Thursday, May 08, 2014

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:

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.


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.


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