COPENHAGEN — There were high hopes that simvastatin, a well-tolerated lipid-lowering therapy, would reduce disability progression in patients with nonflaring secondary progressive multiple sclerosis (SPMS), but a definitive multicenter double-blind randomized trial found no benefit at all.
“There was no effect on the primary outcome of confirmed progression or on any of the secondary outcomes,” reported Jeremy Chataway, MD, PhD, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College of London, England.
For the primary outcome of progression on the Expanded Disability Status Scale (EDSS), the nonsignificant hazard ratio (HR) was, in fact, in favor of placebo (HR, 1.13; P = .26) over 45 months of follow-up and 365 progression events.
No Meaningful Difference Between Study Arms
“There were wide confidence intervals [95% CI, 0.91-1.39], so, really, there were no differences between the two arms,” reported Dr. Chataway, who presented the simvastatin trial, called MS-STAT2, during the late-breaker session of the 2024 ECTRIMS annual meeting.
Over a period of more than 20 years, a series of experimental and clinical studies have indicated that simvastatin and other CoA reductase inhibitors have anti-inflammatory and neuroprotective effects. These studies were the basis for the first MED-STAT study, which was a placebo-controlled randomized trial published in 2014.
Although this study did not have a clinical endpoint, it associated simvastatin with a 43% reduction (P = .003) in the annualized rate of brain atrophy, which has been widely accepted as a surrogate measure of MS progression.
In MS-STAT2, 964 patients were available for the intention-to-treat analysis. An established diagnosis of SPMS, an age of 25-65, and an EDSS score of 4.0-6.5 were among the inclusion criteria. Patients were required to be relapse-free for at least 3 months prior to study entry.
Importantly, patients were excluded if they were taking statin-lowering therapies or were candidates for these therapies due to the presence of cardiovascular disease. They were also excluded from entering the trial if taking immunosuppressants, such as methotrexate or azathioprine, or had exposure to monoclonal antibodies employed in the treatment of MS, such as natalizumab and alemtuzumab, in the prior 12 months.
Randomized to 80 mg of simvastatin (40 mg in the first month followed by rapid upward titration) or placebo in a 1:1 fashion, patients remained on their assigned therapy for 3 years in the absence of progression. At the end of this time, patients who remained progression-free could continue for up to 45 months while still blinded to treatment assignment.
Even though a large proportion of patients who were eligible to remain in the study for the full 45 months did so, the retention did not reflect clinical improvement.
Indeed, the secondary endpoints also produced no signal of benefit. On a composite secondary endpoint of EDSS, ambulation in the form of the 25-foot walk, and upper extremity function in the form of the 9-hole peg test (9-HPT), the numerical odds ratio (OR) went in the wrong direction for simvastatin although the difference was not significant (OR, 1.17; P = .26).
Annualized Relapse Rate Numerically Higher on Simvastatin
The annualized relapse rate, another secondary endpoint, was low in both arms of the study at 0.05 relapses/year for placebo and 0.7 relapses/year for simvastatin. Again, this result, although numerically unfavorable for simvastatin did not reach statistical significance (OR, 1.43; P = .04).
Simvastatin had a placebo-like safety profile. The single case of rhabdomyolysis in the simvastatin arm, which occurred early after randomization, resolved. Otherwise, simvastatin was well tolerated.
Conducted before and through the period of the COVID-19 pandemic, the number of progression events tripled in the year after the COVID-19 pandemic started relative to the prior year. At the end of the pandemic, progression events returned to a level similar to that before its onset. However, although Dr. Chataway noted this was an interesting example of comorbidities exacerbating MS, he emphasized that this increase was similar in the simvastatin and placebo arms.
There are more analyses to come, including patient-reported outcomes, biomarker analyses, and further comparisons of change in MRIs, but Dr. Chataway acknowledged that the study provided no support for the underlying hypothesis.
Several experts commenting after the study was presented, including Ludwig Kappos, MD, PhD, Chair of Neurology at the University Hospital, Basel, Switzerland, agreed.
“Unfortunately, these results are quite disappointing,” he said. When asked if there is any rationale for further pursuing studies of simvastatin for the treatment of SPMS, he said no.
“These data are quite convincing that there is no benefit. I do not see where you could go from here,” Dr. Kappos said in an interview.
Dr. Chataway, asked the same question, reiterated that there are a number of preplanned analyses that will be completed, but he does not foresee further studies with simvastatin for the indication studied in MS-STAT-2 trial.
However, he also emphasized strongly that simvastatin or any other lipid-lowering therapy should not be withheld from MS patients that need these drugs for a cardiovascular indication.
“We saw no benefit seen from simvastatin for patients with stable SPMS, but these drugs were well tolerated and they can be life-saving therapies for patients with increased cardiovascular risk,” Dr. Chataway said.
Dr, Chataway reported financial relationships with Biogen, Genzyme, Ionis, Lucid, Merck NerveGen, Novartis, Roche, and Sanofi. Dr. Kappos reports financial relationships with more than 20 pharmaceutical companies. The MS-STAT2 trial received no funding from industry.