"I don't think any of us would disagree that, if an alternative exists to a GE solution, it's to be preferred" Mr Hodson QC on behalf of the Life Sciences Network at the New Zealand Royal Commission on Genetic Modification, 8th Feb 2001

"I think gene therapy is definitely the future. Right now there's a lot of skepticism about gene therapy, but to me, that's the best to time invest because you can get better deals." -Wei-Wu He, venture capitalist at Emerging Technology Partners LLC

Gene Therapy's Hot Seat
Tuesday, February 20, 2001
By Terence Chea
Washington Post Staff Writer

The death of an Arizona teenager during an experiment 17 months ago intensified public scrutiny of gene therapy, prompting new questions about its medical and commercial promise.

Public confidence in gene therapy has been shaken. Federal regulators are imposing stricter rules on experiments. And investors remain skeptical  about a much-hyped but largely unproven technique that has yet to produce a  single approved drug.

These doubts have created additional challenges for several companies  racing to bring to market the first gene-therapy drugs, which are injected into patients to treat disease with new genes.

GenVec Inc., a Gaithersburg biotechnology company, is among those forging ahead despite the gloomier environment. The company has started advanced human testing of an experimental gene-based drug for heart disease, it recently raised $38 million in an initial public offering of stock, and it has earned $54 million under a research agreement with New York pharmaceutical giant Pfizer Inc. Last week, GenVec announced it will begin its first human tests of a gene-therapy drug to treat cancer.

GenVec is one of about a dozen biotech firms that hope to validate the  field of gene therapy ”” and profit from it ”” by bringing products to market. But the company's success will depend on whether it can convince skeptical doctors, patients, regulators and investors that its drugs work.

"All of the trends are encouraging," said Paul Fischer, the company's president and chief executive, about the progress of its most promising  drug candidate. "But the real evidence comes with larger scientific studies."

Gene therapy is one experimental technique scientists are investigating as they search for new ways to treat disease based on an increasingly  detailed knowledge of human genes. Since the first experiment was conducted 10  years ago, the technique has been viewed as promising, but it has yet to live up to expectations.

"Gene therapy and gene-based medicine will revolutionize medicine over the next 10 to 20 years," said French Anderson, director of gene therapy at  the University of Southern California's medical school, who conducted the  first gene-therapy experiment in 1990. "The big question is when."

GenVec was founded in 1992, not long after the idea of gene therapy first emerged in the 1980s. Its founders launched the company to develop a gene-therapy treatment for cystic fibrosis, a hereditary lung disease. But after running into technical hurdles, the company decided to harness the  new technology to fight heart disease, cancer and blindness, widespread  ailments that offer potentially vast markets.

The company is in the early stages of testing gene-therapy treatments for cancer and blindness, while its treatment for heart disease, BioBypass,  has moved the furthest in the development process.

Last year, the company began advanced human testing of BioBypass, which  aims to treat coronary artery disease and peripheral vascular disease ”” conditions caused by clogged arteries that obstruct blood flow in the  heart and legs, respectively. The two diseases affect millions of Americans and can cause problems ranging from chest pain to heart attacks.

The treatment involves injecting patients with genes that direct the production of proteins, which cause the body to grow new blood vessels.  This allows blood to bypass the clogged arteries. The drug, injected directly into blocked areas, uses a disarmed cold virus known as an adenovirus to deliver the new genes into the patient's cells.

GenVec is developing the drug with Warner-Lambert Co., a Pfizer  subsidiary, which is sponsoring the costly human tests needed to win federal approval. The companies have enrolled 70 patients to test the drug for coronary  heart disease and 105 patients for peripheral vascular disease. Under a 1997 agreement, GenVec has earned $54 million out of a possible $100 million in milestone and research payments from Pfizer.

Craig D. West, a biotech analyst at A.G. Edwards in St. Louis, believes BioBypass could generate $50 million to $250 million in annual revenue ””  of which GenVec would receive a percentage ”” if it is approved for  production. He said results from current human tests, expected this fall, will be critical.

"Their task is to prove that BioBypass works," West said. "If they can  prove that this stuff works, they can come back and get another round of financing."

