Evolution of multiple sclerosis treatment: next generation therapies meet next generation efficacy criteria

Abstract

Multiple sclerosis is thought to be the leading cause of neurological disability in young adults in developed countries, and in most patients is thought to be mediated by a persistant inflammatory reaction in the CNS. The underlying pernicious interplay between the immune system and the CNS has led to intensive joint research efforts, and eventually to the introduction of the first disease-modifying treatments in the 1990s. Beta interferons and glatiramer acetate have set the stage for multiple sclerosis therapy development: the methods and clinical efficacy in all subsequent major trials have been benchmarked against the pivotal approval studies for these agents. Phase 3 studies have primarily focused on a single parameter such as relapse rate and disability progression, whereas concomitant parameters such as subclinical inflammatory activity or lesion burden detected by MRI are regarded as secondary endpoints only. This strategy has made studies of multiple sclerosis therapy feasible and comparable, but is insufficient to capture the effect of treatment on the disease process, and therefore only partly reflects real-world treatment scenarios. In an attempt to improve on these shortcomings, Havrdova and colleagues 1 Polman CH O'Connor PW Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354: 899-910 Crossref PubMed Scopus (2575) Google Scholar suggested a new approach that combines clinical and MRI outcomes in an aggregate measure, and applied this to the phase 3 placebo-controlled natalizumab safety and efficacy in relapsing-remitting multiple sclerosis (AFFIRM) study. 1 Polman CH O'Connor PW Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354: 899-910 Crossref PubMed Scopus (2575) Google Scholar The results of these post-hoc analyses published in The Lancet Neurology in 2009 showed that 37% of patients treated with natalizumab, but only 7% of patients with placebo, were free of any detectable disease activity over 2 years, defined by the absence of relapses, sustained disability progression, gadolinium-enhancing lesions, and new or enlarging T2-hyperintense lesions on cranial MRI. 2 Havrdova E Galetta S Hutchinson M et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009; 8: 254-260 Summary Full Text Full Text PDF PubMed Scopus (373) Google Scholar Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysisTreatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Full-Text PDF Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomesAlemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. Full-Text PDF