NYTIMES
June 1, 2000
Biotechnology Is Taking Aim at Psoriasis With New Drugs
By ANDREW POLLACK
Nancy Wegard for The New York Times
Dr. Alice B. Gottlieb is a research director at Robert Wood Johnson Medical School.
When his psoriasis is at its worst, David G. Metz has a silvery scale covering his entire body except the soles of his feet. "You leave a trail behind you where you've been -- the skin cells just fall off," he said, adding that this makes him very self-conscious and reclusive.
But last Christmas, Mr. Metz, a 27-year-old Wal-Mart sales clerk from Columbia, Ill., visited his girlfriend's family in Chicago without worry. An experimental drug being developed by Genentech and Xoma, he said, left him "as normal looking as a person could look."
The biotechnology industry is taking aim at psoriasis, a chronic disease that affects an estimated seven million Americans and, in its more serious forms, is far more physically and psychologically devastating than the mere cosmetic disease it is often thought to be.
About 30 companies, mainly biotechnology concerns, have psoriasis drugs in clinical trials, according to the National Psoriasis Foundation. In a race for the lead are two industry giants and longtime rivals -- Biogen and Genentech, both of which have drugs that could reach the market in two or three years.
While none of the drugs are expected to cure the disease permanently, early test results show that some of them could be safer and effective for longer periods than is the case with existing drugs.
"We're looking at several drugs that are almost sure things at this point," said Dr. Mark Lebwohl, chairman of the dermatology department at Mount Sinai Medical Center in New York, who is participating in several clinical trials. "So far, they have been remarkably benign."
The new drugs are not expected to greatly affect makers of existing products -- at least not right away -- in part because many products on the market have other primary uses, like preventing transplant rejection. "I don't think anybody necessarily loses business," said Elise Wang, an analyst with PaineWebber.
"These drugs will expand the market."
Though no one knows precisely what causes psoriasis, it is assumed to be an autoimmune disease, in which the body's defenses against infection attack the body's own tissues. It has, in some sense, become a proof-of-principle disease, one used to test drugs that companies hope will also be useful for other autoimmune diseases like rheumatoid arthritis and lupus.
"In psoriasis, you get a pretty easy readout -- you look at the skin," said Gisela Schwab, vice president for clinical development for Abgenix, which has chosen psoriasis as the first disease to try to attack with its antibody technology.
But some analysts caution that psoriasis is deceptively hard to treat and that one company after another has failed in its treatment efforts.
"They think it's going to be a short-cut way to test out their new drug, and it never works out," said Cynthia Robbins-Roth, an industry consultant and the author of "From Alchemy to IPO" (Perseus Books), a new book about the biotechnology business. "It's just a running joke in the biotechnology industry."
Still, hope for better psoriasis treatments is rising anew, in part because of the identification of the cells involved in the attack on the skin by scientists at Rockefeller University in 1995. Moreover, biotechnology companies in recent years have had dramatic success with drugs for other autoimmune diseases like rheumatoid arthritis and Crohn's disease.
"There's been a renaissance in drug development," said Dr. Alice B. Gottlieb, director of clinical research at the Robert Wood Johnson Medical School in New Brunswick, N.J. Most of the exciting new drugs, she said, are from biotechnology companies.
But most must be injected, limiting their appeal.
Still, there are an estimated 200,000 to one million Americans with serious cases of psoriasis.
This could mean annual sales of hundreds of millions of dollars for a successful drug. And for some companies, the stakes are high. The psoriasis drug Amevive is now Biogen's best hope for diversifying beyond its first drug, Avonex, for multiple sclerosis. James C. Mullen, Biogen's chief operating officer, said the market potential of Amevive was similar to that of Avonex, which had sales of $621 million last year.
For patients with severe symptoms of the disease, psoriasis can be debilitating. The red swollen skin covered with the silvery scale, the most common manifestation, can be itchy and can hurt. About 10 to 20 percent of psoriasis patients also develop a painful form of arthritis. Each year, said the psoriasis foundation's Web site, "many people with psoriasis are hospitalized, and a few hundred die from complications of psoriasis or its therapies."
The psychological effects can also be a problem.
Marge Harris, a 46-year-old meeting planner from St. Louis, still recalls being ordered to leave a public swimming pool a decade ago because the lifeguard thought her condition was contagious. (It is not.) "I haven't gone swimming for 10 years now in a public place where I can be humiliated like that again."
Dr. Steven R. Feldman, associate professor of dermatology at Wake Forest University School of Medicine, said that 25 percent of the 317 psoriasis patients responding to a survey by his department said they had considered suicide because of their disease. The paper on the study was published in September.
