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