An Update on Avalanche Biotechnologies A Potential Longer Lasting Wet AMD Treatment

There is breaking news this week about Avalanche Biotechnologies and I would like to share it, as well as a brief update on the clinical trial underway using their proprietary gene therapy approach to treating the wet form of AMD.

(Editors Note: For a comprehensive look at the company, its people, and technology, please take a look at my original writeup, placed online in late February 2012: A Novel Gene Therapy Approach to Treating the Wet Form of AMD: The BioFactoryTM From Avalanche Biotech.)

Now for the breaking news. On May 5th, in a joint announcement, Avalanche and Regeneron Pharmaceuticals said that they were undertaking a broad collaboration “to discover, develop and commercialize novel gene therapy products for the treatment of ophthalmic diseases. The collaboration covers novel gene therapy vectors and proprietary molecules, discovered jointly by Avalanche and Regeneron, and developed using the Avalanche Ocular BioFactoryTM, an adeno-associated virus (AAV)-based, proprietary, next-generation platform for the discovery and development and delivery of gene therapy vectors for ophthalmology.”

Under the terms of the agreement, Avalanche will receive an upfront cash payment, contingent payments of up to $640 million upon achievement of certain development and regulatory milestones, plus a royalty on worldwide net sales of collaboration products. The collaboration covers up to eight distinct therapeutic targets, and Regeneron will have exclusive worldwide rights for each product it moves forward in clinical development. In addition, Avalanche has the option to share in development costs and profits for products directed toward two collaboration therapeutic targets selected by Avalanche.

As part of the agreement, Regeneron has a time-limited right of first negotiation for certain rights to AVA-101, Avalanche's gene therapy product targeting vascular endothelial growth factor (VEGF) currently under development for the treatment of wet age-related macular degeneration (AMD), upon completion of the ongoing Phase 2a trial.

"We look forward to the opportunity to collaborate with Avalanche, a leader in the field of next-generation gene therapy technologies," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. "This collaboration highlights the commitment by Regeneron to invest in potentially breakthrough therapies that could benefit patients with sight-threatening diseases."

"We are excited to work with Regeneron to discover and develop novel gene therapy medicines for serious eye diseases," said Thomas W. Chalberg, Ph.D., co-founder and Chief Executive Officer of Avalanche Biotechnologies. "The collaboration will bring together Avalanche's novel platform technology with Regeneron's proprietary molecules and research capabilities, with the goal of creating a new class of next-generation biologics in ophthalmology. Regeneron is a terrific partner for their scientific leadership, as well as their product development capabilities and commercialization track-record."

For those of you not familiar with Regeneron Pharmaceuticals, they are a leading science-based biopharmaceutical company based in Tarrytown, New York that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions. Regeneron commercializes medicines for eye diseases, colorectal cancer, and a rare inflammatory condition, and has product candidates in development in other areas of high unmet medical need, including hypercholesterolemia, oncology, rheumatoid arthritis, asthma, and atopic dermatitis.

In the eye disease field, their major product is Eylea, an anti-vascular endothelial growth factor (VEGF) agent that is intravitrealy injected for the treatment of  wet AMD, in competition with Roche/Genentech's Avastin, and Lucentis.

The problem with the use of the current anti-VEGF drugs is the need for up to eight to twelve injections yearly, to maintain the gains in visual acuity and/or prevent the re-occurrence of the underlying neovascular degeneration. The reason for the collaboration with Avalanche is that its BioFactoryTM is expected to deliver a therapeutic protein to combat wet AMD for at least 18 months and, potentially for several years, from a single injection. (For more about this technology, again, please see my initial writeup.)

And that leads to the recent clinical trial update provided by founder and CEO, Thomas Chalberg at the the Angeogenisis, Exudation and Degeneration 2014 Conference, held in Miami, FL on February 8, 2014:

Ocular Gene Therapy Showed Fewer Injections Needed, Increased Visual Gain

Retina Today, April 2014

Subretinal delivery of an ocular gene therapy drug was well tolerated, required fewer injections of anti-VEGF, and improved visual acuity in a phase 1 randomized clinical trial, reported Thomas W. Chalberg, PhD, at Angiogenesis, Exudation, and Degeneration 2014.(1)

One hundred microliters of AVA-101 (Ocular BioFactoryTM, Avalanche Biotechnologies) was injected subretinally in patients. Anti-VEGF protein levels ramp-up over 6 to 8 weeks, during which 2 injections of ranibizumab (Lucentis) were given. After 8 weeks, ranibizumab was only given to the treatment group on a prn basis as rescue therapy.

Patients were tracked for 12 months after injection and came in for monthly visits. The control group, which did not receive an injection of AVA-101, required a mean 3 injections of ranibizumab during the 12-month period. The treatment group required a mean 0.3 ranibizumab injections over the same period.

Patients received ranibizumab injections if fluid appeared on OCT or fluorescein angiography, or if there was vision loss attributable to increased area of choroidal neovascularization.

Patients in the study had experience with anti-VEGF treatment, averaging 18 intravitreal anti-VEGF treatments prior to study enrollment.

“Because these patients are coming heavily pre-treated, we didn’t necessarily expect them to gain additional vision,” Dr. Chalberg said. “But treated patients actually gained between 9 and 12 letters over 12 months.”

Dr. Chalberg reported no drug-related adverse events, retinal tears, or retinal detachments. Procedure-related adverse events were minor and self-resolving.

“Ocular gene therapy might be a long-term viable option for patients with wet AMD,” Dr. Chalberg said.

AVA-101 is a strand of therapeutic DNA packaged inside an adeno-associated virus (AAV), which, when injected subretinally, up-regulates the body’s production of anti-VEGF. Subretinal injection appeared to be safe and was well tolerated, Dr. Chalberg reported, and allowed AVA-101 injections to better stimulate anti-VEGF production than if delivered intravitrealy.

Dr. Chalberg reported that an on-going phase 2A study currently has 40 patients enrolled.

Reference:

1. Chalberg TW. Anti-VEGF gene therapy: early clinical results using the Ocular BioFactoryTM in wet AMD. Paper presented at: Angiogenesis, Exudation, and Degeneration 2014; February 8, 2014; Miami, FL.

NeoVista Epi Retinal Strontium 90 Treatment for AMD Update 4

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.

