Multiple Sclerosis Research Repository

1. “Lessons for clinical trials from natalizumab in multiple sclerosis” by Abhiit Chaudhuri

-FDA gave natalizumab accelerated approval to treat relapsing MS

-approval was given on the basis of short term (1 year) data from 2 multi-centre, randomised double blind placebo controlled phase 3 trials; neither trial was published in a peer reviewed journal and the FDA granted approval before final trial and cumulative safety data were available

-primary end point of each trial was: ARR at 1 year

-FDA conclude that natalizumab was superior to all available treatments for relapsing MS (3 types of interferon beta and glatiramer)

-the 2 reported cases of MS do not answer the important question of whether natalizumab had a therapeutic effect on the pathology of multiple sclerosis distinct from demylelination due to PML

-none of the published trials showed convincing evidence of the efficacy of natalizumab in relapsing MS

-the first placebo controlled study where natalizumb (Antegren, Elan) was infused every 2 months showed no clinical effect

-Natalizumab had no proved effect on the progression of disability in these studies or in the two unpublished trials that formed the basis of its approval

-in the unpublished trials, the claimed benefit of natalizumb was based on radiological measures (number of enhancing lesions in MRI images of brain) and relapse rates, none of which correlate with long term disability in MS

-relapse rates are not continuous but discrete number, and fractional relapse rates are meaningless.  Results of the AFFIRM trial indicate that without treatment (and associated risk of side effects) a patient would experience only one extra relapse in 16-18 months.  Although the statistics of these trials may seem impressive, there is no half or three quarter relapse in a patient’s life

-annualized relapse rate for interferon beta-1a alone was slightly worse than for placebo in the natalizumab monotherapy trial (0.78% and 0.74%), a result that questions the effectiveness of the drug

-reducing relapse is not necessarily an effective strategy to prevent serious and chronic disability in MS as indicated by recent epidemiological models

-the cost effectiveness of this treatment approach is also uncertain and has not been confirmed for interferon beta-1a, the most commonly prescribed DMD in MS

-surrogate markers based on imaging results used as outcome measures in MS trials do not mirror the clinical course of the disease

-imaging surrogates for neuroaxonal loss have not been validated for predicting future disability 

-a successful treatment delay progressive tissue loss irrespective of relapse rates and clinical phenotype

-short term solutions for a chronic disease like MS are not likely to be effective, and PML results from treatment with natalizumab should be taken as a signal to change the way we treat this disease