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Simvastatin’s effect on SPMS is not related to lowered cholesterol, study suggests

Simvastatin, a widely prescribed cholesterol lowering drug, may slow brain atrophy and disease progression in secondary progressive multiple sclerosis (SPMS) for reasons unrelated to changes in blood cholesterol, a new analysis of a Phase 2 clinical trial says.

The analysis “Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis,” published in the journal PNAS (Proceedings of the National Academy of Sciences of the USA) looked at the results of a randomised and placebo-controlled Phase 2 trial (NCT00647348) that concluded in 2011, called MS STAT.

In the 2011 MS STAT trial 140 adults with SPMS were assigned to either high doses of simvastatin (80 mg, once a day) or a placebo for two years. The trial results, published in 2014, found Simvastatin reduced brain atrophy (or shrinkage), a common consequence of nerve damage in MS, by 43% compared to placebo. Later analysis of MS STAT results also showed treated patients had improvements in cognitive function and a smaller, but significant slowing of disease progression, as measured by 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 were involved. The new analysis aimed to resolve this. Using mathematical models, researchers looked for possible reasons why treatment with simvastatin might lead to positive clinical outcomes in SPMS. Their study focused on two 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 other based on the idea that the two were unrelated (a cholesterol-independent model).

Results of the new research 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.

A new randomised and placebo-controlled Phase 3 clinical trial, called MS STAT2 is currently underway, and 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.

Source: MS-UK 23/05/19

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