To bring you up-to-date, I began following NeoVista in February 2007, writing an initial piece describing the procedure and initial clinical results. I also asked a series of questions of management and printed their responses. That first piece was:
NeoVista Epi-Retinal Strontium 90 Treatment for Wet AMD

In July 2007, the company announced the initiation of the CABERNET clinical study, and I posted an update, including more questions about the study to management. This piece was:
NeoVista Epi-Retinal Strontium 90 Treatment for AMD Update

In November 2007, during the annual AAO Meeting, NeoVista provided new data from its one-year feasibility study, and I published this data in a second update:
NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2

And, the final update (until now) was written following the 2008 Retina Society Meeting in September 2008. This included 18-month data from the Phase II feasibility study, and concluded with the statement: “With the continued promise of these Phase II trial results, NeoVista continues to enroll patients in the company's pivotal trial, CABERNET. CABERNET is a multicenter, randomized, controlled study that will enroll 450 subjects at 45 sites worldwide, evaluating the safety and efficacy of NeoVista's epiretinal brachytherapy delivered concomitantly with the FDA-approved anti-VEGF therapy Lucentis (ranibizumab) versus Lucentis alone.”
NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3

This new update (Update 4) will attempt to bring you up-to-date on both the clinical trials underway, as well as provide a few quotes from the press releases announcing the patient treatments upon commercialization of the device in Europe.

Commercialization in Italy

From the press release about the  first patients treated in Pisa, Italy, announced November 12, 2009:

The first VIDION patients were treated by Dr. Stanislao Rizzo, from the S. Chiara Hospital,Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, who said, “We are very excited to be the first hospital to perform this innovative one time treatment procedure, which can help to treat a devastating disease that otherwise requires chronic treatment for an indefinite period of time. NeoVista’s targeted epimacular brachytherapy treatment may provide us the ability to improve vision by offering a distinct mechanism of action that affects multiple disease pathways unlike the conventional anti-VEGF therapy, and may dramatically change the patient’s quality of life by eliminating frequent eye injections. This promising treatment is a cost-effective alternative to treat neovascular AMD,” continued Dr. Rizzo. “Monthly injections can become quite expensive for our health care system, whereas a single procedure will potentially allow our specialists to treat more patients and bring down the costs associated with ongoing treatments.”

Commercialization in the United Kingdom

From the press release about the first patient treatments in London, UK, announced November 16, 2009:

The new device is initially being introduced in 15 hospitals across the UK as part of a large clinical trial called MERLOT, where it will be used in patients whose current standard of care treatment involves regular injections of a drug into the eye to control their condition (up to one injection every month, indefinitely). Although the treatment is initially only available at select hospitals, it is anticipated that the number of sites using the device will increase quickly, to provide nationwide availability.

The MERLOT trial has been recently awarded portfolio status by The National Institute for Health Research (NIHR) Comprehensive Clinical Research Network (CCRN). The CCRN was created as part of the government’s research and development strategy, “Best Research for Best Health” to provide a world-class infrastructure for clinical trials in all areas of disease and clinical need within the NHS in UK.

Mr Tim Jackson, a Consultant Eye Surgeon at King’s College Hospital, who is the lead investigator for MERLOT said: “This is a relatively straightforward operation and the published results are very impressive. My experience in our own trials of this device has also been encouraging and it is a big step forward to be able to offer patients this new treatment throughout the UK, within a large randomized controlled clinical trial.”

(For more on MERLOT, see the clinical trial section below.)

Commercialization in Germany

And, from the press release describing the first commercialization of the VIDION ANV in Germany, January 19, 2011:

NeoVista, Inc. announced today the first commercial utilization of Epimacular Brachytherapy in Germany. Epimacular Brachytherapy is performed using the VIDION ANV Therapy system and is being offered as an adjunct therapy to anti-VEGF injections for the treatment of neovascular age-related macular degeneration.

John N. Hendrick, President and CEO of NeoVista commented, "Today is an extraordinary day for NeoVista, our local business partner, OctreoPharm Vertriebs GmbH, and the multitude of patients who suffer from this debilitating and life-altering disease. The burden of wet AMD to those afflicted with the disease, and their caregivers, is enormous."

Professor Gisbert Richard, Professor and Head of the Ophthalmology Department in the University Medical Center of Hamburg-Eppendorf, stated, "Our highly qualified medical staff is quite pleased to now be able to offer another therapeutic option to patients suffering from wet AMD - especially those patients who require frequent anti-VEGF injections." Multiple studies have demonstrated that injections alone are not able to effectively treat this disease in a large portion of the population." 

 
Mr. Hendrick added, "The German health care system presents a welcome opportunity for NeoVista to demonstrate the effectiveness of this emerging technology. I believe the use of Epimacular Brachytherapy in the treatment of wet AMD will continue to gain momentum in Germany, and in many other countries, as the rising cost of health care, on a global basis, encourages more and more patients to continue seeking out additional or alternate therapies."

The NeoVista approach to treating wet AMD delivers a focused dose of strontium 90 beta radiation directly to the back of the eye, without damaging the adjacent healthy retinal vasculature. Importantly for patients, the systemic exposure to radiation is minimal and highly controlled to a local area. The effective dose to the entire body from NeoVista's device is less than that from a typical chest x-ray.

Clinical Trial Studies

Finally, I would like to remind you of the clinical studies that have been undertaken and are continuing in the effort to better understand how epimacular brachytherapy can be utilized in possibly reducing the number of intravitreal injections needed in alleviating/stopping wet AMD.

Pilot Studies:

NVI-068

The NVI-068 trial was a study of subjects treated with a single dose of 15 or 24 Gy epimacular brachytherapy. Safety parameters evaluated included incidence and severity of ocular adverse events identified by slit lamp and indirect ophthalmoscopic examination, fluorescein angiography, and optical coherence tomography. Patients will be followed in this trial for 3 years to evaluate safety. (24 month data has been presented.)

