Simvastatin, Common Statin, Treats SPMS in Ways Distinct from Cholesterol, Study Suggests

Simvastatin, a widely prescribed statin that works to lower cholesterol levels, may slow brain atrophy and disease progression in people with secondary progressive multiple sclerosis (SPMS) for reasons unrelated to changes in blood cholesterol, a new analysis of a Phase 2 clinical trial reports.

These findings are in the study, “Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis,” published in the journal PNAS.

A new Phase 3 trial (NCT03387670) focused on how well treatment with simvastatin might slow disability progression in SPMS patients is underway at sites across the U.K. and in Dublin, and beginning to enroll up to 1,180 eligible adults.

Statins are given to lower the amount of LDL cholesterol (“bad” cholesterol) in the blood, and are normally prescribed to at risk of heart disease. These medications include simvastatin (marketed under the brand name Zocor by Merck), an oral statin  being tested as a potential SPMS therapy.

Besides lowering the levels of fat molecules circulating in the blood, statins have anti-inflammatory and neuroprotective properties that make them appealing candidates for treating multiple sclerosis (MS).

A randomized and placebo-controlled Phase 2 trial (NCT00647348) that concluded in 2011, called MS STAT, assigned 140 adults with SPMS to either high doses of simvastatin (80 mg, once a day) or a placebo for two years. An analysis of trial results, published in 2014, found treatment reduced brain atrophy (or brain shrinkage, a common consequence of nerve damage in MS), measured using MRI scans, by 43% compared to placebo, the study reported.

Later analysis of MS STAT results also showed treated patients with improvements in cognitive function, measured using a questionnaire, and a smaller, but significant slowing of disease progression, as measured via changes in EDSS scores, again compared to placebo.

But the University College London researchers who led that trial were not sure whether  benefits shown were related to simvastatin’s effects on blood cholesterol levels, or if other mechanisms of action related to statin were involved.

Using mathematical models, they looked for possible reasons why treatment with simvastatin might lead to positive clinical outcomes in SPMS.

Their study focused on the creation of two  mathematical models: one based on simvastatin’s positive effects in SPMS being associated with its ability to lower blood cholesterol levels (called a cholesterol-mediated model), and the another based on the idea that the two were unrelated (a cholesterol-independent model).

The researchers tested and compared both models using statistical analyses designed to assess which model most likely to explained findings seen in the MS-STAT trial.

Results showed that simvastatin’s positive effects on SPMS were largely independent on its effects on cholesterol, meaning the cholesterol-independent model was the most likely option.

More specifically, analyses showed that the lessening in physical disability progression observed in treated patients were best explained by a combination of indirect treatment effects on reduced brain atrophy (31%) and a direct treatment effect on disability (69%). All these effects were independent of changes in blood cholesterol levels.

“My study tells us that statins help patients with MS for reasons different from how they help people lower their cholesterol. For example, statins can modulate other elements that are produced in the pathways before cholesterol, but have indirect effects on immune system,” Arman Eshaghi, MD, PhD, a research associate at the UCL Queen Square Institute of Neurology and the study’s lead author, said in a press release.

“This paves the way to find better drug targets for an incurable disease such as MS,” Eshaghi added.

The randomized and placebo-controlled Phase 3 clinical trial, called MS STAT2 and currently underway, will specifically evaluate the effects of simvastatin at halting disease progression in 1,180 adults, ages 25 to 65 and with EDSS scores of 4.0 to 6.5, over three years. This primary goal, or endpoint, will be measured through changes in EDSS scores every six months compared to scores at the study’s start.

The trial is  led by Jeremy Chataway, PhD, a professor at the UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, and a co-author of the current study.

“Simvastatin is one of the most promising treatment prospects for secondary progressive MS in our lifetime,” Chataway said. “While it’s still early days, we believe simvastatin could change lives.”