Multiple sclerosis (MS) is an immune-mediated disorder that affects the central nervous system (CNS), often first affecting people in early adulthood. Although most MS patients have a relapsing-remitting course (RRMS) at disease onset, a substantial proportion later develop chronic progression, termed secondary progressive MS (SPMS). Approximately 10% of MS patients experience chronic progression from disease onset, termed primary progressive multiple sclerosis (PPMS). Although several disease-modifying treatment (DMT) options exist for relapsing forms of this disease, DMT options are few for progressive MS (PPMS and SPMS). Herein, we strive to define progressive MS, review major clinical trials aimed at progressive MS, and delineate potential strategies in the management of progressive MS.

In 2017, the first DMT for PPMS, the B lymphocyte-depleting monoclonal antibody, ocrelizumab, came to market. Ocrelizumab reduced 12-week confirmed disability progression (CDP) by 24% versus placebo. Siponimod, a selective sphingosine-1-phosphate receptor modulator, reduced 3-month CDP by 21% versus placebo in SPMS. Ibudilast slowed brain atrophy in PPMS and SPMS patients in a multicenter phase 2b study. Smaller early phase studies of alpha-lipoic acid and simvastatin each found slowing of rate of whole brain atrophy in SPMS patients.

Reasons now exist for optimism in the search for DMTs for progressive MS. It remains a challenge to identify outcome measures that accurately reflect the underlying pathology in progressive MS, which is less inflammatory and more degenerative than RRMS.