NVI-111

The NVI-111 trial was a study of subjects treated with a single dose of 24 Gy epimacular brachytherapy and two injections of bevacizumab (1.25 mg). Subjects received one injection prior to surgery (10±4 days) or at the time of surgery and the second injection at Month 1. Subjects were re-treated with bevacizumab per the investigator’s discretion at follow-up visits. Safety parameters evaluated included incidence and severity of ocular adverse events identified by slit lamp and indirect ophthalmoscopic examination, fluorescein angiography, and optical coherence tomography. Patients are being followed in this trial for 3 years to evaluate safety. (36 month data has been presented and submitted for Peer Publication)


Feasibility Study:

MERITAGE I

MERITAGE I is a multi center international feasibility study designed to decrease the burden of treatment, it is fully enrolled (n=53) and is ongoing. The study is designed to evaluate the safety and efficacy of epimacular beta radiation therapy in patients that require persistent frequent anti-VEGF therapy to treat Wet AMD. It is planned for two sites, one in the US and one in the UK. (12 month data has been presented and a manuscript is being prepared for Peer Publication)


Pivotal Studies:

CABERNET

With the continued promise from the above two Phase II trial results (NV-068 and NV-111), NeoVista has finished enrollment in the company’s pivotal trial, CABERNET. CABERNET is a multicenter, randomized, controlled study that has enrolled 492 subjects at 45 sites worldwide, evaluating the safety and efficacy of NeoVista’s epiretinal brachytherapy delivered concomitantly with the FDA-approved anti-VEGF therapy Lucentis® (ranibizumab) versus Lucentis alone. (Initial results will be reported in Q4, 2011)

Meritage II

A pivotal study for FDA approval treating chronic wet AMD patients. (This study idea has been abandoned)


Special Population/Reimbursement Studies:

Pinot

A feasibility study treating a specific vascular tumor. Begun in Q3 2009, and still underway..

Merlot

An investigator-sponsored study in the UK;  It is a head-to-head comparison of NeoVista epimacular beta radiation therapy and standard-of-care treatment with Lucentis®, begun in Q4 2009 and >40% enrolled.

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

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 .

AMD Update 6 An Overview of New Treatments for Dry AMD

Those of you who have been following this space know that I have been reporting on new drug and device treatments for wet age-related macular degeneration for the past several years. I haven’t paid much attention to the treatments under development for the dry form, basically because most are drug-related, and my knowledge of how drugs work is limited. However, I recently read an excellent overview of the new drugs that are being developed for dry AMD, written by Dr. Philip Rosenfeld (the father of Avastin for use in AMD) and John Legarreta, a medical student at State University of New York at Buffalo, which presents a clear picture of current developments in this important field.

I have previously written about the potential for the use of lasers to treat dry AMD by Iridex, but that attempt did not prove successful. I have also written about the Ellex 2RT (retinal regeneration) program that might hold potential in the early intervention in dry AMD. Links to both of these writeups are shown at the end of this posting.

With about 80% to 90% of newly diagnosed AMD cases being of the dry variety, and with no effective treatment currently in use, it is important to track the developmental work underway in this area. This review appeared in the November 2009 issue of Retinal Physician, and with the permission of the magazines publishers, here is the complete writeup:

Preclinical and Phase 1 Drugs in Development for Dry AMD: An Overview

Retinal Physician, November 2009

Philip J. Rosenfeld, MD, PhD ● John Legaretta, BFA

Philip J. Rosenfeld, MD, PhD, is professor of ophthalmology at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Florida. He receives significant research support from Potentia and Alexion, and he has a minimal advisory relationship with Potentia. John Legarreta, BFA, is a medical student at the School of Medicine and Biomedical Sciences, State University of New York at Buffalo. He has no financial interest in any products mentioned in this article. Dr. Rosenfeld can be reached at prosenfeld@med.miami.edu.


The vast majority of AMD patients have the nonexudative or dry form of the disease, characterized by a constellation of clinical features, including drusen, disturbances of the retinal pigment epithelium (pigment clumping and/or dropout), and geographic atrophy (GA) of the macula. As defined by the Age-Related Eye Disease Study (AREDS), the severity of AMD can be classified into three categories: early, intermediate, and advanced.

[Editors Note: For a breakdown on the number of people in the three categories noted above in both dry and wet AMD in 2007, as estimated by Market Scope, please see the link to the table shown at the end of this posting.]

While drusen alone, particularly those of smaller size, do not seem to be associated with vision loss, at least one large druse measuring 125 μm in diameter is sufficient for the diagnosis of intermediate AMD. Dry AMD may remain static or progress slowly to produce a greater number and distribution of drusen with areas of GA. The increase in size or area of drusen or pigment abnormalities (focal hyper- or hypopigmentation of the retinal pigment epithelium [RPE]) predicts the likelihood of developing vision-threatening lesions in AMD, which include central GA and neovascularization, the advanced forms of AMD.(1)

CURRENT TREATMENT OPTIONS FOR DRY AMD

Antiangiogenic therapies have been developed to treat wet AMD. While drugs such as ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) have revolutionized the care of patients with neovascular AMD, under the best of circumstances, treatment converts the neovascular form of AMD back to dry AMD. There is no evidence to suggest that these antiangiogenic drugs have any beneficial effect on the underlying degenerative process known as dry AMD. Currently, there is no proven drug treatment for dry AMD; however, the cessation of smoking and treatments based on nutritional recommendations and supplements can slow disease progression. Nutrient-based treatments for AMD were evaluated in the AREDS trial.(2)

TARGETING THE CAUSE OF AMD

The overall goal of treatment for dry AMD is to target the underlying cause of the disease and halt, or at least slow, the loss of vision. This approach has been hampered by two major issues. First, there are no reliable in vitro systems for testing the efficacy of any drug for dry AMD, and second, no true animal model exists for AMD. A well-developed macula is only found in primates and birds, and while numerous attempts have been made to develop nonprimate models for AMD, and these models highlight various pathological features of human AMD, none of these animal models truly replicates the disease process seen in humans. The only model that may be useful for potential drug testing is the naturally occurring monkey colonies that have been found to develop drusen.(3)

The second issue that has hampered drug development is the uncertainty surrounding the best molecular pathway to target for the treatment of dry AMD. However, several different strategies have evolved. These strategies have targeted three major therapeutic areas of investigation: preservation of photoreceptors and the RPE (neuroprotection), prevention of oxidative damage, and suppression of inflammation. Each strategy is supported by varying degrees of scientific evidence and will have to await validation based on clinical trial outcomes.

CLINICAL TRIAL ENDPOINTS IN DRY AMD

The most obvious study endpoint for dry AMD therapies would be the preservation of visual acuity; however, studies using visual acuity as an endpoint will take many years to complete. To decrease the time required to show a benefit from a drug, surrogate endpoints have been developed that might indicate a positive outcome without waiting the years required to show visual acuity benefit.

