Medical Edge Newspaper Column

New Drug Offers Rare Opportunity
To Better Understand MS

Aug. 28, 2006
DEAR MAYO CLINIC:
The U.S. Food and Drug Administration recently reapproved Tysabri, a drug that earlier was said to be a big advance in the treatment of multiple sclerosis but caused a few instances of deadly side effects. Now that this medication is back on the market, what difference will it make in how MS patients are treated? And is it really safe?

ANSWER:
Tysabri (brand name for natalizumab) will not make a big difference for most multiple sclerosis (MS) patients -- at least, not right away -- because the Food and Drug Administration (FDA) reapproval carries a variety of restrictions. And the drug's link to that deadly side effect, a rare brain infection called progressive multifocal leukoencephalopathy (PML), means that physicians will likely consider Tysabri mainly for aggressive or unresponsive cases.

In MS patients with frequent and severe flare-ups whose condition is rapidly deteriorating or for those who cannot tolerate or are not helped by other available drugs, Tysabri's benefits may well offset its one-in-a-thousand risk (based on present data) of PML.

The good news is that the FDA's TOUCH Prescribing Program -- which specifies limited access to Tysabri and frequent follow-up -- is essentially a long-term clinical trial that could have a big impact on the overall understanding of MS and its future treatment.

MS is a chronic disease that affects the central nervous system. In patients with MS, the body incorrectly directs immune cells against the myelin sheath that surrounds the nerves. These attacks cause inflammation and injury to the sheath and eventually to the nerves, resulting in multiple areas of scarring (sclerosis). Such damage can slow or block nerve signals that control muscle coordination, strength, sensation and vision.

Typically, MS advances in two steps: 1) initial episodes of inflammatory demyelination associated with neurologic dysfunction, which are sometimes debilitating but usually soon subside, and 2) a subsequent slow and irreversible progression of the disease. Scientists are still unsure whether the frequency and severity of flare-ups affect the MS patient's subsequent rate of decline. They may be unrelated; or it's possible that they are related but that available drugs have been unable to reduce inflammation enough to show benefit.

With Tysabri, the research community finally has an opportunity to determine whether limiting inflammation early will slow the disease's progression. This is because the drug has reduced flare-ups by some two-thirds, and 96 percent of patients treated with Tysabri showed no new active lesions on brain imaging. If preventing early inflammation does indeed slow progression, Tysabri may be able to prove it. And if that is the case, this new approach to treating MS -- whether with Tysabri or a safer successor -- could make a substantial difference in the prognosis of many MS patients.

Tysabri's effectiveness appears to rest on its unique mode of action. Current treatments attempt to limit damage caused by inflammatory immune-system agents (called T-lymphocytes) that have already crossed the blood-brain barrier and entered the central nervous system. But Tysabri -- the first MS drug that is a monoclonal antibody -- prevents the T-lymphocytes from penetrating the nervous system in the first place.

Tysabri's remarkable performance prompted the FDA to quickly approve its use in 2004, subject to continuing trials by the manufacturer. When those trials yielded three cases of PML (in about 3,000 patients) a year later, the company and the agency agreed to withdraw it. But regulators decided that the potential for Tysabri to prevent neurologic worsening in certain MS patients outweighed its small but serious risk and prompted the FDA to reapprove Tysabri for use and continued study in 2006.

-- Claudia F. Lucchinetti, M.D., Neurology, Mayo Clinic, Rochester, Minn.