Atorvastatin Fails to Meet Primary Objective for Relapse Reduction in Clinically Isolated Syndrome: Researchers Suggest Exploring It as Add-on MS Therapy

Neurology Today
21 October 2010; Volume 10(20); p 20

Collins, Thomas R.

Investigators reported that significantly more MS patients taking atorvastatin remained free of new T2 lesions than a placebo group. But the study failed to demonstrate a significant risk reduction in the development of three new T2 lesions or a clinical exacerbation between the treatment group and the placebo group.

SAN FRANCISCO — Disappointing results from a study on atorvastatin's effects on the earliest stages of multiple sclerosis (MS) have left physicians and researchers wondering about the future of the drug's role in treating the disease and whether any other meaningful investigations will be done.

The results, which were reported here at the American Neurological Association annual meeting, come as other disease-modifying drugs have come into wider use, and the FDA approved fingolimod as the first oral therapy for relapsing, remitting MS.

The investigators reported that significantly more patients taking atorvastatin (Lipitor) remained free of new T2 lesions than the placebo group. But the study failed to meet its primary endpoint — to demonstrate a significant risk reduction in the development of three new T2 lesions or a clinical exacerbation between the treatment group and the placebo group. Those meeting that endpoint were offered interferon beta-1a (Avonex).

DR. EMMANUELLE WAUBANT:“The primary endpoint was negative and some secondary endpoints are positive, which suggests that it might be a moderate or marginal effect. The question is whether we will use it in standard practice, and the answer is no. We need more information, ideally a larger study.”

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The investigators involved in the trial — Atorvastatin (Lipitor) Therapy in Patients With Clinically Isolated Syndrome (CIS) at Risk for Multiple Sclerosis (STAYCIS) — said there should be more work to evaluate the statin's effects in combination with other drugs.

“The feeling that we had, and so do others, is that the signal in the trial is sufficient that statins should be studied further, possibly in association with an approved MS drug,” said lead investigator Scott Zamvil, MD, professor of neurology at the University of California-San Francisco (UCSF). ”

The STAYCIS study measured the effects of atorvastatin in patients with clinically isolated syndrome, the neurological incident that is often the first sign of MS.

The investigators said they were hampered by under-enrollment, signing up just 81 patients, when the intent was to enroll 152 patients, before it was stopped by the Immune Tolerance Network — a non-profit, government-funded consortium of researchers working together to establish new treatments for immune system diseases — which funded the study.

“It's a small study,” said Emmanuelle Waubant, MD, PhD, the co-primary investigator on the study and associate professor of neurology at the UCSF. “That's the limitation of having a small study. At the end, you can't say whether for sure there is an effect worth pursuing or not.”

When the trial began in 2005, it was not common to treat CIS patients right away with disease-modifying therapy. But as the trial unfolded, interferon emerged as an effective, disease-modifying treatment, making it difficult to recruit patients in a trial that included a placebo control arm.

Although 53 percent of those taking atorvastatin at 80 mg daily met the primary endpoint, the results were not statistically different from those of the placebo group, 56 percent of whom met the primary endpoint (p = 0.82).

Aside from the enrollment problem, the study was troubled in that, at baseline, the patients in the atorvastatin group tended to have more active disease already, compared to the placebo group, which might have made it more difficult for the drug to show an effect, Dr. Waubant said.

Still, researchers pointed to other data they say might show value for atorvastatin for early MS patients.

Significantly more subjects in the atorvastatin group ?55 percent ?remained free of new T2 lesions, compared to 27 percent in the placebo group (p = .032). The odds of remaining free of new T2 lesions was higher in the atorvastatin arm (Odds Ratio = 3.93, p = .012).

“The primary endpoint was negative and some secondary endpoints are positive, which suggests that it might be a moderate or marginal effect,” Dr. Waubant said. “The question is whether we will use it in standard practice, and the answer is no. We need more information, ideally a larger study.”

Opinions vary about the value of the data on remaining free of new T2 lesions.

“They missed on the primary endpoint so they are fishing,” said Mark Freedman, MD, director of the Multiple Sclerosis Research Unit at the Ottawa Hospital. “Being free of disease in clinically isolated syndrome is dicey because it could be driven by people who may not even have MS.”

He said further studies of statins and a placebo would be a “hard sell.”

But the STAYCIS investigators contend that future research should focus on the study of atorvastatin as an add-on, not as a platform drug.

DR. MARK FREEDMAN:“Being free of disease in clinically isolated syndrome is dicey because it could be driven by people who may not even have MS.”

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Dr. Waubant said financing might be an issue. “The bulk of the money came from the Immune Tolerance Network because the companies making statin drugs are not interested in the MS market,” Dr. Waubant said. “It's a drop in their bucket.”

The STAYCIS investigators have taken criticism that the study was underpowered, while others say the circumstances were beyond their control.

Dr. Zamvil said he and the other investigators had a tight window during which to recruit patients — patients had to be enrolled within three months of their first event, so that the drug could be tested at the very earliest sign of MS. That meant that a patient had to have the clinically isolated syndrome identified by outside physicians quickly enough to be referred to a trial center.

The Immune Tolerance Network was in the process of extending the enrollment to six months from the CIS when it ended enrollment, leaving investigators perplexed, Dr. Zamvil said.