One surrogate endpoint is the prevention of disease progression from dry to wet AMD. This endpoint was first used in the study investigating anecortave acetate (Retaane, Alcon) for the treatment of dry AMD. While the drug failed to prevent progression of dry to wet AMD, the study demonstrated the feasibility of this study design. Another strategy is to assume that a treatment for dry AMD might also affect the underlying stimulus for neovascularization in wet AMD. If true, then a potential endpoint might be to demonstrate that a drug for dry AMD is able to decrease the need for retreatment with antiangiogenic therapy in wet AMD or improve the visual acuity outcome. This study design has not been tested.

A feature of dry AMD that could serve as a surrogate endpoint is the area of drusen in the macula. While drusen area as measured by fundus photography has already been explored as an endpoint in the failed laser-to-drusen trials, (4-6) the change in drusen volume in response to pharmacotherapy is a novel clinical trial endpoint that has not been explored previously. Spectral-domain optical coherence tomography has the potential to reliably and reproducibly identify drusen in the macula and provide truly automated volume quantification. The most likely surrogate clinical trial endpoint, based on a symposium held in Washington, DC, and sponsored by the National Eye Institute and the Food and Drug Administration, is an endpoint that assesses a drug’s effects on the growth of GA, since GA is a feature of dry AMD that directly causes loss of photoreceptors and the RPE. (7)

DRUGS TO PROMOTE SURVIVAL OF PHOTORECEPTORS AND THE RPE

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 (8) 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).

Yet another strategy is to interfere with the normal visual cycle and preserve vision by decreasing the accumulation of toxic metabolites, such as lipofuscin and the retinal fluorophore A2E. This strategy is being pursued by Sirion Therapeutics (Tampa, FL) with the use of fenretinide - N-(4-hydroxyphenyl) retinamide - for the treatment of dry AMD. Fenretinide binds retinol-binding protein in the circulation and prevents uptake of retinol by the RPE, thus downregulating photoreceptor metabolism. The phase 2 study investigating fenretinide for the treatment of GA is fully enrolled and in its second year of follow-up.

Downregulation of photoreceptor activity is also being investigated using the drug ACU-4429 (Acucela, Bothell, WA). ACU-4429 is a small nonretinoid molecule that functions as a modulator of the isomerase (RPE65) required for the conversion of all transretinol to 11-cis-retinal in the RPE. By modulating isomerization, ACU-4429 slows the visual cycle in rod photoreceptors and decreases the accumulation of A2E. The ongoing phase 1 study has shown so far that the drug is safe and well tolerated in healthy volunteers. A phase 2 study for treatment of dry AMD is currently being planned.

A novel strategy for the preservation of photoreceptors and the RPE borrows a therapeutic strategy used for the treatment of Alzheimer's disease. An antibody against amyloid ß has completed a phase 1 study as an intravenous treatment for GA in AMD patients. This antibody, known as RN6G (Pfizer, New York, NY), was shown to decrease the amount of amyloid ß in the eye from a mouse model of AMD when given as a systemic therapy.(9) A phase 2 study is currently under way.

The therapies under investigation that seek to preserve photoreceptors and the RPE are summarized in Table 1.


(Note: I have reproduced the tables included with the article. By clicking on the tables they will open in a new window or tab in a larger more readable size. Or, go to the original online writeup for a clearer view of the table contents.)

DRUGS TO PREVENT INJURY FROM OXIDATIVE STRESS AND MICRONUTRIENT DEPLETION

In AMD, oxidative stress and the depletion of essential micronutrients are considered to be driving forces in disease progression. This disease paradigm assumes that AMD is caused by a lifelong exposure to free radicals - a byproduct of high oxygen consumption in the neural retina and RPE - combined with exposure to environmental toxins, such as those derived from smoking, in conjunction with inadequate levels of naturally occurring antioxidants. These exposures and deficits result in the accumulation of cellular debris - particularly oxidized lipids, which promote inflammation and may be directly toxic to the macular tissues - resulting in the clinical manifestations known as AMD. This paradigm is supported by epidemiologic studies showing that diets rich in antioxidants decrease the risk of AMD, while smoking was associated with an increased risk of AMD.(10)

Support for this nutrient-based paradigm was provided by the AREDS trial. This multicenter, NEI-sponsored study evaluated the effect of pharmacological doses of zinc and/or a formulation containing nutrients with antioxidant properties (vitamin C, vitamin E, and beta-carotene) on the rate of progression to advanced AMD and on visual acuity. The use of these vitamins and micronutrients reduced the risk of developing advanced AMD by about 25%.(2) The overall risk of moderate vision loss was reduced by 19% at five years. The theory of oxidative damage as a cause for AMD has also been supported by the findings that individuals have an increased risk of developing AMD if they carry a specific genetic polymorphism in mitochondrial DNA (A4917G), an organelle important for oxidative metabolism, and in nuclear DNA within the 5'-upstream region of a genetic locus important for DNA repair (ERCC6). DNA damage can be caused by oxidative stress.(11,12)

The AREDS2 trial, now under way, is designed to evaluate the effect of dietary xanthophylls (lutein/zeaxanthin) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFA), known as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on the progression to advanced AMD (www.areds2.org). These micronutrients are believed to function not only as antioxidants, but also as anti-inflammatory and antiangiogenic agents, according to epidemiologic and laboratory studies. In addition, AREDS2 will investigate the effects of eliminating betacarotene and the effects of reducing zinc in the original AREDS on the development and progression of AMD.

A topical antioxidant called OT-551 (Othera Pharmaceuticals, Exton, PA) was being explored as a treatment for dry AMD. OT-551 (4-cyclopropanoyloxy- 1-hydroxy-2,2,6,6-tetramethylpiperidine HCl) is a small lipophilic molecule that readily penetrates the cornea. OT-551 is converted by ocular esterases to TEMPOL-H (TP-H), the active metabolite that is a potent free-radical scavenger that does not penetrate the cornea. In animal studies, topical therapy has resulted in excellent ocular bioavailability, with significant levels of TP-H achieved in the retina.

