Thursday, November 15, 2007

Natalizumab for Multiple Sclerosis

Ransohoff RM. NEJM 2007; 356:2622-9. Clinical Therapeutics. Review article. Introduction cites that 50 % of patients reach the following disability milestones at the following times: loss of employment, 10 years after diagnosis; use of assistive devices to walk (15 years); inability to walk (25 years).The cost of care is about $47,500 per patient per year. Natalizumab contains humanized MAB's against leukocyte alpha 4 integrins, which, together with Beta chain, comprise heterodimeric glycoprotein responsible for trafficking leukocyte entry in to the CNS. In trial one, 942 patients were randomized to infusion v. placebo. Natalizumab decreased cumulative probability of sustained disability progression from 29 to 17 % (p<0.001, NTT=9), and reduced number of enhancing lesions on MRI at year 2 by 92 %. The second study, N was added to interferon beta (or not) in 1171 patients, reduced sustained disability from 29 to 23 %, NTT = 17, increased relapse free patients from 37 to 61 %, NTT=5, 89 % reduction in enhancing lesions. The review article indicates the necessity of a three month hiatus from immunosuppressant medication before starting the drug, and ensuring the diagnosis of MS is secure. TOUCH program mandates assessment of the patient at 4,7,13 and every 6 months therafter.

The fragile benefit of BENEFIT

Coles A. The Lancet Neurology 6: 753-754 2007.
Coles provides a classically British look at the BENEFIT trial noting that the study was a complicated look at Betaseron in CIS looking at disability. The first trial agaist placebo replicated CHAMPS and ETOMS by showing a delay to diagnosis of MS in a two year study of Betaseron. (N=292 on Betaseron, 176 on placebo). He offers that in the treatment arms of CHAMPS, ETOMS and BENEFIT, the conversion rate was 0.35, 0.34, and 0.28 respectively; in the respective placebo arms, the conversion rates were ).5, 045, and 0.45). In the third year everyone got betaseron (some placebo patients got betaseron earlier if they converted to MS earlier) (early treated v. late treated). In the second analysis, Betaseron was associated with less disability (the only interferon with that endpoint). In the third analysis the later treated patients had worse MRI scans. However, Coles notes that only 42/292 early treated patients accumulated disability v. 40/176 delayed treated patients. The Number to treat (NTT) to prevent one additional case of accumulated disability was 11.9. However 68 patients were lost during the trial, suggesting the possibility of statistical blips. Coles believes the trial was too small to draw conclusions and might have been compromised by dropouts or multiple endpoints measured and states another larger trial is needed.