ECTRIMS 2024: Simvastatin fails to slow disability progression in SPMS
Phase 3 trial finds progression in 40% of 964 patients on treatment or placebo
Daily treatment with high-dose simvastatin, a widely used cholesterol-lowering medication, failed to slow disability progression in adults with secondary progressive disease or SPMS, according to top-line data from a Phase 3 clinical study.
Jeremy Chataway, PhD, a professor of neurology at University College London (UCL) in the U.K., presented the findings at this year’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, held Sept. 18-20 both online and in person in Copenhagen, Denmark.
His oral presentation was titled, “Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2 trial): a multicentre, randomised controlled, double-blind phase 3 clinical trial.”
Simvastatin is thought to lower inflammatory responses that damage nerve cells
Simvastatin belongs to a group of drugs called statins, a type of medication used along with exercise and diet to lower blood cholesterol levels and the risk of heart problems. How exactly simvastatin helps in multiple sclerosis (MS) isn’t fully understood, but it appears to work through “a number of different mechanisms,” Chataway said.
For example, simvastatin may reduce the overactive inflammatory response that’s damaging to nerve cells in the brain and spinal cord. At the same time, it’s thought that simvastatin may protect nerve cells from damage and improve blood flow in the brain, which could slow the progression of MS symptoms.
In the earlier Phase 2 MS-STAT (NCT00647348) clinical trial, 140 adults with SPMS were treated with simvastatin, at a 40 mg dose for the first month and at 80 mg thereafter, or given a placebo daily for two years. Findings showed the therapy was well tolerated and resulted in a yearly 43% reduction in brain atrophy, or loss of brain volume, compared with a placebo.
Building on these data, UCL also sponsored the Phase 3 MS-STAT2 study (NCT03387670) to test how daily treatment with simvastatin for up to 4.5 years — three years in the main trial and up to 1.5 years in its extension — could slow the accumulation of disability in a larger group of adults with SPMS.
In this type of MS, disability levels increase steadily over time, with or without relapses. The study enrolled 964 patients from 31 hospitals across the U.K. who could be experiencing relapses, but their major cause of disability worsening over the previous two years had to be steady progression. Patients’ mean age was 54.3, and over two-thirds (73%) were women.
Patients also had to have an Expanded Disability Status Scale (EDSS) score of 4 to 6.5 points, indicating some ability to walk. But their disability is significant enough to limit them to either short distances without assistance, or requiring two walking aids to walk a short distance. Among enrolled patients, the median EDSS score was 6.
Study patients treated daily with simvastatin for at least three years
Patients were randomly assigned to either simvastatin, at an 80 mg daily dose after a starting month at 40 mg, or a placebo, both as oral tablets. Compliance, defined as the proportion of patients who took their assigned treatment as defined by the study’s protocol, exceeded 80% at different time windows over the first three years. It “was very good,” Chataway said.
The main goal was to determine the proportion of patients with six-month confirmed disability progression during the trial, defined as an increase in EDSS scores that’s sustained for at least six months. Results showed that about 40% of patients in both groups — treatment and placebo — experienced confirmed progression over four years, failing to meet the trial’s primary goal.
“There was no effect on simvastatin in reducing the progression rates in this population,” Chataway said.
Consistent with this finding, the proportion of patients who progressed based on changed in EDSS scores, mobility, and finger dexterity, also was similar between the two groups (59% with simvastatin and 55% with a placebo). In both groups, relapses were “almost zero,” Chataway added.
Treatment seen to be safe, but not effective with steadily progressing MS
Part of the study ran during the COVID-19 pandemic. While the number of progression events nearly doubled or tripled during this time, which Chataway suggested might be due to a more sedentary lifestyle or disrupted physiotherapy, the pandemic had no significant effect on the proportion of patients with confirmed disability progression or relapses.
Simvastatin was well tolerated and had a safety profile similar to that of the placebo, with no unexpected serious side effects. One patient on simvastatin was admitted to the hospital for rhabdomyolysis, or muscle tissue breakdown, which resolved as soon as the treatment was stopped. Nine patients died, four in the placebo group and five on simvastatin, but no deaths were deemed to be related to treatment.
While “treatment was safe and well tolerated,” the researchers wrote in the presentation, there’s “no evidence of benefit of simvastatin over placebo in reducing disability progression rates in a truly non-active progressing SPMS [group].”
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