The drug OT-551 was shown to possess antiinflammatory and antiangiogenic properties, as well as antioxidant properties. OT-551 was also shown to protect against oxidative damage in vitro, protect against light damage in vivo,(13) suppress photoreceptor cell death in animal models, and block angiogenesis stimulated by growth factors. Based on these preclinical data, OT-551 was being investigated as a therapy for GA in AMD. This two-year, phase 2 trial, known as the OMEGA (OT-551 Multicenter Evaluation of Geographic Atrophy) study, was stopped after 18 months, due to an apparent lack of efficacy in preventing the enlargement rate of GA in AMD.

The therapies under investigation that seek to prevent injury from oxidative stress and micronutrient depletion are summarized in Table 2.


DRUGS TO SUPPRESS INFLAMMATION

Genetic association studies using different populations have shown that inflammation appears to be the driving force behind AMD.(14) In 2005, four groups identified a genetic polymorphism in complement factor H (CFH), which was associated with an increased risk of developing AMD.(15-18) The documented risk-conferring single-nucleotide polymorphism (SNP) was a thymine (T) to cytosine (C) substitution at nucleotide 1277 in exon 9, which results in a tyrosine-to-histidine change at amino acid position 402 (Y402H) of the CFH protein.

Since complement is a system of serum proteins that comprise an important arm of the innate immune system, association studies have definitively linked AMD to the immune system. Also, two independent studies reported the association of the complement factor 3 gene with AMD, (19,20) as well as the complement factor B/component 2 gene.(21) An association between the complement factor 1 gene and AMD has been reported too.(22) Less robust associations have been reported between AMD and SERPING1, which regulates the first component of complement (C1), (23) and between AMD and C7 and mannose binding lectin 2 (MBL2) loci.(24) Protective alleles associated with the complement pathway have also been reported. Two of the five CFH-related genes (CFHR1-5), which lie within the regulators of complement activation (RCA) locus on chromosome 1q32, known as CFHR1 and CFHR3, are considered to be protective against AMD.(25)

These genetic association studies would imply that inhibition of complement activation would be a reasonable strategy for the treatment of AMD. However, after a lifetime of complement-mediated damage, such a strategy might have no effect on disease progression later in life. One drug being investigated is POT-4 (Potentia Pharmaceuticals, Louisville, KY), a cyclic peptide comprised of 13 amino acids, that is derived from compstatin. POT-4 binds reversibly to complement component 3 (C3) and prevents its proteolytic activation to C3a and C3b and the subsequent release of all downstream anaphylatoxins, as well as the formation of terminal membrane attack complex. As a C3 inhibitor, POT-4 inhibits all three major pathways of complement activation. POT-4 has unique slow-release properties due to the formation of an intravitreal gel at higher doses, which should permit less frequent intravitreal injections to achieve prolonged complement inhibition.

The phase 1 dose-escalation study, known as Assessment of Safety of Intravitreal POT-4 Therapy for Patients with Neovascular AMD (ASaP), was performed on patients with advanced neovascular lesions with the intention to pursue POT-4 as a treatment for dry AMD. To date, POT-4 appears safe up to a dose of 1.05 mg, with evidence of efficacy at the higher doses.

Another complement inhibitor under investigation is eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal antibody derived from a murine antihuman C5 antibody. Eculizumab specifically binds the terminal complement protein C5, thereby inhibiting its cleavage to C5a and C5b during complement activation. The strategic blockade of the complement cascade at C5 prevents the release of the downstream anaphylatoxin C5a and prevents the formation of the cytolytic membrane attack complex.

Eculizumab is FDA-approved for the intravenous treatment of another complement-mediated disease known as paroxysmal nocturnal hemoglobinuria. At the Bascom Palmer Eye Institute, we are performing a phase 2 investigation with eculizumab for the treatment of patients with dry AMD, known as the COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration (COMPLETE) Study. Patients with GA or high-risk drusen are being randomized 2:1 to receive intravenous infusions of eculizumab or placebo.

Ophthotech's ARC-1905 (Princeton, NJ), an anti-C5 aptamer, is another complement inhibitor being tested in AMD. ARC-1905 is being administered by intravitreal injection. The phase 1 dose-escalation study was performed in combination with ranibizumab therapy for the treatment of wet AMD. Genentech/Roche are developing an anti-Complement Factor D antibody Fab (FCFD4514S), which is in a phase 2 trial. Another phase 1 study using ARC1905 for dry AMD is currently under way.

Another complement inhibitor in preclinical studies is JPE1375 (Jerini Ophthalmic, New York, NY), a small, peptidomimetic molecular antagonist against the C5a receptor, which prevents binding of C5a, thus inhibiting the biological activity of C5a. Additional complement inhibitors are being pursued in preclinical studies by several companies, but details are not yet available.

More generalized immune suppression for the treatment of dry AMD is being pursued with the use of subcutaneous glatiramer acetate (Copaxone, Teva Pharmaceuticals, Kfar- Saba, Israel), intravitreal sustained-release fluocinolone acetonide (Iluvien implant, Alimera Sciences, Alpharetta, GA), and subcutaneous sirolimus (rapamycin), a macrolide fungicide with immunosuppressive properties.

The therapies under investigation that seek to suppress inflammation are summarized in Table 3.


SUMMARY

Several different strategies are being investigated, but it will take years before we know if any of them are successful. While we await positive outcomes, these clinical trials will produce a wealth of natural history data on the progression of dry AMD and provide us with extensive experience using several different imaging modalities to track disease progression. With this experience, our clinical trial designs will improve over time and the appropriate clinical trial endpoints should become obvious. With all the drugs in development, there is a good chance that a treatment breakthrough should occur within the next decade. RP

