Sticking to its Guns with Gene Therapy, Genzyme To Present Key Findings Within Days

3/25/09Follow @xconomy

Dozens of companies have given up on gene therapy after the technology failed to live up to its early promise, but not Genzyme. The world’s largest maker of drugs for genetic diseases has stuck with this field through two decades of ups and downs, and it expects to see important results in coming days on whether it has found an effective approach in people.

Genzyme (NASDAQ: GENZ), with headquarters in Cambridge, MA and a gene therapy manufacturing unit in San Diego, is planning to present results this month at the American College of Cardiology from a clinical trial of 289 patients who took its experimental gene therapy for peripheral artery disease. This treatment is designed to encourage re-growth of new blood vessels to circumvent clogged arteries in the legs. If successful, this trial will show whether a single shot can help patients with severely limited mobility keep walking for longer periods without pausing to rest.

Gene therapy, in simple terms, is about modifying viruses to carry copies of genes into cells where they can replace missing or faulty genes at the root cause of certain types of disease. This technique was hyped in the early 1990s as a panacea for many ills beyond the reach of conventional medicine. Time magazine published a cover story in 1994 titled “Genetics: The Future is Now.” More than 100 biotech companies were formed with dreams of becoming the next Amgen or Genentech. Then the field ran into a brick wall in 1999 when Arizona teenager Jesse Gelsinger died of a massive inflammatory response in a gene therapy clinical trial.

That scared away most investors, and provoked a fierce ethical debate. Gene therapy regained some momentum in 2002 when French researchers found that the technique could restore a functioning immune system for infants with severe combined immunodeficiency, sometimes called “bubble boy” disease. But even that step forward was followed by a setback when four of nine were later found to have developed leukemia between ages of 3 and 6. There are still no FDA-approved gene therapies on the U.S. market. Yet Genzyme still has about 100 people on any given day working on gene therapy programs, for peripheral artery disease, Parkinson’s disease, and age-related macular degeneration, among other conditions.

“Gene therapy was probably oversold in the early days,” says Sam Wadsworth, who oversees the company’s gene therapy research as Genzyme’s group vice president of translational research. But he’s quick to add that the scientists have a reason to keep going. “We believe that one day we will bring these therapies to patients. We know it. We will not pursue things that have no hope.”

Genzyme has been forging ahead in this field since the early days in 1991. Like some other companies, notably Seattle-based Targeted Genetics (NASDAQ: TGEN), it went after what was then considered low-hanging fruit—cystic fibrosis, a deadly lung disease in children and young adults that’s caused by a single faulty gene. Deliver the correct gene inside cells, and gene therapy was supposed to offer a cure.

It didn’t work out that way. Genzyme dropped that program long ago. The company now has three programs—peripheral artery disease, Parkinson’s disease, macular degeneration—that share some features in common. They can be treated with localized therapy that doesn’t need to circulate throughout the body, they are serious illnesses that don’t require treatments with absolutely squeaky-clean safety profiles, and they appear suitable to a single-shot gene therapy approach. Eliminating the need for multiple injections is especially useful in the case of gene therapy for Parkinson’s, in which doctors drill a hole in the skull to deliver genes to a precise region of the brain, or for macular degeneration, in which doctors make an injection behind the eye.

Local delivery is the key, Wadsworth says. Doing it that way makes it much less likely that the body’s immune system will mount a reaction to the viruses used to deliver the genes, he says.

“It’s like in real estate, where you’ve heard it’s about location, location, location,” Wadsworth says. “This is about delivery, delivery, delivery. If you can place the vector (for delivering genes) right where you want it, you’re better off.”

Part of this philosophy is built on some the hard knocks from past experiments with gene therapy, which have shown it is difficult to get tiny modified viruses to deliver genes everywhere they need to go in the body. More successes have been reported with local delivery, including a couple of people who had “amazing” results with a rare genetic form of blindness,Wadsworth says.

Wadsworth sees reason for encouragement based on these cases of Leber’s Congenital Amaurosis, that were published in 2007 in the New England Journal of Medicine. He didn’t have any more data like that to share with me about bringing back people’s eyesight, but he said Genzyme does have some data it is looking forward to presenting soon.

This trial examines whether Genzyme can deliver new copies of a gene for HIF-1 alpha, a protein associated with growth of new blood vessels. The idea is that people with peripheral artery disease have clogged arteries, and one to help them improve circulation in the legs is to form new vessels that circumvent the blockages, Wadsworth says. If that trial turns out positive, Genzyme will be prepared to advance that program into the final stage of clinical trials—where a competing gene therapy from Sanofi-Aventis has already ventured.

If scientists can report a couple of successes in trials this large, Wadsworth says he still thinks gene therapy could repeat the history of antibody drugs. There was an initial wave of hype in the early days of the 1970s, followed by failures, and then the first successful products arrived more than 20 years after the seminal discoveries.

“With monoclonal antibodies, it was hyped and then it took a long time to work out the kinks,” Wadsworth says. “The analogy of gene therapy to monoclonal antibodies is not a bad one.”

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