In psoriasis, infection-fighting blood cells known as T cells swarm into the skin cells. They release chemicals known as cytokines that cause the skin to go into overdrive. New skin cells proliferate as if trying to heal a wound that is not there.
Existing treatments can often clear the skin but either lose their effectiveness over time or have severe side effects that force patients to stop using them.
Exposure to ultraviolet light slows the proliferation of skin cells but raises the risk of skin cancer. Drugs called retinoids can cause birth defects; women using Roche Pharmaceuticals' Soriatane, the newest such drug and one safer than its predecessors, are still cautioned not to become pregnant for three years after treatment stops.
Steroidal creams can cause deterioration of the skin.
Cyclosporine, made by Novartis under the name Neoral (some generics of older forms are also available) and used primarily to suppress rejection of transplanted organs, can cause kidney disease. Methotrexate, basically a generic product and originally a cancer chemotherapy drug, can cause liver toxicity. Both drugs take a sledgehammer approach, suppressing the entire immune system to stop the immune attack on the skin.
The biotechnology drugs aim to interfere with the immune reaction that is responsible for the attack on the skin without affecting the functioning of the rest of the immune system -- an exceedingly difficult balancing act. The immune system has multiple pathways, so blocking just one might not blunt the undesired immune attack. If a drug is too general in depressing the immune system, however, the patient becomes susceptible to infections or an increased risk of cancer.
Biogen's Amevive, for instance, depleted the number of active T cells in some patients, forcing the company to stop giving the highest dose. Dr. Burt Adelman, vice president for medical research, said there was no evidence that patients actually suffered more infections or cancer. A lower dose, he said, should solve the problem and still be as effective, though analysts cautioned that this remained to be seen.
Amevive is designed to prevent T cells from being activated, which occurs when so-called antigen-presenting cells display a protein that the T cell recognizes as foreign. The drug disrupts the mating of the T cell and antigen-presenting cell. The problem is that this can also affect other T cells, not just the ones aimed at the skin.
In Phase 2 trials, an intravenous infusion once a week for 12 weeks completely cleared the skin of 30 percent of the patients, with the improvements lasting six to eight months, Dr. Adelman said. He said the company hoped to apply for approval of Amevive, now in Phase 3 trials, by the end of 2001, which would mean an approval could come by the end of the following year.
Genentech and Xoma are just entering Phase 3 trials and appear to be some months behind Biogen. Their drug is a monoclonal antibody that neutralizes CD-11a, a molecule that is instrumental in helping the T cells leave the bloodstream and enter the skin. The idea is to keep the T cells from getting to the skin but to allow them to survive in the blood, where they fight infections.
The drug, for now being called Anti-CD11a, has not had the same problem with T cell depletion that Amevive has had, but some patients did experience an immune system reaction called cytokine release syndrome, which produces flu-like symptoms.
In an early clinical trial, 48 percent of patients who got an intravenous infusion once a week for eight weeks had at least a 50 percent improvement compared with 15 percent for a placebo. Mrs. Harris of St. Louis, who tried the drug, marveled at its lack of side effects. But she relapsed within a month after she stopped taking it.
Many other drugs are in Phase 1 or Phase 2 clinical trials, with less evidence of their safety and effectiveness. Abgenix, which is based in Fremont, Calif., has an antibody that is intended to neutralize IL-8, one of the immune chemicals that are found in elevated levels in the skin lesions. The Immune Response Corporation of Carlsbad, Calif., is working on a therapy that uses the immune system to attack the T cells specifically involved in the skin inflammation.
Corixa of Seattle is basing its approach on the fact that there are two types of T cell responses, TH1 and TH2. It is in early tests of an immune stimulator that elicits a TH2 response, which tends to shut down the TH1 response that is prevalent in inflammatory diseases.
Others are developing drugs that can be swallowed or spread on the skin, hoping to reach a broader market. Isis Pharmaceuticals of Carlsbad is testing a topical drug. Ligand Pharmaceuticals of San Diego is trying to develop a safer version of retinoids.
Also being tested for psoriasis are two drugs that have already proved successful in other autoimmune diseases: Enbrel, an arthritis drug made by Immunex, and Remicade, which is used for arthritis and Crohn's disease and is made by the Centocor unit of Johnson & Johnson. Dr. Gottlieb said there would be room for several drugs because each one produces a "socko" response in only about 20 percent of the patients.
Longer term, scientists around the world are trying to find genes involved in the disease. That is the best hope for a real cure.
For now, though, doctors are just hoping for better treatments.
Dr. Craig L. Leonardi, a dermatologist in St. Louis, said, "This is a disease that's been waiting for a new approach for a long, long time." |
