Best Practices
The Multiple Sclerosis Centers of Excellence: A Model of Excellence in the VA
The MS Centers of Excellence at the VA improves the consistency and quality of care for veterans with MS.
DMT for Progressive MS
Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.
In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.
Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.13 Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.
The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.14 However, a North American trial that followed in 2004 was unable to replicate this finding.15 The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.16 Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.
Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.17 Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.
B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.18 With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.11 There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.19 While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.