Research in context
Evidence before this study
A MEDLINE search from inception to Nov 9, 2017, with language restrictions, with the search terms (“secondary progressive multiple sclerosis”[Title] OR “secondary progressive MS”[Title] OR “SPMS”[Title]), identified 320 articles; search results were supplemented by a review of abstracts from recent major neurology conferences. Ten primary reports of randomised, masked, placebo-controlled clinical trials were identified as relevant. Five studies assessed interferon beta, whereas one each investigated the myelin-basic protein-derived synthetic peptide MBP8298, the antineoplastic agent mitoxantrone, the anti-α4-integrin monoclonal antibody natalizumab, intravenous immunoglobulins, and the immunomodulator linomide; this latter study was terminated prematurely. No active comparator studies were identified. The primary endpoint in six of the nine completed studies was disability progression confirmed by changes in Expanded Disability Status Scale (EDSS) score; this was a secondary endpoint in one study of interferon beta-1a, the primary endpoint of which was disability progression assessed using the Multiple Sclerosis Functional Composite scale. Two studies had composite primary endpoints: one study combined results of the EDSS, the timed 25-foot walk test, and the 9-hole peg test; the other study combined five clinical measures (change in EDSS, change in ambulation index, number of relapses requiring corticosteroids, time to first untreated relapse, and change in standardised neurological status). In the European interferon beta-1b study, patients receiving interferon beta-1b benefited from a significant reduction in time to confirmed disability progression (assessed by EDSS) compared with placebo, whereas patients in the subsequent US and Canadian interferon beta-1b study did not. Post-hoc analyses of the combined populations from these two trials showed that patients with active relapsing disease and above-average progressive disease before enrolment were most likely to benefit from treatment. In the study of intramuscular interferon beta-1a, patients receiving active treatment benefited from a reduction in disability worsening on the Multiple Sclerosis Functional Composite scale, but not on the EDSS relative to placebo. Mitoxantrone reduced disability progression and clinical exacerbations (as a composite endpoint) in a small study of fewer than 200 patients with worsening relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis (SPMS). Data supporting an effect on disability progression in the SPMS subgroup were not provided. None of the other trials showed a delay in disability progression.
Added value of this study
So far, no drug has consistently been shown to reduce disability progression in a representative SPMS population. EXPAND recruited a large population of patients with fewer signs of inflammatory disease activity and higher levels of disability at baseline than was the case in the European interferon beta-1b study, ensuring that outcomes were relevant to a representative SPMS population. For patients with SPMS, even numerically small changes in EDSS score can correspond to substantial changes in neurological function and daily activities. Accordingly, the delay in disability on EDSS (primary endpoint) and the benefits observed for several other clinical and MRI-related secondary outcomes are clinically relevant.
Implications of all available evidence
The siponimod EXPAND study is, to our knowledge, the first large trial of any disease-modifying therapy to show superiority over placebo in terms of disability progression in a representative population of patients with SPMS, including a large proportion of patients who had reached the non-relapsing stage of SPMS and had a high level of established disability.