard involved attaching the healthy RPGR gene to a "promoter," a piece of genetic code that would "switch on" the gene only if the virus penetrated the correct cell.

Selecting the right promoter was critical; the lead researchers at the University of Florida, William W. Hauswirth and Alfred S. Lewin, had to find one that that would be turned on exclusively in rods and cones. This way, even if the virus made its way to a non-photoreceptor cell, that cell would not start activating the RPGR gene.

That both the promoter and the RPGR gene it activates are taken from humans is a strong sign that the treatment may be translatable to patients.

"While there is still much work to do to assess long-term efficiency and safety with this approach, there is hope that this vector and knowledge could be used in a few years to treat the many patients losing vision from XLRP," Jacobson said.

Provided by University of Pennsylvania

January 23, 2012

A new gene therapy method developed by University of Florida researchers has the potential to treat a common form of blindness that strikes both youngsters and adults. The technique works by replacing a malfunctioning gene in the eye with a normal working copy that supplies a protein necessary for light-sensitive cells in the eye to function. The findings are published today (Monday, Jan. 23) in the Proceedings of the National Academy of Sciences online.

Several complex and costly steps remain before the gene therapy technique can be used in humans, but once at that stage, it has great potential to change lives.

"Imagine that you can't see or can just barely see, and that could be changed to function at some levels so that you could read, navigate, maybe even drive - it would change your life considerably," said study co-author William W. Hauswirth, Ph.D., the Rybaczki-Bullard professor of ophthalmology in the UF College of Medicine and a professor and eminent scholar in department of molecular genetics and microbiology and the UF Genetics Institute. "Providing the gene that's missing is one of the ultimate ways of treating disease and restoring significant visual function."

The researchers tackled a condition called X-linked retinitis pigmentosa, a genetic defect that is passed from mothers to sons. Girls carry the trait, but do not have the kind of vision loss seen among boys. About 100,000 people in the U.S. have a form of retinitis pigmentosa, which is characterized by initial loss of peripheral vision and night vision, which eventually progresses to tunnel vision, then blindness. In some cases, loss of sight coincides with the appearance of dark-colored areas on the usually orange-colored retina.

The UF researchers previously had success pioneering the use of gene therapy in clinical trials to reverse a form of blindness known as Leber's congenital amaurosis. About 5 percent of people who have retinitis pigmentosa have this form, which affects the eye's inner lining.

"That was a great advance, which showed that gene therapy is safe and lasts for years in humans, but this new study has the potential for a bigger impact, because it is treating a form of the disease that affects many more people," said John G. Flannery, Ph.D., a professor of neurobiology at the University of California, Berkeley who is an expert in the design of viruses for delivering replacement genes. Flannery was not involved in the current study.

The X-linked form of retinitis pigmentosa addressed in the new study is the most common, and is caused by degeneration of light-sensitive cells in the eyes known as photoreceptor cells. It starts early in life, so though affected children are often born seeing, they gradually lose their vision.

"These children often go blind in the second decade of life, which is a very crucial period," said co-author Alfred S. Lewin, Ph.D., a professor in the UF College of Medicine department of molecular genetics and microbiology and a member of the UF Genetics Institute. "This is a compelling reason to try to develop a therapy, because this disease hinders people's ability to fully experience their world."

Both Lewin and Hauswirth are members of UF's Powell Gene Therapy Center.

The UF researchers and colleagues at the University of Pennsylvania performed the technically challenging task of cloning a working copy of the affected gene into a virus that served as a delivery vehicle to transport it to the appropriate part of the eye. They also cloned a genetic "switch" that would turn on the gene once it was in place, so it could start producing a protein needed for the damaged eye cells to function.

After laboratory tests proved successful, the researchers expanded their NIH-funded studies and were able to cure animals in which X-linked retinitis pigmentosa occurs naturally. The injected genes made their way only to the spot where they were needed, and not to any other places in the body. The study gave a good approximation of how the gene therapy might work in humans.

"The results are encouraging and the rescue of the damaged photoreceptor cells is quite convincing," said Flannery, who is on the scientific advisory board of the Foundation Fighting Blindness, which provided some funding for the study. "Since this type of study is often the step before applying a treatment to human patients, showing that it works is critical."