REFERENCES

1. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for agerelated macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123:1570-1574.
2. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
3. Kaidzu S, Tanito M, Ohira A, et al. Immunohistochemical analysis of aldehydemodified proteins in drusen in cynomolgus monkeys (Macaca fascicularis). Exp Eye Res. 2008;86:856-859.
4. Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial. Ophthalmology. 2006;113:1974-1986.
5. Friberg TR, Musch DC, Lim JI, et al. Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients. Ophthalmology. 2006;113:622 e1.
6. Owens SL, Bunce C, Brannon AJ, et al. Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: final results of the drusen laser study. Am J Ophthalmol. 2006;141:276-281.
7. Csaky KG, Richman EA, Ferris FL 3rd. Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci. 2008;49:479-489.
8. Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43:3292-3298.
9. Ding JD, Lin J, Mace BE, et al. Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res. 2008;48:339-345.
10. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology. 2000;107:2224-2232.
11. Canter JA, Olson LM, Spencer K, et al. Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoS One. 2008;3:e2091.
12. Tuo J, Ning B, Bojanowski CM, et al. Synergic effect of polymorphisms in ERCC6 5' flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci U S A. 2006;103:9256-9261.
13. Tanito M, Li F, Elliott MH, et al. Protective effect of TEMPOL derivatives against light-induced retinal damage in rats. Invest Ophthalmol Vis Sci. 2007;48:1900-1905.
14. Patel M, Chan CC. Immunopathological aspects of age-related macular degeneration. Semin Immunopathol. 2008;30:97-110.
15. Edwards AO, Ritter R, 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.
16. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227-7232.
17. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
18. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in agerelated macular degeneration. Science. 2005;308:385-389.
19. Maller JB, Fagerness JA, Reynolds RC, et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007;39:1200-1201.
20. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-561.
21. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458-462.
22. Fagerness JA, Maller JB, Neale BM, et al. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet. 2009;17;100-104.
23. Ennis S, Jomary C, Mullins R, et al. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet. 2008;372:1828-1834.
24. Dinu V, Miller PL, Zhao H. Evidence for association between multiple complement pathway genes and AMD. Genet Epidemiol. 2007;31:224-237.
25. Hughes AE, Orr N, Esfandiary H, et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet. 2006;38:1173-1177.


Links:

Laser Treatments for AMD Show Promise; Ocular Surgery News, January 15, 2000.

Ellex 2RT Retina Regeneration Therapy: A First Report

AMD Cases in the U.S. by Type and Stage in 20007

Preclinical and Phase 1 Drugs in Development for Dry AMD: An Overview

A Novel Gene Therapy Approach to Treating the Wet Form of AMD The BioFactoryTM From Avalanche Biotech

I originally contacted this company in November 2010, when they were still in “stealth mode” and weren't able to share details about what they were doing. Recently, the company got back in touch to provide an update, having announced, in December 2011, a clinical trial of their gene therapy approach to treating the wet form of AMD.

Since their approach is unique, and possibly “game changing” for the treatment of the wet form of AMD, I asked if I could prepare a writeup about the company and its technology for publication in my online Journal, and the co-founder and CEO Tom Chalberg agreed to answer my questions, as best as he could.

So, here in their own words is what Avalanche Biotech is all about.

The Company

Founded in 2006, as an outgrowth of co-founder Thomas Chalberg’s PhD work in genetics while at Stanford University (along with pioneering work with gene therapy at Prof. Elizabeth Rakoczy’s lab at the Lions Eye Institute in Perth, Australia), Avalanche Biotech is a privately held biotechnology company that develops technologies and products for sustained delivery of therapeutic proteins to the eye to treat wet age-related macular degeneration (AMD), as well as other ophthalmic disorders, such as diabetic retinopathy, retinal degeneration, and glaucoma.

The company was incubated at the Berkeley Entrepreneurship Laboratory at the UC Berkeley Haas School of Business in 2010-2011 while Tom was completing his MBA at that school. The company set up offices in San Francisco’s SOMA district, near the UCSF Mission Bay Campus, in July 2011.

The company’s lead product treats wet AMD by using the body's own cells to produce therapeutic proteins on an ongoing basis after only a single injection. The goal is effective long-term treatment of wet AMD without the burden of frequent, ongoing intra-ocular injections.

In June 2011, Avalanche Biotechnologies licensed additional intellectual property from the University of California, Berkeley, property related to novel adeno-associated virus (AAV) vectors for use with the company's proprietary BioFactory^TM drug delivery platform. A BioFactory™ is a long-term ocular drug delivery technology that secretes a therapeutic protein over years following a single eye injection. The company’s intellectual property includes access to a pipeline of next-generation vectors for non-invasive drug delivery to the retina.

In November 2011, Avalanche began a collaboration with Lions Eye Institute in Perth to commercialize AAV-based approaches, developed using the company’s proprietary BioFactory™ drug delivery platform.

The People – Founders and Management Team

Thomas W. Chalberg, PhD

Co-Founder & Chief Executive Officer

Dr. Chalberg, earned his PhD in Genetics from Stanford University where, as a Howard Hughes Medical Institute Fellow, he focused on retinal diseases and novel technologies for gene therapy. He was interested in retinal diseases, including retinal degenerations and age-related macular degeneration (AMD). During his PhD program at Stanford, he worked with Dr. Mark Blumenkranz, his committee member and a co-founder of Avalanche Biotech, on creating a sustainable solution for sustained delivery of therapeutic proteins to the retina. They were joined by Mitchell Finer PhD, a biotechnology industry expert with experience in gene therapy, and Steven Schwartz MD, an expert in retinal disease and early-stage clinical development.

Prior to joining Avalanche, Dr. Chalberg worked on the ophthalmology team at Genentech, helping to launch Lucentis (ranibizumab by injection), a novel therapeutic for age-related macular degeneration. Dr. Chalberg holds an A.B. from Harvard University, where he graduated magna cum laude and Phi Beta Kappa. He earned a PhD in Genetics from the Stanford University School of Medicine and an MBA from the UC Berkeley Haas School of Business. Tom is a member of the Board of Visionary Scientists for Hope for Vision, a non-profit charity supporting vision research.

Dr. Chalberg joined Avalanche Biotechnologies, Inc. on a full-time basis as President and Chief Executive Officer on October 11, 2010.

Mark S. Blumenkranz, MD

Co-Founder & Director

Dr. Blumenkranz is an ophthalmologist and trained vitreoretinal surgeon at the Byers Eye Institute at Stanford University, where he has served as Chairman of Ophthalmology since 1997. Prior to that, he served on the faculty of the Bascom Palmer Eye Institute in Miami, Florida, and as founder and Director of the Vitreoretinal Fellowship Program at William Beaumont Hospital in Royal Oak, Michigan – two of the top retinal training programs in the United States. His primary clinical interests center on medical and surgical treatment of vitreoretinal diseases, with a specific emphasis on macular problems. Dr. Blumenkranz was also a founding member of the Eyetech Pharmaceuticals Scientific Advisory Board and a founder or director at several Silicon Valley-based biotech startups, including Oculex Pharmaceuticals, MacuSight, Optimedica, and PEAK Surgical. Mark received his B.A. and Master of Medical Science in Biochemical Pharmacology of Brown University and M.D. degree at Brown University followed by a Residency in Ophthalmology at Stanford.

