[Updated, 2:00 pm ET] Like most everyone else in biotech, Biogen Idec bailed out of gene therapy research over a decade ago when it looked like the tantalizing field would never deliver on the hype. But gene therapy’s renaissance is now well underway, catalyzed by better delivery technologies, and importantly, promising human clinical data. And over the past year or so, Cambridge-based Biogen (NASDAQ: BIIB) has started betting on it again. That effort is continuing today, with a disease the company is well familiar with—hemophilia.
Biogen is teaming with two Italian entities—the non-profit organization Fondazione Telethon and the research institution Ospedale San Raffaele—to develop two gene therapies that treat the underlying causes of hemophilia A and B, respectively. The development efforts will take place at a joint venture between those two entities, the San Raffaele – Telethon Institute for Gene Therapy (TIGET), which will get $5 million up front, potentially additional milestone payments, and Biogen’s financial support as it develops the therapies.
Biogen has an option to grab worldwide rights to the gene therapy candidates after initial proof-of-concept studies.
Gene therapy, of course, has a checkered past. The idea is to use a modified virus or some other “vector” to deliver healthy genes into a cell to replace faulty or missing ones. In theory, this could attack the root cause of a patient’s disease and cure it for the rest of a patient’s life—potentially in a single treatment. But despite the billions of dollars poured into gene therapy research and startups in the ‘90s, no gene therapy has won FDA approval for commercial use. Safety problems and difficulties with delivering the new genes dogged the space.
That sentiment has changed over the last few years, however. In 2012, UniQure won approval in Europe of the first gene therapy treatment, for a rare metabolic disorder, lipoprotein lipase deficiency. Bluebird Bio (NASDAQ: BLUE) has produced some impressive, early results using gene therapy for a rare blood disorder called beta-thalassemia. Investment dollars have poured back into the field, leading to new startups like Spark Therapeutics, Dimension Therapeutics, Audentes Therapeutics, AAVLife, and others—and large firms, such as Biogen, Pfizer, and Baxter International getting their feet wet.
Biogen’s return to gene therapy started with a January 2014 deal with Sangamo Biosciences (NASDAQ: SGMO) focused on using its zinc finger technology as a treatment for blood disorders like sickle cell. Several months later, in September, Biogen made it clear that the Sangamo deal was the first move in what would be a broad effort by hiring Olivier Danos to steer a newly created gene therapy unit. Danos is a veteran of the field; he’d been assembling a gene therapy program at New York-based Kadmon before going to Biogen, and led a gene therapy research team at Paris’s Necker Hospital – Enfants Malades before that.
“We have a number of therapeutic areas internally, so those are the starting points,” Danos told me a few months ago. “But we’re also thinking of, if gene therapy can make sense, it can also bring new therapeutic areas into Biogen. We’re not focused on a couple of disease applications; we’re thinking of many different things.”
At Biogen, Danos has been leading a small team, currently about 12 or so, to scout for opportunities to get the biotech’s foot in the door in the reemerging field. Biogen’s R&D chief, Doug Williams, recently told Xconomy that the move into gene therapy was to put “another arrow in our quiver to treat various diseases.” Biogen’s plan is to start out with partnerships, and then build out its capabilities internally, he said.
[Updated with Danos’ comments] In an interview today, Danos said that Biogen aims to build on the Sangamo and hemophilia deals with “at least two” additional collaborations by the end of June. Those deals would focus on areas outside of hematology, opening Biogen up to “novel therapeutic areas” where it doesn’t already have a presence (Danos declined to specify).
Hemophilia is a logical place for Biogen to place a bet. It’s got a big presence in the space, having won FDA nods for two treatments for the bleeding disorder over the past year: Eloctate for hemophilia A and Alprolix for hemophilia B.
Hemophilia is also sensible application for gene therapy. Patients with the disease have to get intravenous infusions of the clotting factor they’re genetically missing either a few times a week or every few weeks, depending on the treatment they’re getting. The prospect of inserting a better-functioning gene that allows patients to produce the clotting factor on their own, a much more lasting solution, would dramatically shift the treatment landscape. That’s why the field has crowded with a bunch of hopefuls developing gene therapy treatments. Among them: Dimension (though a deal with Bayer), Baxter International, and Pfizer (via a partnership with Spark).
What sets Biogen from many of those competitors in the case of hemophilia is its choice of vector. Most gene therapy hopefuls are using adeno-associated viruses (AAVs) as their vectors in these programs. These tiny viruses, which don’t cause disease in humans, are relatively easy to manufacture, and have been shown in a large number of studies so far to be safe. Dimension/Bayer, Baxter, and Spark/Pfizer are all using AAVs in their hemophilia programs.
In this collaboration, however, Biogen is turning to lentiviruses—the family that includes HIV—which are modified so that they can no longer cause disease. Lentiviruses are larger than AAVs, can deliver larger amounts of genetic material into a cell, and integrate into a cell’s genome. Bluebird, for instance, is using lentiviruses for a gene therapy it’s developing for beta-thalassemia and sickle cell disease.
“[With lentivirus], every cell that’s made afterwards has that fix,” Bluebird CEO Nick Leschly explained to me recently. “Whereas AAV…just sits there and produces your protein, but if it dies, it dies.”
[Updated with Danos’ comments] Indeed, Danos noted that a lentivirus approach might have a more lasting effect in children with hemophilia because with an AAV, young patients could see “diminishing returns over time” as their livers grow and “dilute the signal.”
“This is not expected to happen with lentivirus,” Danos said. “This is what’s being seen in the preclinical data that [TIGET] has.”
That advantage would be mitigated if any safety issues crop up and the newly introduced genes create any other problems. Danos said the risk of such an event is low, but Biogen will keep a close eye on that as it digs through TIGET’s preclinical data.
Williams told Xconomy recently that Biogen was looking at both AAV and lentivirus, and that it would depend on the situation which vector it’d go for. “We’re sort of agnostic on platform, it’s driven by therapeutic area,” he said at the time. “Right now, for hemophilia, there’s a lot of activity…using AAV [vectors].”
Indeed, Biogen started with zinc fingers, and is now adopting a lentivirus approach for the hemophilia therapies that was developed at TIGET; those viruses shepherd the functioning genes to the liver. The Italian institution has already been testing a hemophilia B treatment in experimental models, but will now expand to hemophilia A with Biogen’s support.
[Updated with Danos’ comments] Danos said if everything goes well, Biogen would like to begin the first clinical trial in 2016.
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