The researchers plan to repeat their studies on a larger scale over a longer term, and make a version of the virus that proves to be safe in humans. Once that is achieved, a pharmaceutical grade of the virus would have to be produced and tested before moving into clinical trials in humans. The researchers will be able to use much of the technology they have already developed and used successfully to restore vision.

Provided by University of Florida

Editor’s Note: The lead author of the article about the study, Dr. William Beltran, said privately that much more pre-clinical work needs to be done before entertaining thoughts on beginning human clinical trials.

Thursday, March 08, 2012

NeoVista Update 5: CABERNET Study Did Not Meet Primary Endpoint at Two Years

In an unexpected outcome, Dr. Pravin Dugel presented the 2-year results of the CABERNET study, evaluating the use of NeoVista’s VIDION ANV epimacular brachytherapy device at the Bascom Palmer Eye Institute's (BPEI) Angiogenesis, Exudation, and Degeneration 2012 Meeting in Miami on Februay 4th.

As described in the following extensive writeup from Retina Today, the Phase 3, multicenter, prospective, randomized study did not achieve its primary endpoint after two years.

As I have previously written (see Update 4), the device has been commercialized extensively in Europe and the company was hoping that promising results in the CABERNET study would lead to FDA approval for marketing in the U.S. Those plans may now be on hold until subset analysis is completed and/if a subset of patients can be identified that would benefit from use of the device.

I asked NeoVista if they wished to comment about this development, and the company said that they would have no comment at this time.

Retina Today eNews, 2/13/12

Based on visual acuity outcomes, the CABERNET study evaluating epimacular brachytherapy for the treatment of wet age-related macular degeneration (AMD) did not achieve its primary endpoint at 2 years, according to Pravin U. Dugel, MD. Dr. Dugel presented the 2-year results of the CABERNET study at the Bascom Palmer Eye Institute's (BPEI) Angiogenesis, Exudation, and Degeneration 2012 meeting in Miami.

The phase 3, multicenter, prospective, randomized CABERNET study included 457 treatment-naïve patients who were divided into 2 arms. Patients in the treatment arm (n=302) underwent strontium-90 beta radiation with epimacular brachytherapy (NeoVista) and 2 mandatory ranibizumab (Lucentis, Genentech) injections. Patients in the control arm (n=155) received ranibizumab injections following a modified PIER protocol, which included 3 initial monthly injections followed by injections once every 3 months. In the CABERNET study, patients were seen on a monthly basis, and rescue therapy was permitted, as per the investigators' discretion.

The primary endpoint of CABERNET was visual acuity, specifically, the percentage of patients losing fewer than 15 letters of vision. In patients treated with epimacular brachytherapy, 6 injections were required at the 2-year mark for a mean 2.5 letter loss. Patients treated with ranibizumab required 11 injections and achieved a mean 4.4 letter gain.

In a post-study, unplanned subgroup analysis, the investigators identified 44% of patients in the epimacular brachytherapy group who required no rescue injections through the first 12 months and 1 rescue injection through the second 12 months, with a mean 3.3 letter gain, Dr. Dugel said.

In a similar analysis, the investigators identified 25% of patients in the epimacular brachytherapy arm who required no rescue injections throughout the 2-year course of the study, with a mean gain of 5.7 letters.

Cataract formation occurred in 48% of patients in the epimacular brachytherapy arm, which was suspected to be due to vitrectomy procedures, according to Dr. Dugel. The difference in the APTC events between the 2 study groups was not clinically significant.

At the 2-year mark, there were 10 patients with suspected radiation-based retinopathy. "There are 2 important things about these patients," Dr. Dugel said. "The first being that these 10 patients had changes that were nonproliferative and nonprogressive throughout the 2-year course of the study; the second, as a group, these patients tended to do fairly well. The mean change in visual acuity was +4.4 letters of vision. None of these patients lost significant vision, and the mean number of injections was 4."

