F.D.A. Approves a Multiple Sclerosis Drug

The Food and Drug Administration yesterday approved a drug for multiple sclerosis that has shown early evidence of being more effective than existing drugs.

The drug, Tysabri, was developed by Biogen Idec and Elan and was called Antegren until the F.D.A. requested a name change to avoid confusion with other drugs. Some analysts predict annual sales will eventually surpass $2 billion.

Doctors and analysts say the drug represents an advance but is far from a cure. Long-term data on safety and efficacy are still lacking.

"The initial data suggests that it's better than the other drugs but it doesn't shut it off completely," said Howard L. Weiner, a professor at Harvard and head of the multiple sclerosis center at Brigham and Women's Hospital in Boston.

The F.D.A. approved the drug based on only one year's worth of data from clinical trials, rather than the two customarily required, because of positive results. In one trial, Tysabri reduced the rate of relapses - the flaring up of symptoms - by two-thirds, to 25 per 100 patients per year compared with 74 per 100 patients per year for a placebo.

That relapse reduction appears to be about twice as much as other drugs achieved in separate trials. "It's a striking reduction in relapse rate but you cannot compare across trials," said Stephen Reingold, vice president for research programs at the National Multiple Sclerosis Society.

The society estimates that there are 400,000 Americans with multiple sclerosis. It is widely considered an autoimmune disease, in which the person's immune system attacks the insulation around nerve cells. Until now there have been four drugs for the early stages of the disease: Biogen Idec's Avonex, Schering's Betaseron, Serono's Rebif and Teva Pharmaceutical's Copaxone.

Biogen Idec and Elan say 40,000 to 50,000 Americans have dropped one of these drugs because of side effects, leaving them ready for Tysabri.

"We see it as first great new hope for those people with MS who have been on one of these therapies and fallen through," Kelly Martin, chief executive of Elan, said. The drug, known generically as natalizumab, is also being tested for Crohn's disease and rheumatoid arthritis.

Elan, an Irish drug maker, is counting on Tysabri to help return it to profitability after it was financially hobbled by an accounting scandal.

Biogen Idec, the third-largest American biotechnology company after Amgen and Genentech, needs a new product because its two big drugs, Avonex and the lymphoma drug Rituxan, are showing signs of age. Two newer products have been disappointments.

The risk for Biogen Idec, which is based in Cambridge, Mass., is that Tysabri will take sales away from Avonex, which had $1.2 billion in sales last year. Biogen hopes that patients getting Avonex will add Tysabri rather than switch to Tysabri. But the real question, not addressed, is whether Tysabri alone is as good for these patients as the combination. Combination therapy might also face more hurdles getting insurance reimbursement because it will be more expensive.

The two companies said they would announce the price in a few days when they are ready to ship the drug. The delayed announcement appears in part to be a way to avoid having discussion of high prices included in news reports about the drug's approval. The companies have indicated Tysabri will be more expensive than the existing drugs, which cost $14,000 to $17,000 a year, and some analysts say the price will be much higher.

Tysabri is given by an intravenous infusion once a month. The existing drugs are given by injections, often by the patients themselves, from once a day to once a week. But many neurologists are not set up to give intravenous infusions, which could slow the acceptance of the drug.

I'm not certain, but I think it's actually been around for more than two years (the results of the one year study were just recently analyzed). Because the trials were so promising, Biogen / Elan applied for expedited review. But I just have a cursory knowledge of the drug. My assessment is based mainly on the optimism of the doctors with whom I've spoken.

One other interesting aspect of the drug is that it also treats Crone's disease, although, from what I understand, the results have not been as remarkable. If you are really interested you may want to visit this page: http://brain.hastypastry.net/forums/forumdisplay.php?s=99f656133f845be3954779b971c4dc7a&f=181

It's a neurological forum provided by a consortium of Boston hospitals and there is much discussion of the drug (among other things).

Mult Scler. 2004 Oct;10(5):511-20. Related Articles, Links

An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis.

Vollmer TL, Phillips JT, Goodman AD, Agius MA, Libonati MA, Giacchino JL, Grundy JS.

Division of Neurology, Barrow Neurological Institute at St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. tvollmer@chw.edu

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

1: N Engl J Med. 2003 Jan 2;348(1):15-23. Related Articles, Links

A controlled trial of natalizumab for relapsing multiple sclerosis.

Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O'Connor PW; International Natalizumab Multiple Sclerosis Trial Group.

Department of Neuroinflammation, Institute of Neurology, London, United Kingdom. d.miller@ion.ucl.ac.uk

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis. Copyright 2003 Massachusetts Medical Society

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