What treatments are available for primary progressive multiple sclerosis (MS) (PPMS), and how effective are they?

Updated: Oct 08, 2019
  • Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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Few treatments are available for primary progressive MS (PPMS). Ocrelizumab was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for PPMS was based on results from the ORATORIO phase 3 trial that included 732 patients with PPMS who received the treatment or matching placebo. Ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04). The total volume of brain lesions on T2-weighted MRI decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P< 0.001), while the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). [24]

Siponimod was approved by the FDA in 2019 for adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Siponimod approval was based on results of the phase 3 EXPAND trial, which randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3–6.5 to siponimod 2 mg once daily (1105 patients) or placebo (546 patients) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events. At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and 32% of those receiving placebo (hazard ratio, 0.79; 95% confidence interval [CI], 0.65 - 0.95; relative risk reduction, 21%; P = .013). Siponimod also meaningfully delayed the risk of 6-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression. [14]

Cladribine gained FDA approval in 2019 for relapsing forms of MS, to include relapsing-remitting disease and active secondary progressive disease. Because of its safety profile, use is generally recommended for patients with inadequate response to, or unable to tolerate, an alternate MS drug therapy.

The ORACLE MS trial (n=903) demonstrated that cladribine significantly delayed MS diagnosis compared with placebo (p < 0.0001) when initiated in patients following a first clinical demyelinating event. [25] In the CLARITY study, cladribine treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. [26]

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