Third Rock’s Voyager Hunts For CNS Disorders With Gene Therapy

2/12/14Follow @benthefidler

Several biotechs have tried over the years to come up with a way to reverse the course of crippling central nervous system disorders like amyotrophic lateral sclerosis (a.k.a. Lou Gehrig’s Disease), only to see their efforts fall short. Now, Third Rock Ventures will try to see if gene therapy can succeed where so many drugs have failed.

Third Rock today is announcing that it’s formed Cambridge, MA-based Voyager Therapeutics, and backed it with a $45 million Series A round of equity financing. Voyager isn’t seeing all of that cash up front right away—it has to hit several milestones to bring in all those dollars. But Voyager will be using it to pursue a big effort: to use gene therapy, and to a certain extent, micro RNA tools, to try to either cure, or significantly reverse the effects of a wide range of serious central nervous system disorders like Lou Gehrig’s Disease, Friedreich’s Ataxia, and Parkinson’s. The company would do so by injecting modified viruses into the spine or brain containing either specific proteins, or micro RNA silencing molecules, that are supposed to either replace a faulty gene, or shut down a disease-causing one.

“These horrible CNS disorders that no one can do anything with, gene therapy really is going to be the answer, we believe, to a lot of these,” says Mark Levin, the co-founder of Third Rock, and Voyager’s interim CEO. “We don’t know what’s going to work for sure, but we know we’re going to make a difference for a lot of patients.”

Mark Levin, co-founder of Third Rock Ventures

Mark Levin, co-founder of Third Rock Ventures

Levin is being joined by three other Third Rock members to staff Voyager’s management team: Philip Reilly (interim chief medical officer), Steven Paul, (interim president of R&D), and Jim Geraghty (interim chief business officer). The staff also includes former Alnylam Pharmaceuticals executive Dinah Sah (interim senior vice president of neuroscience); one-time Evercore Partners managing director Jeff Goater (vice president of business development); former National Institutes of Health senior investigator Rob Kotin (vice president of production); and former Third Rock associate James McLaughlin (head of operations).

There are 20 people in the company total, though Third Rock wants to swap out all of its partners by the end of the year with a permanent management team and boost the number of full-time employees to 25, Levin says.

Voyager was founded based around advances in developing adeno-associated viruses, or AAV’s, as delivery tools for gene therapy. For those unfamiliar, the concept of gene therapy is to use a modified virus—a viral vector—as a vehicle to deliver healthy genes into a cell to replace faulty or missing ones. Doing so, in theory, could permanently fix a genetic error and the disease it causes. These type of procedures are primarily done today with two methods of delivery: a genetically engineered lentivirus, the type that another Third Rock portfolio company, Bluebird Bio (NASDAQ: BLUE) is using in its clinical trials, or modified AAV vectors, which startups like Dimension Therapeutics, Audentes Therapeutics, and others, are using to deliver gene therapies.

Third Rock wanted to start a gene therapy company that could target central nervous system diseases, because of the number of rare genetic disorders affecting the brain that don’t have any effective treatments. The firm favored AAV’s as the vector of choice for a few reasons: early studies are showing that they appear to distribute their payloads through “large portions of the brain”; they’ve been tested in far more patients than other types of vectors; and they don’t appear to provoke an immune response in the brain, according to Levin.

“We thought it would be on the safer side,” Levin says.

So Third Rock rounded up four experts in the fields of neuroscience, gene therapy, and RNA interference, and cut licensing deals with them to put Voyager together. The four are UCSF neurology and neurosurgery professor Krystof Bankiewicz, who has been developing various methods to deliver therapeutics to the brain; Guangping Gao, the director of the University of Massachusetts Medical School’s Gene Therapy Center and an expert at engineering AAV’s, according to Levin; Stanford University AAV virologist Mark Kay; and Phillip Zamore, one of the founders of Alnylam and the co-director of the RNA Therapeutics Institute at the University of Massachusetts Medical School. They then formed Voyager with plan of building a proprietary in-house library of AAV’s that the company could either use to develop its own gene therapies for rare neurological disorders, or to form licensing deals with pharmaceutical companies for diseases it isn’t interested in working on, according to Levin.

“We’re going to be taking pieces from each one of the viruses and even changing pieces of the virus and create a whole new estate of intellectual property,” he says.

Still, Voyager is facing some big challenges. The company plans to deliver these therapies by injecting them either into the spine, or directly into the brain, depending on the disease it’s targeting. And despite the early indications that AAV’s generally don’t trigger an immune reaction, there’s always the risk. That’s something Levin says the company will pay very close attention to.

“The delivery systems are important, they have to be safe,” Levin says. “There are different technologies and different approaches for all of these, but they’re doable.”

To get a product through clinical trials and to FDA approval, Voyager will have to break new ground. There are no FDA approved gene therapies, and there’s only one approved in Europe. An AAV gene therapy San Diego-based Ceregene had been developing for Parkinson’s, for instance, failed in Phase II clinical trials last year. Richmond, CA-based Sangamo Biosciences (NASDAQ: SGMO) has since acquired Ceregene, and with it, a mid-stage gene therapy program for Alzheimer’s Disease.

Initially, Voyager has three programs in mind: Friedreich’s Ataxia, ALS, and Parkinson’s. Freidreich’s is characterized by genetic mutations that limit the production of frataxin. Voyager’s plan is to inject an AAV into a patient that would deliver frataxin into the body over a long period of time. For ALS, Voyager would inject an AAV with a micro RNA molecule that would knock down a gene called SOD1 that is known to mutate in patients with the disease.

Parkinson’s, meanwhile, is a bit of an outlier program for Voyager in that the company is not looking to address an underlying genetic mutation. Instead, Voyager would use an engineered virus containing an enzyme known as AADC through a shot directly to the putamen, a part of the brain. That enzyme helps the brain convert levodopa into dopamine, which scientists hope will quell the symptoms of Parkinson’s. Bankiewicz is running a Phase 1b clinical trial testing this method in human patients. The idea is that this would provide a long-term relief, rather than require a bunch of repeat shots, though the extent of the therapy’s effect hasn’t really been proven in humans yet.

“It’s not a cure for the disease, but it’s a real dramatic increase in the quality of life, we believe,” Levin says.

Voyager isn’t the only company trying such an approach in Parkinson’s. Netherlands-based Uniqure (NASDAQ: QURE) and UK-based Oxford BioMedica are developing different gene therapies for Parkinson’s, and Uniqure cut a deal with Bankiewicz in 2012 to test its gene therapy in an early study. That deal is independent of what Voyager is doing, Levin says. The trial is ongoing, according to regulatory filings.

Even with the specter of competition, Bankiewicz’s study represents Voyager’s most advanced program. If that study goes well, Voyager would then optimize the AAV vector he’s using and potentially use a souped-up version of it in a bigger trial late next year. The company is still designing the viral vectors that it wants to use to treat Friedrich’s Ataxia and ALS, and expects to finish those and begin trials in a couple years. Those are just a few of the AAV’s the company wants to have in the library it’s putting together.

“This has not really been done at this scale before, so we really need to do this carefully and with a lot of thought,” Levin says. “When you think of the future of proteins and large molecules and delivery to different parts of the brain, the AAV virus really becomes a key product engine to do that.”

Ben Fidler is Xconomy's Deputy Biotechnology Editor. You can e-mail him at bfidler@xconomy.com Follow @benthefidler

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