The year 2020 will be remembered for virtual visits and virtual congresses. It was also a year of the Food and Drug Administration adopting what might be termed virtual evidence-based medicine (EBM).
It was a year ago when the FDA reviewed an application for siponimod as a treatment for secondary-progressive MS. The application was based on the results of the EXPAND trial, which compared siponimod versus placebo in 1651 SPMS patients (Kappos et al. Lancet 2018;391:1263-1273). This cohort differed from that of RMS trials: patients were 10 years older (mean age 47 years) with long-standing MS (mean 17 years since MS onset) and most did not have inflammatory disease activity (64% relapse-free in the previous two years; 75% with no Gd+ lesions). The relative reduction in 6-month confirmed disability progression was 26% with siponimod after a median time on treatment of 21 months.
The FDA rejected the SPMS indication, stating that there was insufficient evidence of a treatment benefit for patients with non-active SPMS. Instead, it opted to approve siponimod for relapsing MS, which included clinically isolated syndrome, RRMS and active SPMS. The FDA review also remarked: “The siponimod labeling will be the first explicitly describing that relapsing forms of multiple sclerosis include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, but all sponsors of the drugs approved for the treatment of relapsing forms of multiple sclerosis will be requested to update their indication statements to conform with this contemporary nomenclature.”
Among the first to benefit from this contemporary nomenclature was glatiramer acetate, which is now indicated for active SPMS despite a lack of evidence that it slows progression. Other DMTs were quick to follow, receiving approvals for CIS and SPMS despite an absence of trial data in these populations. Cladribine was relabelled for SPMS with no trials but was not approved for CIS despite having a trial (ORACLE-MS).
In 2020, these differing views of the evidence led to the curious situation of Health Canada (using non-contemporary nomenclature) approving siponimod for active SPMS based on SPMS data while the FDA was approving ozanimod for active SPMS based on RMS data (a label that fingolimod now shares). The three S1P modulators are certainly similar and all are indicated for SPMS in the U.S. But strictly speaking, from an evidence-based standpoint, only siponimod has shown efficacy in progressive MS. Fingolimod did not in the INFORMS trial (Lublin et al. Lancet 2016 Mar 12;387:1075-1084). Ozanimod could not show a significant effect on progression versus interferon-beta IM in the RADIANCE trial (Cohen et al. Lancet Neurol 2019;18:1021-1033).
This anomalous situation suggests some unfortunate conclusions: that drug labels need not be based on the evidence; that a treatment effect on progression can be primarily attributed to an anti-inflammatory effect; and the view that the pathophysiology of active SPMS differs from that of CIS or RRMS is simply being persnickety.
Some of this confusion about SPMS can be traced back to the decision by the International Advisory Committee on Clinical Trials in MS to split SPMS into active and non-active forms (Lublin et al. Neurology 2014;83:278-286), with the term ‘active SPMS’ (in North America) and ‘SPMS with active disease’ (in the wordier Europe) essentially replacing ‘transitional SPMS’. ‘Transitional’ was entirely agreeable in depicting a process but did not describe a phenotype, so it was abandoned.
In 2020, the Advisory Committee acknowledged that its phenotype classification of active SPMS had created confusion, but its clarification rather missed the point (Lublin et al. Neurology 2020;94:1088-1092). The Committee noted that disease activity is defined by the FDA as relapses alone, whereas European regulators define activity as relapses or MRI features. The concern of the Clinical Trials Committee was that drug developers would be uncertain about who to include in clinical trials. A more likely scenario is that drug developers would no longer go to the trouble of doing SPMS trials at all since the FDA is willing to expand RRMS data to include anyone with a relapse.
In Canada, where DMT labelling is largely determined by economic rather than clinical considerations, the situation is a little clearer if no more satisfactory. Disease-modifying therapies are generally indicated for primary-progressive MS (ocrelizumab), secondary-progressive MS (siponimod, some but not all interferons), or relapsing-remitting MS (all other DMTs). Two of the interferons have adopted the indication “relapsing forms of MS”, with one (IFN-beta-1a IM) approved for relapsing-progressive MS (RPMS), a phenotype that is no longer recognized. This categorization may not be ideal. But at the very least, it enables clinicians to hew more closely to an evidence-based medicine approach when selecting treatment for patients at different phases of the disease process.