The CABERNET demonstrated an acceptable safety profile for epimacular brachytherapy at the 2-year mark and identified a subgroup of patients that tended to respond well to the treatment. However, the CABERNET study did not achieve its primary endpoint, and it is not yet known whether the subgroup of patients who benefitted from the device can be reliably and consistently identified in clinics, Dr. Dugel concluded.

"At the end of the day, I think it is important to keep this study in proper perspective," Dr. Dugel said. "It was started in 2006 when there were few treatment alternatives. In retrospect, the CABERNET study should not have included treatment-naïve patients, but rather, should have treated previously ranibizumab-treated patients only. The CABERNET study should have [also] placed a lot more importance on probe placement."

Editor’s Note: It should be noted that Dr. Dugel is a consultant to and minority shareholder of NeoVista.

Tuesday, March 06, 2012

Gene Therapy in Ophthalmology Update 9: Oxford BioMedica/OHSU Preparing to Treat First Usher Syndrome Patient & Oxford BioMedica Ophthalmic Program Update

In an announcement today from the Foundation Fighting Blindness, and confirmed by Oxford BioMedica, the Casey Eye Institute of the Oregan Health & Science University (OHSU) is preparing to treat the first Usher Syndrome patient under the clinical protocol designed by Oxford BioMedica using its UshStat gene therapy treatment.

Here is the complete text of the FFB news release:

March 6, 2012 - The first-ever gene therapy for Usher syndrome, a devastating condition that causes both blindness and deafness, has moved into a Phase I/IIa clinical trial at the Foundation-funded Casey Eye Institute, Oregon Health & Science University (OHSU). The research team, led by Dr. Richard Weleber, is preparing to treat its first patient.

Developed by Oxford BioMedica, a biopharmaceutical company in the U.K. and a Foundation partner, the UshStat treatment is designed to halt vision loss in people affected with Usher syndrome type 1B, which is caused by defects in the MY07A gene. Based on results in lab studies, researchers believe a single UshStat treatment may last several years, perhaps a lifetime.

"We are delighted to see Oxford's innovative gene therapy for Usher 1B move into human studies. It is a critical milestone in our campaign to overcome vision loss from a particularly challenging condition," says Dr. Stephen Rose, the Foundation's chief research officer. "UshStat is great news for the Usher syndrome community, because there are virtually no vision-related treatment options available for any form of the disease. While the treatment is for Usher 1B, success in the trial will open the door for using gene therapy to treat other forms of Usher syndrome."

UshStat is the third Oxford BioMedica gene therapy to move into a clinical trial. StarGen, the company's gene therapy for Stargardt disease, is in a Phase I/IIa human study at OHSU and the Centre Hospitalier Nationale d'Ophthalmologie des Quinze-Vingts in Paris. The company's RetinoStat, a gene therapy for wet age-related macular degeneration, is in a Phase I clinical study at Wilmer Eye Institute at Johns Hopkins Hospital in Baltimore, Maryland.

Oxford says that the first six patients in the RetinoStat trial and the first four in the StarGen study are doing well. No safety issues or adverse events have occurred. The company will report additional results for RetinoStat in the first half of 2012 and for StarGen in the second half of the year.

The two-year UshStat study will enroll 18 patients affected by Usher syndrome type 1B. One eye of each patient will be injected with the therapy. The trial will evaluate the treatment's safety as well as changes in retinal function of the treated eye versus the untreated eye.

To participate in the UshStat trial, patients will need to be 18 years or older and have had a genetic test confirming the diagnosis of Usher syndrome type 1B. For more information on trial participation, visit the clinical trials page of the Foundation's website, which requires registration.

The UshStat treatment is contained in a tiny drop of liquid that is injected beneath the retina and absorbed by retinal cells in a matter of hours. The treatment uses Oxford's LentiVector gene delivery technology, a re-engineered virus, to enable healthy copies of the MYO7A gene to penetrate the cells. A key benefit of the LentiVector technology is its ability to deliver large genes, like MYO7A, which other viral systems are not able to deliver.

Usher syndrome is the leading cause of combined deafness and blindness in the world. It affects approximately 45,000 people in the United States. There are three primary types of Usher syndrome, designated by numerals, and 12 subtypes, designated by letters.

