October 15, 2007 (Prague, Czech Republic) — An interim analysis of the Simvastatin as an Add-on Treatment to Interferon-Beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis (SIMCOMBIN) trial has found that simvastatin does not block the anti-inflammatory effect of interferon-beta (IFN-beta) when both of these drugs are taken together by patients with multiple sclerosis (MS).

Results of the interim analysis were presented here by lead investigator Per Soelberg Sørensen, MD, from Copenhagen University Hospital, Righospitalet, Denmark at the 23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS).

Rationale for the Study

SIMCOMBIN is an ongoing double-blind, placebo-controlled, randomized, parallel-group, phase 4 study designed to determine if there is any benefit to adding simvastatin to IFN-beta-1a ( Avonex, Biogen Idec) in patients with MS. This large, multicenter trial began in February 2006 and is planned to be complete in November 2009.

"Why combine interferon-beta with statins?" Dr. Sorensen asked rhetorically, as he began his presentation. The reason for this, he said, is that statins are potent immunomodulators and have been found to be beneficial in several studies involving animal models of MS. One small, open-label study using human subjects with relapsing-remitting MS reported a more than 40% reduction in both the number and volume of gadolinium-enhancing lesions, after they were treated with simvastatin 60 mg daily for 6 months, he noted.

The main reason for conducting the interim analysis was because of a presentation of a double-blind, placebo-controlled study of atorvastatin in combination with IFN-beta-1a, presented by Gary Birnbaum, MD, from the University of Minnesota, during this year's annual meeting of the American Academy of Neurology (AAN), Dr. Sorenson said. That study reported an increase in the combined composite endpoint of new and enhancing magnetic resonance imaging (MRI) lesions and/or relapses in patients receiving IFN-beta plus atorvastatin vs those receiving IFN-beta plus placebo.

The authors of that study hypothesized that these results might be because statins block the anti-inflammatory effect of IFN-beta. "So this urged us to do this safety analysis," Dr. Sorensen explained.

Safety Analysis

Among 61 patients that had been randomized in the SIMCOMBIN study by April 2007, the authors performed an interim safety study in 47 patients who had been treated for at least 3 months with either simvastatin 80 mg daily or placebo as add-on therapy to INF-beta-1a given intramuscularly at a dose of 30 µg weekly.

A subgroup of 27 patients underwent a safety MRI during May 2007 and an analysis of in vivo IFN-beta bioactivity. The primary outcome measure was IFN-beta bioactivity, as assessed by mRNA expression of the IFN-beta biomarkers MxA and TRAIL. Secondary outcome measures included the annualized relapse rate, time to first relapse, and gadolinium-enhancing lesion and new or enlarged lesions on T2-weighted MRI.

An analysis of the results showed that all 27 patients had a full in vivo response to IFN-beta in MxA and TRAIL mRNA expression studies. The mean observation time on therapy was 6.9 months. The annualized relapse rate in all patients was 0.36, which is comparable to relapse rates found previously in other patient populations treated with IFN-beta. Additionally, there was no statistically significant difference in the time to first relapse between the 2 treatment groups.

"These results led our data safety monitoring board to conclude that there are no safety concerns regarding the continuation of the trial as defined by the protocol, and we encouraged the steering committee to carry on the study as planned," Dr. Sorensen told the audience. "This recommendation was based on our own interpretation of the relapse and MRI data," he added.

Remove the Concern

This interim analysis "successfully removed a concern" regarding any potential antagonistic effects of simvastatin vs. IFN-beta, according to Roland Liblau, MD, PhD, from Toulouse University Hospital, France, who cochaired the session. "I think they did the job properly, and I think they removed the concern that statins might antagonize interferon beta and vice versa," Dr. Liblau told Medscape Neurology and Neurosurgery.

He cautioned, however, that the study is still ongoing, and no conclusions should be drawn on the efficacy of this approach.

"The interim analysis didn't show any significant difference between the 2 groups, but you don't expect at this stage to find differences," he said. "So, in terms of efficacy, we cannot conclude anything. This study was done to remove doubt, and I think the doubt has been removed properly."

Funding for this study was provided by Biogen Idec, maker of Avonex (INF-beta-1a).

23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis: Parallel Session 7 (85). Presented October 13, 2007.

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