Steven D. Schwartz, MD

Co-Founder & Director

Dr. Schwartz is an ophthalmologist and trained vitreoretinal surgeon at the UCLA Jules Stein Eye Institute, where he serves as Director of the Retina Service. At UCLA, he has served as principal investigator in a number of early-stage clinical trials for retinal diseases, including the initial studies for ranibizumab (Lucentis) and novel products in gene and cell therapy. Dr. Schwartz has held various key positions at Eyetech Pharmaceuticals, and has served on a number of Scientific Advisory Boards, including Genentech, Ophthotech, Optos, and Optimedica. Steve received his B.A. from UC Berkeley and his M.D. from USC School of Medicine, followed by a Residency in Ophthalmology at UCLA and vitreoretinal fellowship at Moorefield's Eye Hospital in London.

Mitchell H. Finer, PhD

Co-Founder & Senior Consultant

Dr. Finer has over 25 years of experience in biotechnology, building and managing companies from discovery through market launch, in addition to pioneering the development of human monoclonal antibodies, and cell and gene therapies. Currently, Dr. Finer serves as a Senior Consultant to Avalanche and is the Chief Scientific Officer of bluebird bio. Previously, he served as senior vice president of development and operations for Novocell (now Viacyte), a stem cell engineering company researching treatments for diabetes and other chronic diseases. Dr. Finer has served as CEO of Intracel Holdings LLC and Genteric Inc., and as vice president of research and development for the Gencell division of Aventis Pharma (now Sanofi). He was also a founder and vice president of research for Cell Genesys Inc., and a founder of Abgenix. Mitch received a B.S. in biochemistry and molecular biology from the University of California at Berkeley and a Ph.D. in biochemistry and molecular biology from Harvard University. He completed a postdoctoral fellowship at the Whitehead Institute for Biomedical Research.

Advisory Boards

On October 1, 2010, Avalanche announced the founding members of its Scientific and Clinical Advisory Board. The Scientific Advisory Board is chaired by Dr. Elizabeth Rakoczy, Winthrop Professor of Molecular Ophthalmology at the Lions Eye Institute, University of Western Australia. Joining her is Dr. Mitchell Finer, Chief Scientific Officer of bluebird bio and a co-founder of Avalanche.

The Clinical Advisory Board will be chaired by Dr. Ian J. Constable, Founder and Professor at the Lions Eye Institute, University of Western Australia. Joining him is Dr. Mark S. Blumenkranz, Chairman of Ophthalmology at the Byers Eye Institute at Stanford, Dr. Steven D. Schwartz, Chief of the Retina Division at the UCLA Jules Stein Eye Institute, Dr. Judy Gordon, a clinical regulatory consultant with extensive experience in ophthalmology products, and Dr. Steven Butler, Consulting Senior Biostatistician.

On September 1, 2011, Avalanche announced the addition of three renowned scientific leaders in academia and industry to its Scientific Advisory Board: Dr. Jean Bennett, F.M. Kirby professor of ophthalmology at the University of Pennsylvania; Dr. Estuardo Aguilar-Cordova, CEO of Advantagene; and Dr. J. Fraser Wright, Director of the Clinical Vector Core at Children's Hospital of Philadelphia. They will join an august group of colleagues on Avalanche's Scientific and Clinical Advisory Boards.

The Technology

The Avalanche Approach

Currently, wet age-related macular degeneration is treated with frequent injections of an anti-VEGF protein directly into the vitreous of the eye, requiring frequent office visits to assess progress and for retreatment injections with the drug, as many as 8-12 retreatments per year. This creates a burden for both patients and physicians, and limits access for those who are not able to comply with frequent visits and injections.

Avalanche’s lead product is AVA-101, currently in clinical testing for the treatment of wet AMD. Following a single injection, AVA-101 creates an Ocular BioFactory^TM that continuously secretes a therapeutic protein over an extended period, avoiding the need for frequent intraocular injections of recombinant anti-VEGF protein. The therapeutic protein is a potent inhibitor of vascular endothelial growth factor (VEGF), a clinically validated target in wet AMD. Drug delivery technology for the Ocular Biofactory™ has been pioneered under the leadership of Elizabeth P. Rakoczy, Winthrop, Professor of Molecular Ophthalmology at the Lions Eye Institute. As of mid-December 2011, Phase I/II clinical trials are in progress to evaluate safety and efficacy of a single subretinal injection of AVA-101 into eyes of patients with exudative age-related macular degeneration (wet AMD).

The Ocular BioFactory^TM

Avalanche has developed a proprietary drug delivery system which uses the body's own cells to produce therapeutic protein on an ongoing basis after only a single injection This, in effect, creates a "BioFactory^TM" in the patient's eye to treat wet AMD.

The Ocular BioFactory^TM

How it Works

Avalanche delivers its therapeutic treatments through the use of a vector made from a small biological nanoparticle called Adeno-Associated Virus (AAV). Humans are commonly exposed to AAV without any known safety issues or association with disease. AAV-based therapies are in development for a wide range of diseases including heart failure, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), among others, along with a litany of retinal diseases in addition to the treatment of AMD.

To create a safe therapeutic vector, viral genes are removed from AAV and replaced with specific genes encoding a therapeutic protein that specifically treats AMD. AAV can infect a variety of retinal cell types and remain stable, resulting in long-term therapeutic protein expression in a variety of retinal cell types. In clinical studies, AAV appears safe and well-tolerated when injected into the retina.

The Avalanche Difference

As opposed to the current standard of care, which is effective for a short period of time, the Ocular BioFactory^TM continues to express therapeutic protein, gathering momentum and reaching peak expression after 4-6 weeks. At that point, the treatment continues to be maintained on an ongoing basis. The result is a continuous, steady-state level of therapeutic protein, which eliminates the need for frequent re-injections. Based on preclinical studies, the therapeutic effect will be maintained for at least 18 months and has the potential to last for several years following treatment from a single injection.(1)

Collaborations

Avalanche collaborates with leading academic institutions and pharmaceutical companies to develop and market its drug delivery platforms. We are looking for strategic partnerships with companies focused on ophthalmology and drug delivery for eye disease.