"We are excited about the potential for our powerful gene therapy technology to save and restore vision, and we are grateful to the Foundation Fighting Blindness for playing a critical role in moving it out of the lab and into clinical trials. It has been an outstanding partnership," says Stuart Naylor, Ph.D., chief scientific officer, Oxford BioMedica.

In addition, Oxford BioMedica provided some updated information about its other ophthalmic gene therapy programs, as part of the release of its end of year report.

Lead RetinoStat Phase I trial in “wet” AMD on track

Six patients have been treated with RetinoStat in the on-going US Phase I study in neovascular “wet” age-related macular degeneration (AMD). Three patients received the first dose level, three received the second dose level and the third patient cohort (dose level 3) is underway. The open label, dose escalation Phase I study will enroll 18 patients with “wet” AMD at the Wilmer Eye Institute at Johns Hopkins, Baltimore (USA). Led by Professor Peter Campochiaro, the study will evaluate three dose levels and assess safety and aspects of ocular physiology. Oxford BioMedica is on track to announce first results in H1 2012.

First gene therapy clinical trials in Stargardt disease and Usher syndrome underway

There are currently no approved treatments for Stargardt disease and Usher syndrome type 1B and other potential strategies do not target the root cause of the disease. As such, StarGen and UshStat have received both European and US Orphan Drug Designation which brings development, regulatory and commercial benefits.

In June 2011, the first patient in the StarGen Phase I/IIa study in Stargardt disease was treated in the US.

In July 2011, the French regulatory agency (AFSSAPS) approved the opening of a second clinical site in France. In the US, the study is led by Professor David Wilson at the Oregon Health & Science University, Portland, Oregon. In France, Professor Jose-Alain Sahel leads the study at the Centre Hospitalier National D'Opthalmologie des Quinze-Vingts, Paris.

Four patients have been treated to date at the first dose level and the second cohort using dose level 1 in earlier-stage patients is underway. The open label, dose escalation Phase I/IIa study will enroll up to 28 patients and will evaluate three dose levels for safety, tolerability and aspects of biological activity. First results are expected in H2 2012.

In February 2012, the UshStat Phase I/IIa study in Usher syndrome type 1B commenced in the US at the Oregon Health & Science University's Casey Eye Institute. Led by Professor Richard Weleber as Principal Investigator, the open label, dose escalation Phase I/IIa study will enrol up to 18 patients and will evaluate three dose levels for safety, tolerability and aspects of biological activity. Initial results are expected in H2 2012.

Glaucoma-GT: new collaboration with Mayo Clinic for chronic glaucoma

In October 2011, Oxford BioMedica entered into a research and development collaboration with Mayo Clinic, Rochester (USA) to develop a novel gene therapy for the treatment of chronic glaucoma. Under the terms of the agreement, Mayo Clinic and Oxford BioMedica will undertake pre-clinical studies to establish the feasibility of treating glaucoma using Oxford BioMedica's proprietary LentiVector gene delivery technology expressing a COX-2 gene and a PGF-2α receptor gene to reduce intraocular pressure.

Since the start of the collaboration, the teams have successfully initiated the first pre-clinical study which aims to demonstrate gene transfer using Oxford BioMedica’s LentiVector platform technology to target ocular tissues following transcorneal administration. Preliminary results from this study are encouraging and indicate effective and robust gene transfer into the target ocular tissues. A second pre-clinical study is expected to begin in Q2 2012 to evaluate the lowering of intraocular pressure following administration of the collaboration’s Glaucoma-GT.

Friday, March 02, 2012

AMD Update 18: A New Approach to Fighting Retinal Degeneration

I just learned this afternoon, of a start-up company, MitoChem Therapeutics, which is apparently an outgrowth of the Vision Research program at the Ophthalmology department at the Medical University of South Carolina. Two of their scientists, Drs. Rohrer and Beeson, have been looking into compounds that can provide “energy” to “reduced capacity” mitochondria in retinal cells that are possibly at the root of retinal degenerations in such diseases as retinitis pigmentosa and macular degeneration.

