In what has proved to be a slow and somewhat bumpy road for gene therapy research, one company - Avigen Inc. - is gracefully bowing out in order to focus on more traditional drug development.
For about 15 years, scientists have studied gene therapy in humans and yet most companies are still in early clinical trials, evaluating safety. The 1999 death of 18-year-old Jesse Gelsinger didn't help matters. He participated in a gene therapy study using an adenoviral vector at the University of Pennsylvania.
Then in 2003, the FDA stopped all gene therapy trials that use retroviral vectors when a second child with X-linked severe combined immunodeficiency disease, or "bubble boy syndrome," acquired a leukemia-like condition.
Even Alameda, Calif.-based Avigen, which uses an adeno-associated virus (AAV) to deliver genes, discontinued a seven-patient Phase I study of Coagulin-B last year after two patients experienced mild elevations in liver enzymes, leaving no therapeutic window. Coagulin-B used AAV to deliver Factor IX, the missing or deficient protein that causes hemophilia B. (See BioWorld Today, June 1, 2004.)
But Avigen's president and CEO, Kenneth Chahine, said the decision not to fund AAV gene therapy has nothing to do with disappointing data. It purely is a strategic decision.
"There are some challenges in gene therapy," he said. "The technology needs to be mature. So we're trying to be honest and objective about what the company needs to do to build a sustainable business."
Some companies, such as Los Angeles-based Epeius Biotechnologies Corp., are forging ahead in the field. Epeius started a Phase I trial in New York this week to test the safety and efficacy of Rexin-G, its tumor-targeted gene delivery vector developed to treat metastatic colon and pancreatic cancer. The product has orphan drug status.
Avigen's decision to step aside from AAV gene therapy does not negate the program's potential, Chahine said. It just provides the company with a better chance of increasing shareholder value with the tried-and-true approach to drug development.
The company will either spin out the AAV technology into an independent venture-backed company, combine assets with another gene therapy company, or operate clinical programs through academic institutions. Avigen expects to reduce its burn by 40 percent, down from $23 million last year to $13 million this year. Depending on the scenario - a spinout, a merger, a sub-lease of facilities - Avigen could reduce its expenses to as low as $10 million.
"There are viable options in all three areas," Chahine said. The company is at the point of putting verbal offers into writing. "It's just going to come down to the economics, and what we think will provide our shareholders the greatest potential for upside."
The AAV programs include the Phase I trial for AV201 for Parkinson's disease and an open investigational new drug application for the treatment of hemophilia B. The latter program was licensed exclusively to Bayer AG, of Leverkusen, Germany, but the rights were returned to Avigen in December.
Data from the Parkinson's disease trial have been positive, with no adverse events and the first treated patient showing signs of cure. With the high placebo effect of Parkinson's disease, and the fact that the Phase I trial is meant to evaluate safety, and not efficacy, Avigen has not publicly released specific data on that first patient.
"It's not that we don't feel encouraged by what's going on," Chahine said, "but we also feel a sense of responsibility to [not focus on] how one patient is doing in a 15-patient trial."
AAV is a member of the parvoviridae family of small, non-enveloped viruses that gets its name from being discovered as a contaminant in a clinical sample of adenovirus more than 40 years ago. AAV vectors are produced by removing the viral genes and replacing them with genes for therapeutic proteins.
Part of the problem with gene therapy research has been the slow enrollment of patients. Although it has worked on AAV gene therapy for more than a decade, Avigen has had little news on the program in the last year.
"We've shared over the months the rather rigorous guidelines the FDA has imposed in terms of patient accrual," said Thomas Paulson, the company's chief financial officer. "They seem to have lightened that, but that was one of the issues we had to deal with."
Avigen also could have invested millions of dollars more into its AAV technologies only to discontinue development at a later stage. That's what happened last month to Seattle-based Targeted Genetics Corp., which dropped development of tgAAVCF in patients with mild to moderate cystic fibrosis after a Phase IIb study missed its primary endpoint. The product also used AAV-based delivery technologies and was designed to deliver a functional copy of the cystic fibrosis transmembrane regulator gene to the lung epithelium. The company's stock plummeted 35 percent that day. (See BioWorld Today, March 18, 2005.)
Avigen has 40 U.S. patents and 29 foreign patents, covering AAV technologies, its manufacture, delivery and treatment of several diseases. The company also has two GMP manufacturing facilities that can produce commercial-scale quantities of AAV, but also could be used to manufacture cell therapeutics, recombinant proteins and monoclonal antibodies.
Chahine said the company has been working for more than a year to position itself to redirect its resources from viral-based gene therapy to more traditional drug development. The company's resources now will go toward its preclinical programs in neuropathic pain and toward acquiring or in-licensing late-stage clinical products.
Avigen is working on a new class of molecules through an exclusive license to treat chronic pain using anti-inflammatory cytokines, including interleukin 10, from the University of Colorado at Boulder. In the past, pain research has focused exclusively on neurons, which relay pain messages to the brain. However, Avigen's research also will look at glial cells, which create and maintain pain.
The company's candidate AV333 has reversed neuropathic pain in preclinical models. The product is a nonviral-based therapy designed to deliver the gene that expresses the anti-inflammatory IL-10, eliminating the pain signals.
Investors barely flinched at Avigen's news Tuesday. The company's stock (NASDAQ:AVGN) rose 4 cents to close at $2.85.