Our Partners Include:

Lions Eye Institute

In 1975 the Lions Save-Sight Foundation (LSSF) established the Lions Chair in Ophthalmology at the University of Western Australia (UWA). Professor Ian Constable AO was appointed to this position and subsequently established the Lions Eye Institute (LEI). As LEI's inaugural Managing Director, Professor Constable spearheaded its efforts to eradicate blindness worldwide. LEI conducts first class scientific research into blindness and incorporates one of Australia's largest ophthalmic practices. The Institute also houses the Lions Eye Bank and the LSSF.

As noted above, Avalanche announced its collaboration with the Lions Eye Institute in November 2011, and its first human clinical trial is being undertaken at the institution.

Merck Sharp & Dohme Corporation

Merck (known as MSD outside the United States and Canada) is a global healthcare leader working to help the world be well. Through prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, Merck works with customers and operates in more than 140 countries to deliver innovative health solutions.

The therapeutic protein used in the Ocular BioFactory^TM is exclusively licensed by Avalanche from Merck Sharp & Dohme Corp, formerly Merck & Co., Inc.

The Clinical Trial

The initial clinical trial, Safety and Efficacy Study of rAAV.sFlt-1 in Patients With Exudative Age-Related Macular Degeneration (AMD), NCT01494805, is currently recruiting participants at the Lions Eye Institute, in Perth, Western Australia, and was established on December 14, 2011.

It is a Phase I/II controlled dose-escalating trial to establish baseline safety and efficacy of a single subretinal injection of AVA-101 (rAAV.sFlt-1) into eyes of patients with exudative age-related macular degeneration.

The study will involve 24 patients aged 65 or above who have wet AMD. The patients will be radomized to receive one of two doses of the agent (16 patients) or assigned to the control group (8 patients). Patients in all three groups will be eligible for rescue therapy with ranibizumb (Lucentis). The study is estimated to be completed in three years (December 2014), with a primary completion date of December 2012 (i.e., final data collection for primary outcome measurement). (For more information, please follow the NCT hyperlink above.)

The Future

The company is involved in researching several other therapeutic proteins for the following indications, according to the Clinical Trials and Milestones graphic shown below:

AVA--201 – is in research for the treatment of specific cells in the retina, including possible treatment for rare genetic diseases.

AVA--301 – is in research for the treatment of diseases associated with photoreceptor cells.

Editor’s Comments – As I noted in my introduction, if this approach is successful, it could result in a “game change” in the way wet AMD is treated. Instead of multiple injections to gain control of neovascularization, one injection at the first signs of neovascularization could stop it dead in its tracks and the effect could last, potentially, for several years.

In addition, it is conceivable that patients at risk of developing wet AMD could receive a therapeutic injection of AVA-101 to prevent the occurrence of wet AMD! This would be a definite paradigm shift in the treatment of AMD.

With the human clinical testing now underway, we should have an indication of initial results with this unique approach within about a year.

Stay tuned!

For more on the technical aspects of the company’s technology, please see reference 2.

References:

1. AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness ; Bennett, J., Ashtari, M., Wellman, J., Marshall, K. A., Cyckowski, L. L., Chung, D. C., McCague, S., et al.; (2012). Science translational medicine, 4(120), 120ra15–120ra15. doi:10.1126/scitranslmed.3002865

2. Preclinical safety evaluation of subretinal AAV2.sFlt-1 in non-human primates; Lai, et al, Gene Therapy, (10 November 2011) | doi:10.1038/gt.2011.169

Stem Cells in Ophthalmology Update 3 ACT Files IND to Treat Dry AMD

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.

Dry AMD reportedly afflicts more than 30 million people worldwide, including an estimated13-15 million Americans. Approximately 10% of people 66 to 74 years of age will have findings of macular degeneration, and this prevalence increases to 30% in patients 75 to 85 years of age.

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 RPE layer of cells just below the retina. Dry AMD is much more common than wet AMD, which results from aberrant blood vessel formation in the eye. Some 85-90 percent of all people with intermediate and advanced AMD combined suffer from the dry form. Despite representing a $25-30 Billion market opportunity, there are currently no FDA-approved treatments for Dry AMD available.

The Phase I/II trial will be a prospective, open-label study that is designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation to patients with dry AMD. A total of 12 patients will be enrolled in the study at multiple clinical sites. The sites which are currently under consideration are the Jules Stein Eye Institute at UCLA; the Ophthalmology Department at Stanford University School of Medicine; and the Edward S. Harness Eye Institute at Columbia University College of Physicians and Surgeons; additional sites may be considered.

"We can generate a virtually unlimited supply of healthy RPE cells," said Robert Lanza, MD, ACT's Chief Scientific Officer. "In our animal studies, we observed significant improvement in visual performance over untreated animals, and did not find any adverse effects of the injection of RPE cells. In extending our studies to human patients, it is our hope that we will show that the injected RPE cells will rescue photoreceptors and slow, if not stop, the progression of macular degeneration."

On November 22, ACT announced that it had received FDA approval to begin treating patients as part of the company's Phase I/II Clinical Trial treat Stargardt's Disease, a form of juvenile macular degeneration. (See Stem Cells in Ophthalmology: Update 2) Company scientists view the use of the same hESC derived RPE cells for both trials as the most efficacious approach, as it permits the company to leverage its experience with the FDA that it gained through the process of obtaining approval for the Stargardt's clinical trial to expedite the approval of its clinical trial in Dry AMD.

"We are seeing the beginning of new era in medical treatment," continued Dr. Lanza. "The hope that stem cell therapies may one day repair and regenerate diseased organs and tissue goes far beyond what can be accomplished with traditional medicine. This approval shows an apparent readiness by the FDA to work with researchers to move exciting new stem cell based therapies out of the lab and into the clinic."

"Filing this IND represents the culmination of years of innovation and hard work by ACT's scientific team," said William M. Caldwell IV, Chairman and CEO of ACT. "With this second IND, and our plans to expand our studies in Europe, ACT is positioning itself as a true `translational' leader in the field of regenerative medicine. When you are the first, the whole world's eyes are on you, and in our case, most especially the eyes of the patients that suffer from AMD. We do not intend to let them down. We welcome this challenge, and of course plan to scale up our operations, as necessary, to continue to meet our milestones and help validate this technology platform."