The Foundation Fighting Blindness is providing $2 million to the company to support their research. After screening a library of 50,000 drug compounds, they have apparently identified three compounds that appear to boost mitochondrial function, and will now attempt to identify which one will work best in people as an eye drop, and move it into a clinical trial.

Here is the complete news release from FFB:

March 2, 2012 - A key to survival for any organism, plant or animal, is energy. And, in humans, every cell gets its energy from a tiny, organ-like structure called a mitochondrion. It operates like a power plant, providing the energy needed to stay alive and functioning. Among their many functions, mitochondria combine sugar and oxygen, which serve as the cells' supply of fuel.

One consequence of most retinal degenerations, including retinitis pigmentosa and macular degeneration, is that mitochondria operate at reduced capacity, because of disease-related stress. Ultimately, photoreceptors, the cells in the retina that provide vision, are lost.

The Foundation Fighting Blindness is giving $2 million to MitoChem Therapeutics, a start-up company which, thanks to prior Foundation support, has identified three compounds that appear to boost mitochondrial function and, thus, show potential for slowing vision loss caused by a variety of retinal degenerations. The goal is to determine which one will work best in people and move it into a clinical trial.

Dr. Stephen Rose, chief research officer of the Foundation, says that finding treatments which benefit people with a range of conditions is an important part of the Foundation's mission. "We are always excited by cross-cutting therapies. With defects in more than 200 genes causing these retinal conditions, we are very attracted to potential treatments like MitoChem's that can help a lot of people, including those for whom we can't find the gene causing their disease."

In 2009, the founders of MitoChem - Dr. Barb Rohrer, an expert in retinal degenerations, and Dr. Craig Beeson, a medicinal chemist - screened a library of 50,000 compounds to identify those which enhanced mitochondrial function. They used a high-throughput screening technology combining robotics, data processing systems and sensitive detectors to determine, both quickly and efficiently, which compounds have vision-saving properties. Three emerged from that process and subsequently showed good results in preserving and even restoring vision in animal models of retinal degeneration.

With the goal of moving a cross-cutting treatment into a clinical trial, MitoChem will now: determine which compound is the best drug candidate; develop a drug formulation that will work as an eye drop; and conduct further toxicity and efficacy studies to ensure the drug is ready for human studies.

An important focus of the project is meeting FDA requirements to gain authorization to launch the study. "The FDA will look closely at everything from animal model study results, to manufacturing and production of the compound, to the actual design of the trial before giving MitoChem the OK to begin the study in humans," says Dr. Rose. "We will be working closely with Drs. Rohrer and Beeson to help ensure that those requirements are met. It's challenging and expensive, but it's what we have to do to get the treatment into and through the trial and out to the people who need it."

Thursday, March 01, 2012

Iluvien Update 5: European Approval on the Horizon

Finally, some good news for Alimera (and pSivida). A few days ago, the company announced that it had received a positive outcome to the Decentralized Procedure (DCP) for Iluvien in Europe. Iluvien is now expected to be the first sustained release pharmaceutical in the European Union for the treatment of diabetic macular edema (DME).

The regulatory process will now enter the national phase of the DCP in which the Reference Member State (RMS), the Medicines and Healthcare products Regulatory Agency of the United Kingdom (MHRA), and each Concerned Member States (CMS) grants its national license. The CMS include Austria, France, Germany, Italy, Portugal and Spain.

While it appears that this drug for DME is not going to be moving forward in the US (see Update 4: FDA Turns Down Alimera’s NDA for Approval of Iluvien Again), approval for marketing in Europe appears on track. It has been estimated that the European market may be the same size as the US market.

Just for reference, Iluvien is licensed by Alimera from pSivdia.

For more on the background of this unique sustained release drug for the treatment of retinal disease, please see my original report on the product, and the four updates, listed (and linked) at the end of this writeup.

Here are excerpts from the twin press releases issued by both Alimera and pSivida:

Alimera Sciences, Inc., a biopharmaceutical company that specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals, today announced the positive outcome of the Decentralized Procedure (DCP) for Iluvien in Europe. The announcement follows the issuance of the Final Assessment Report from the Reference Member State (RMS), the Medicines and Healthcare products Regulatory Agency of the United Kingdom (MHRA), and the agreement of all the Concerned Member States (CMS) that Iluvien is approvable.

