Simvastatin Fails to Reduce Disease Progression in Phase 3 MS-STAT2 Trial of Secondary Progressive Multiple Sclerosis
A phase 3 trial revealed that simvastatin, while safe, did not significantly slow disability progression in patients with non-active secondary progressive MS.
Jeremy Chataway, PhD, FRCP
In the phase 3 MS-STAT2 trial (NCT03387670), treatment with simvastatin, a medication for high cholesterol, was safe and well tolerated, but demonstrated no evidence of benefit in reducing disability progression rates in patients with non-active progressing secondary progressive multiple sclerosis (SPMS). Investigators plan to release additional analyses from the trial that cover secondary outcomes, fluid biomarkers, and MRI.
These data were presented at 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held September 18-20, in Copenhagen, Denmark, by Jeremy Chataway, PhD, FRCP, a professor of neurology at University College London. MS-STAT2, a multicenter, placebo-controlled, double-blind trial, comprised of 964 patients with non-active SPMS who were allocated to either simvastatin 80 mg (n = 482) or placebo (n = 482) and followed for a 54-month treatment period.
The primary outcome, confirmed disability progression up to 48 months post-randomization, did not significantly differ between simvastatin- and placebo-treated patients. Across 365 progression events, investigators recorded an estimated hazard ratio of 1.13 (95% CI, 0.91-1.39; P = .26) on the cumulative incidence of confirmed Expanded Disability Status Scale (EDSS) progression. Progression was defined as a 1 point increase if EDSS score at baseline visit was less than 6, or a 0.5 point increase if EDSS score at baseline was at least 6.
During the meeting, Chataway et al also reported on certain secondary outcomes, including a multi-component measure of confirmed disability progression up to 36 months, as well as relapse rate up to 36 months. The multi-component progression, which included EDSS, 25-foot walk, and 9-hole peg test, showed an odds ratio of 1.17 (95% CI, 0.89-1.53; P = .26), while the relapse rate revealed an incidence rate ratio of 1.43 (95% CI, 1.01-2.01; P = .04). For background, the multi-component measure used a mixed effects logistic regression model, while the incidence relapse rate ratio was derived from mixed effects negative binomial regression model. Both were adjusted for minimization variables such as sex, age, and baseline EDSS.
The study included only patients with a confirmed diagnosis of MS that have entered the secondary progressive stage. These individuals, aged between 25-65 years old, had steady progression rather than relapse as the major cause of increasing disability in the 2 years prior to study onset. Patients who had a relapse within 3 months of baseline visit and those who have been treated with steroids for a recent relapse were excluded from the trial. The study also excluded those who were currently on statins or had any use within the last 6 months, as well as those with primary progressive MS, diabetes myelitis type 1, and any use of immunosuppressants within the previous 6 months.
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In terms of safety, there were no suspected unexpected serious adverse reactions with treatment of simvastatin. Notably, there was a case of rhabdomyolysis that resulted in hospital stay for a simvastatin-treated patient; however, this resolved on stopping IMP. In addition, there were 9 deaths in the trial, all unrelated to treatment, and even spread between the placebo (n = 4) and simvastatin group (n = 5).
The study also took place during the COVID-19 pandemic, and thus, a separate analysis was conducted to test the treatment effect of simvastatin. Overall, investigators found no evidence for a difference in treatment effect between the 3 pandemic periods (P = .22), which included pre-COVID-19 restrictions, during COVID-19 restrictions, and after COVID-19 restrictions.
MS-STAT2 was a follow-up to a previously completed phase 2b trial, dubbed MS-STAT (NCT00647348), that first showed the potential of simvastatin in SPMS. The double-blind, controlled trial, which took place from 2008 to 2011, randomly assigned 140 patients with SPMS to either simvastatin (n = 70) or placebo (n = 70). At the conclusion of the treatment period, the annualized atrophy rate was significantly lower in patients in the simvastatin group (0.288% per year [SD, 0.521]) than in those in the placebo group (0.584% per year [SD, 0.498]).2
Additional data from the trial revealed that the adjusted difference in atrophy rate between the groups was –0.254% per year (95% CI, –0.422 to –0.087; P = .003), a 43% reduction in annualized rate. Simvastatin was considered well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs 9 [13%]).
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