GenVec executives believe BioBypass could eventually replace heart  surgery, the most common treatment for heart disease. BioBypass could be one of the first approved gene-therapy drugs, ushering in a new generation of genetic medicine.

"It would begin to show a new approach to treating chronic diseases by  using the body's own natural mechanisms," Fischer said. "It could really improve the quality of life for patients."

But GenVec has a long way to go. It will be at least five years before BioBypass reaches the market, and even then the company must sell it in a climate changed by the death of 18-year-old Jesse Gelsinger.

Gelsinger's death dealt a serious blow to the emerging field of gene  therapy and to biotechnology companies. In September 1999, Gelsinger volunteered  for an experiment at the University of Pennsylvania to treat a rare genetic liver disease. Although 17 patients underwent the same treatment without side effects, Gelsinger suffered a severe immune reaction and died of  liver and other organ failure four days after receiving an injection of genes.

The case spurred investigations into the monitoring and reporting  practices of gene-therapy researchers. It led to calls for stricter rules to govern gene-therapy trials, including a proposal last month that would substantially increase public disclosure of safety information related to such experiments. And, at a time when gene therapy had yet to produce a single proven drug, the case fueled doubts about the field's future.

"It just caught everybody totally off-guard," said USC's Anderson. He said the case hurt public trust, as well as investor confidence, in gene  therapy. And it made researchers realize gene therapy was not absolutely safe and  its development would take longer than expected, he said.

"It's just a lot more complex than conducting a mouse experiment and  setting up a clinical trial," Anderson said.

GenVec was not involved in Gelsinger's death, but it was particularly troubling to the company because it involved the same type of virus GenVec uses to deliver genes. The case triggered an investigation into the use of adenoviruses, a common vehicle for gene therapy. Most scientists have  since concluded that adenoviruses are safe when used in low doses, but some doctors and patients aren't convinced.

GenVec executives say their gene therapy uses an extremely low dose of the drug ”” one-thousandth of the amount used in the Gelsinger case ”” and delivers it directly to the disease site, minimizing potential side  effects.

"When we've done our clinical studies, the drug has been extremely well tolerated," Fischer said, pointing out that its lead product was approved for advanced human testing after earlier tests showed the drug to be safe.

Even if scientists are convinced that gene therapy is safe, it may be  harder to change public attitudes toward the new technology.

"I don't think public perception has changed at all," said West, the analyst, comparing attitudes toward gene therapy to those toward  genetically modified foods. He said gene therapy "will undoubtedly present some deeply unsettling ethical concerns."

Many investors are still skeptical of a concept that has yet to be scientifically or commercially proven, a sentiment that may make it difficult for companies like GenVec to raise money to fund their research.

"I'm not saying progress hasn't been made, but I think we're still far  from the finish line," said Alidad Mireskandari, a portfolio manager at  Monument Medical Sciences Fund in Bethesda. "From an investor's perspective, I'd be hesitant putting a majority of my assets into these companies."

Meanwhile, GenVec faces competition from several firms seeking to develop gene-therapy drugs to combat clogged arteries. Its two main rivals are Collateral Therapeutics Inc. of San Diego and Vascular Genetics Inc. of Durham, N.C. Vascular Genetics, which is working with Human Genome  Sciences Inc. of Rockville, delivers new genes by injecting raw DNA into the  patient, bypassing safety concerns over the use of adenoviruses.

Despite the challenges, GenVec executives remain optimistic about the  future of gene therapy. Chief executive Fischer said Gelsinger's death ultimately helped the emerging field by alerting scientists to potential risks.

"As tragic as that event was, I think it helped people understand how to move forward in the future safely and carefully," Fischer said. "It made people double-check the safety issue."

Fischer said the public must be educated about the benefits and risks of gene therapy. He believes new rules and government oversight will help to restore public confidence in the field.

Although doubters abound, some investors are bullish about gene therapy's prospects. Wei-Wu He, a venture capitalist at Emerging Technology Partners LLC in Bethesda, said he believes the treatment, once technical issues are resolved, will become a major force in the medical arsenal.

"I think gene therapy is definitely the future," he said. "Right now  there's a lot of skepticism about gene therapy, but to me, that's the best to time invest because you can get better deals."   

© 2001 The Washington Post Company