The Effectiveness and Value of Siponimod for Secondary Progressive Multiple Sclerosis

Abstract

The most frequently reported adverse events in the EXPAND trial were headache, nasopharyngitis, urinary tract infection, falls, and hypertension. Bradychardia at treatment initiation, hypertension, lymphopenia, and macular edema have been associated with S1P-receptor modulation, although these events were relatively uncommon in the EXPAND trial. Data from an ongoing 7-year open-label extension of EXPAND may provide further evidence on the long-term safety of siponimod. An integrated analysis of safety data from studies of fingolimod, another S1P receptor modulator, with up to 10 years of follow-up did not identify any unexpected or new safety signals. 2 Limitations of the Clinical Evidence A central issue raised by any treatment for SPMS is whether it functions by reducing relapses (and thus is effective mainly for active disease) or whether it also is able to reduce progression in the absence of relapses (and thus has efficacy in nonactive disease). In EXPAND, siponimod trended towards, but did not confer, a statistically significant improvement in confirmed disability progression for subgroups defined by the absence of gadolinium-enhancing lesions or absence of relapses in the previous 2 years. 1 The U.S. Food and Drug Administration (FDA) explored this question further by conducting additional analyses in subgroups with nonactive disease (e.g., patients who did not relapse in the 2 years previous to or during the study) and concluded that results from these "analyses support the hypothesis that the delay in 3-month [confirmed disability progression] is more clearly related to the anti-inflammatory effect of siponimod (yielding a significant treatment effect on the relapsing or active aspect of the disease) than to an effect on the poorly understood 'degenerative' process felt to [dominate] the pathophysiology of SPMS." 3 Siponimod was ultimately approved by the FDA for relapsing forms of MS, which include active SPMS but not nonactive SPMS. Long-Term Cost-Effectiveness We also evaluated the cost-effectiveness of siponimod versus best supportive care in the overall SPMS population (active and M ultiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Relapsing-remitting MS (RRMS) is the most common disease course and is characterized by intermittent periods of worsening neuro-logic symptoms ("relapses") followed by partial or complete recovery. Incomplete recovery from relapses may contribute to progression of disability. Over time, RRMS may transition to secondary progressive MS (SPMS), wherein disability progression occurs in the absence of, or independent of, relapses. Siponimod (Mayzent) is a sphingosine-1-phosphate (S1P) receptor modulator approved for relapsing forms of MS, which has a similar mechanism of action to fingolimod. Although there are many disease-modifying therapies (DMTs) approved for patients with RRMS and patients with SPMS who still experience relapses ("active SPMS"), therapies labeled for the treatment of nonactive SPMS are lacking. The Institute for Clinical and Economic Review (ICER) reviewed the clinical effectiveness and cost-effectiveness of siponimod for patients with active and nonactive SPMS, which represents the population where it has primarily been studied. ■■ Summary of Findings Clinical Effectiveness We evaluated the evidence comparing the clinical effectiveness of siponimod to best supportive care, as estimated by the placebo arm of the pivotal trial. The primary source of evidence was the phase 3, randomized placebo-controlled EXPAND trial in patients with active and nonactive SPMS. 1 In this trial, siponimod reduced the risk of 3-month confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS; hazard ratio [HR] = 0.79; 95% confidence interval [CI] = 0.65-0.95). 1 Siponimod also reduced the risk of relapse (HR = 0.54; 95% CI = 0.41-0.70) and decreased measures of inflammatory disease activity on magnetic resonance imaging (MRI), including the number of gadolinium-enhancing lesions on T1-weighted scans and number of new or enlarging lesions on T2-weighted images. Significant benefits were not observed for other mobility-related measures, including the timed 25-foot walk test and the 12-point Multiple Sclerosis