By Timothy Tankosic, M.D.

According to the National Multiple Sclerosis Society, an estimated 400,000 Americans have MS, and as many as 2.5 million people worldwide are affected with the disease. Many important advances in the treatment of MS were achieved since the early 1990s, when the first agents that reduced the frequency of MS attacks through activities on the immune system were introduced. The first of the following U.S. FDA approvals occurred in 1993

• Betaseron® (interferon beta-1b; Berlex, Inc./Schering AG)
• Avonex® (interferon beta-1a; Biogen Idec, Inc)
• Copaxone® (glatiramer acetate; Teva Pharmaceutical Industries, Ltd)
• Novantrone® (mitoxantrone; Serono International, SA)
• Rebif® (interferon beta-1a; Serono/Pfizer, Inc)

Four of the drugs are approved for life-long use. The exception is Novantrone, a cancer chemotherapeutic agent associated with cardiotoxicity, which is restricted to four (in-hospital) administrations per year for no more than three years.

Most recently, Tysabri® (natalizumab; Biogen Idec and Elan Corp.), a humanized MAb alpha-4 antagonist, was approved by FDA for relapsing multiple sclerosis (November 2004). In February 2005 it was voluntarily suspended from the U.S. market by the manufacturers, based on reports of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal, demyelinating disease of the CNS. All ongoing clinical trials were halted. In August, the companies reported results of a safety evaluation review that found no new cases of PML among more than 2,000 patients treated for MS in clinical trials and in commercial use, leaving the total at 3 (previously reported) confirmed cases; 2 were fatal. Safety evaluations in Crohn's disease and rheumatoid arthritis are expected soon, as are submissions to regulatory agencies. The companies, encouraged by the safety findings to date, have initiated preliminary steps to restart clinical trials in MS because of the "high unmet medical need in MS and the therapeutic benefit we have seen with Tysabri."

If approved, it is not clear how much of an impact Tysabri would have on the treatment of MS. Before and immediately after its approval, analysts had forecast annual sales of $2 billion to more than $3 billion. One analyst, Steven Harr of Morgan Stanley, suggests that Tysabri will become a niche drug, with sales of about $500 million. In addition to fear about causing PML in patients, he cites broader adverse events associated with the drug, particularly opportunistic infections (which might require monitoring), all of which are likely to be closely scrutinized at FDA and of great interest to the medical community. Biogen Idec reported to investors that, in clinical trials, they found no significant differences between subjects receiving Tysabri and those receiving placebo.

Table 1 lists select recent events and drugs in development for MS.

Table 1

Source: D&MD

This clinical update on Tysabri and select developmental advances for the treatment of multiple sclerosis was written by Timothy Tankosic, M.D.

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