When the immune system goes bad, it goes very, very bad. Some 80 known diseases are caused by out-of-control immune cells that attack the body's own organs -- among them multiple sclerosis, rheumatoid arthritis, type 1 diabetes, asthma, psoriasis, and Crohn's disease. For more than a decade, the pharmaceutical industry has been trying to come up with drugs to hold wayward immune systems in check. The recent experience with Tysabri, the breakthrough multiple sclerosis drug from Biogen Idec Inc. (BIIB) and Elan Pharmaceuticals Inc., shows the perils of tampering with the body's defenses.
A variety of immune-modulating drugs are now in the pipeline, and the need for them couldn't be more urgent. But this class of drugs, perhaps more than any other, requires that both manufacturers and regulators be extra-vigilant in monitoring for deadly side-effects -- and in educating patients about the dangers.
It's possible Tysabri can still be saved. Approved by the Food & Drug Administration last November, it is the first new MS drug in more than a decade and is a "fantastic advance," according to Dr. Aaron Miller, chief medical officer at the National Multiple Sclerosis Society. When Biogen and Elan pulled it from the market on Feb. 28 after learning that two patients had developed a rare brain disease, fatal in one case, Miller and others in the field were saddened. The company and the FDA are seeking ways to reintroduce Tysabri safely, but Miller notes that it will be extremely difficult to screen out patients vulnerable to brain infections.
The problem is that the mechanism that makes Tysabri such an effective MS fighter may also turn it into a traitor. MS occurs when immune cells mysteriously run amok, attacking the myelin sheath that protects nerve fibers. Tysabri blocks marauding immune cells from entering the brain. But in at least two patients who took the drug in combination with an older MS treatment, it apparently exposed the brain to the ravages of a common virus called JC.
Virtually all drugs that target the immune system leave the body susceptible to infections, and this yin-yang has tripped up a number of promising treatments in the past. Often, as with Tysabri, the infections didn't become manifest until patients were on the drugs for years. That's a bad omen for newer immune-targeting drugs, given the risk-averse climate surrounding drug development. "You will need to study a larger number of patients over years of therapy," warns Viren Mehta at investment advisor Mehta Partners LLC. The high costs of such large-scale human testing could seriously impede this area of cutting-edge research.
That would be a harsh setback for patients. The American Autoimmune Related Diseases Assn. estimates that one in every five people in the U.S. suffers from such an illness. Yet there are few effective treatments. The most common MS drug right now is interferon, which leaves patients exhausted by flu-like symptoms.
The good news is that the pharmaceutical industry has continued to identify autoimmune diseases as one of the largest unmet needs in medicine. BioPortfolio Ltd., a British market researcher, estimates that annual sales of autoimmune drugs based on biotech could triple by 2008, to about $20 billion.
The market will grow, in part, because patients suffering from these chronic and very painful diseases are often willing to accept a good deal of risk for an effective treatment. That fact has been proven by the success of Amgen's (AMGN) Enbrel, Johnson & Johnson's (JNJ) Remicade, and Abbott Laboratories' (ABT) Humira, rheumatoid arthritis drugs whose sales topped $5.5 billion last year despite a long roster of side effects. All three block tumor necrosis factor (TNF), a protein produced during the inflammatory process that leads to the breakdown of bone and cartilage. The three drugs represent a major advance against this debilitating disease, but all leave patients more susceptible to tuberculosis and respiratory infections, and there are concerns that they increase the risk of lymphoma and worsen heart failure.
There are many immunomodulating drugs in the pipeline that have yet to show problems. Bristol-Myers Squibb Co. (BMY) is seeking FDA approval for Abatacept, a rheumatoid arthritis treatment that shuts down an immune signal that triggers inflammation. And La Jolla Pharmaceutical Co. is testing Riquent, a lupus drug that blocks damaging antibodies. The drug received an "approvable" letter from the FDA last October, with the final nod contingent on the success of further clinical trials.
There is also hope that immunomodulators will ultimately be able to treat more than one disease. Rituxan may be the first to prove the point. The drug, jointly developed by Biogen Idec, Genentech (DNA), and Roche Holdings, was approved a decade ago for non-Hodgkin's lymphoma. It blocks a potentially dangerous immune-system B cell, and is in late-stage clinical trials against rheumatoid arthritis.
Such multiple uses are just what doctors had expected for Tysabri. Before being pulled, the drug was in clinical trials against rheumatoid arthritis and Crohn's disease, a bowel disorder. Biogen has not given up on the drug, and has set up meetings with a number of medical specialists to figure out a way to minimize its dangers. It is hoped that any lessons learned will be useful for other drugs in this class. Patients will then at least have options, imperfect though they may be.
By Catherine Arnst with Amy Barrett in Philadelphia and John Carey in Washington