The regulatory process will now enter the national phase of the DCP in which the RMS and each CMS grants its national license. The CMS include Austria, France, Germany, Italy, Portugal and Spain. Iluvien will be indicated for the treatment of vision impairment associated with chronic DME considered insufficiently responsive to available therapies.

The International Diabetes Federation estimates that, in these seven countries alone, 22.1 million people are currently living with diabetes. By comparison, the Centers for Disease Control and Prevention estimate that Americans with diabetes now number 25.8 million. Alimera estimates that within the seven CMS countries, 1.2 million people suffer from DME.

"Achieving a favorable conclusion for Iluvien in Europe is a significant milestone for Alimera and very encouraging for the many patients with this challenging chronic disease," said Dan Myers, president and chief executive officer, Alimera Sciences. "We will continue to work closely with the UK and the Concerned Member States to ensure that Iluvien is made available to patients as soon as possible."

Iluvien is Alimera's sustained release intravitreal implant that releases sub-microgram levels of fluocinolone acetonide (FAc) for up to 36 months for the treatment of chronic DME. The clinical trial data showed that in patients with chronic DME at month 30, after receiving the Iluvien implant, 38 percent of patients experienced an improvement from baseline in their best corrected visual acuity on the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart of 15 letters or more. At the completion of the 36-month study, 34 percent had achieved the same result. This effect was highly statistically significant as compared to the sham control group, which received laser and other intravitreally administered therapies.

"Our market research indicates that, given DME is a leading cause of blindness in working-age adults, there is a significant opportunity for an effective ophthalmic drug to treat patients insufficiently responsive to available therapies," said Dave Holland, senior vice president of sales and marketing, Alimera Sciences. "An effective, truly long-term treatment option could have a very positive impact on the quality of life for patients with this chronic debilitating disease."

In July 2010, the Marketing Authorization Application (MAA) was submitted to seven European countries via the DCP with the UK MHRA as the RMS. The MAA included data from two Phase 3 pivotal clinical trials (collectively known as the FAMET Study) for Iluvien conducted by Alimera. The trials involved 956 patients in sites across the United States, Canada, Europe and India to assess the efficacy and safety of Iluvien for the treatment of DME. Based on a consensus arrived upon by the RMS and the CMS, the MHRA issued its Final Assessment Report that Iluvien is approvable.

About the FAMET Safety

Safety was assessed among those patients treated with Iluvien who were in the subgroup of patients with DME for three years or more and were considered to have chronic DME. Intraocular pressure (IOP) increases to 30 millimeters of mercury (mmHg) or greater at any time point were seen in 12.7% of these patients by month 36, compared to 18.4% in the full Iluvien treated patient population. By month 36, 3.6% 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 84.1% at month 36, with 87.3% undergoing a cataract operation, compared to 81.7% and 80%, respectively, in the full patient population.

And, the release from pSivida:

pSivida Corp., a leader in developing sustained release, drug delivery products for treatment of back-of-the-eye diseases, today announced the positive outcome of the Decentralized Procedure (DCP) for the approval of Iluvienr in Europe. The announcement follows the issuance of the Final Assessment Report to pSivida's licensee, Alimera Sciences, Inc. from the Reference Member State (RMS), the Medicines and Healthcare products Regulatory Agency of the United Kingdom (MHRA), and the agreement of all the Concerned Member States (CMS) that Iluvien is approvable.

The regulatory process will now enter the national phase of the DCP in which the RMS and each CMS grants its national license. The CMS include Austria, France, Germany, Italy, Portugal and Spain. Iluvien will be indicated for the treatment of vision impairment associated with chronic DME considered insufficiently responsive to available therapies.

"I'm very pleased about this favorable outcome of the EU regulatory process for Iluvien," said Paul Ashton, president and chief executive officer of pSivida.

Iluvien is an injectable, sustained-release intravitreal insert that releases sub-microgram levels of fluocinolone acetonide (FAc) for up to 36 months for the treatment of chronic DME. pSivida is developing an insert of the same design for the treatment of uveitis affecting the posterior of the eye.

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