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Biotech / Medical : Elan Corporation, plc (ELN) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (4289)	4/17/2003 9:43:51 AM
From: Icebrg	Read Replies (4) \| Respond to of 10345

Natalizumab for Relapsing Multiple Sclerosis NEJM published a letter to the editor with regard to the Antegren in the indication MS. A kind soul posted it to Yahoo! from where I have copied it. to the editor: As participants in the original exploratorystudy,1 we did not find that treatment withantia integrin antibody was of clinical benefit. Miller and colleagues (Jan. 2 issue) report that monthly natalizumab infusions in patients with multiple sclerosis significantly reduced relapse rates and enhancing lesions on magnetic resonance imaging (MRI), but this effect was not carried forward in the six months after treatment. The treatment had no effect on the disability score (on the Kurtzke Expanded Disability Status Scale). There was no evidence that long-term natalizumab infusions modify the course of multiple sclerosis. Epidemiologic studies have shown a biologic dissociation between relapses and progressive disability once a score of 4 to 4.5 on the Expanded Disability Status Scale is reached. It may be argued that all patients with multiple sclerosis should start receiving natalizumab at the time of their first clinical presentation; however, the effects of pregnancy in multiple sclerosis clearly indicate that the progression of disability is independent of clinical relapses. Longitudinal MRI studies show that perivenous inflammatory changes are associated with local alterations in the bloodbrain barrier and are not obligatory events in the evolution of the plaques in multiple sclerosis. The results of immunotherapy trials in multiple sclerosis suggest that although such treatments may reduce relapse rates, they do not modify progressive loss of function. In a three-year follow-up of a trial of treatment for acute optic neuritis, a benefit of antiinflammatory treatment was not evident. We are not convinced that the effects of natalizumab on relapsing multiple sclerosis are any exception. Abhijit Chaudhuri, D.M., M.D. Peter O. Behan, D.Sc. University of Glasgow Glasgow G51 4TF, United Kingdom ac54p@udcf.gla.ac.uk the authors reply: Chaudhuri and Behan refer to an early exploratory study of natalizumab in multiple sclerosis. This was a study of 72 patients, of whom 37 were randomly assigned to receive two doses of natalizumab, one month apart (and 35 toreceive placebo). There was a significant decrease in the number of new gadolinium-enhanced on MRI during the 12 weeks after the first dose of natalizumab, as compared with placebo. Given the small size of the study and the limited duration of treatment, however, it is not surprising that no clinical benefit was observed. The positive MRI result did, however, provide us with a reason to undertake our six-month study. Although this study was powered only to investigate the effect of treatment on MRI activity, it showed a significant treatmentassociated reduction in relapses. It is not surprising that there was no significant change in disability in either the treated groups or the placebo group over a six-month period. The mechanisms by which irreversible disability develops in multiple sclerosis are not well understood. Chaudhuri and Behan cite evidence supporting the independence of the progression of disability and relapses, but these events are not completely unrelated. Incomplete recovery from relapses is one mechanism of permanent disability. The effect of natalizumab on long-term progression of disability can be addressed only by larger, longerterm, phase 3 studies. Two such studies designed to investigate this issue are currently under way. In our article, we omitted acknowledgment of J. ORiordan and J. Parratt (Ninewells Hospital, Dundee, United Kingdom), who were investigators in the trial, and Dr. Martin Sanders, who provided helpful comments on the manuscript. David H. Miller, M.D. Institute of Neurology London WC1N 3BG, United Kingdom d.miller@ion.ucl.ac.uk Paul W. OConnor, M.D. University of Toronto Toronto, ON M5B 1W8, Canada