Extension CombiRx Data Show No Benefit of Combined MS Drugs

Susan Jeffrey

March 21, 2013

San Diego, California — Seven-year data from a large clinical trial comparing the combination of interferon-β1a and glatiramer acetate (GA) to monotherapy with either drug alone continue to show no additional benefit of the combination therapy in patients with relapsing-remitting multiple sclerosis (MS).

"The combination was not superior to the single agent winner, glatiramer acetate, in risk of relapsing, using either definition — the protocol-defined or the non–protocol-defined, up through 90 months," Fred Lublin, MD, director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York, and co-investigators concluded.

Further, they found that GA was superior to interferon in reducing the risk for relapse over time in this study, and the combination did not reduce confirmed disability progression vs monotherapy, Dr. Lublin noted.

"In the extension phase, the combination therapy resulted in a higher proportion of participants with disease activity-free status compared to either single arm, driven by the MRI results, but the effect lessens over time," he added.

"The longer-term extension phase has not found that the earlier observed difference in MRI and disease activity–free status that is in the core 3-year study translated into a later clinical difference," he added. "This was one of the things we wanted to look for in this extension, and it hasn't shown yet."

The extension results were presented here at the American Academy of Neurology (AAN) 65th Annual Meeting.

CombiRx Published

Drugs shown effective for the treatment of MS may have additive or synergistic effects when used together, if they have different presumed mechanisms of action. CombiRx tested the hypothesis that the combination of interferon and GA might be more effective than either alone.

The main trial was a 3-year, double-blind, multicenter study that randomly assigned 1008 patients with relapsing-remitting MS to 1 of 3 groups: GA (Copaxone, Teva Neuroscience) plus placebo (25%), interferon-β1a (Avonex, Biogen Idec) plus placebo (25%), or a combination of both active drugs (50% of patients). The study was funded by the National Institute of Neurological Disorders and Stroke, and the drugs were provided free of charge by Teva and Biogen Idec.

The primary endpoint was the annualized relapse rate over 3 years, comparing the combination with the best single-agent group.

At the AAN meeting last year, the CombiRx investigators presented the main results of the trial showing that the combination was not more effective than either agent alone on the primary endpoint, but GA was found to be superior to interferon-β1a in reducing the risk for relapse according to any 1 of the 3 relapse definitions used in the trial.

Further, although the combination was not better than either agent at reducing confirmed disability progression, it was superior to both agents in reducing new lesion activity and accumulation of total lesion volumes on MRI. Combination therapy also resulted in a higher proportion of patients achieving disease activity–free status, largely driven by these latter findings on MRI.

The main results, reported at that time by Medscape Medical News, were just recently published online March 11 in the Annals of Neurology.

In this new analysis, the authors report the results of a long-term extension phase of the study out to 7 years in 687 patients who consented to remain in the trial. Some 81% of follow-up visits were completed in the core trial, compared with 85% in the extension phase.

Results for the primary endpoint of annualized relapse rates were very similar to the 3-year data, Dr. Lublin said. The combination was not better than the results seen with the better of the single agents, "which in this case is glatiramer acetate. GA was better at reducing the risk of exacerbation than interferon and the combination was as well."

Table. CombiRx: Primary Endpoint at 7 years

Endpoint Combination GA Interferon-β1a
Annualized relapse rate 0.10 0.13 0.09


The results were similar when broader criteria were used.

The percentage of patients relapsing over 7 years did not differ between groups according to the most stringent of the definitions for relapse used in the trial, Dr. Lublin noted. "When you get out to the somewhat less stringent definition, then you start to see a difference occurring here between the combination and interferon, but the combination was not better than the better of the 2 agents, and that was our rule for declaring success."

There was no difference in time to first relapse between the groups, or percentage of patients with 6-month confirmed progression in disability measured by using the Expanded Disability Status Scale (EDSS).

The investigators also assessed the number of patients who were clinical disease activity free: that is, free of both relapse activity and EDSS progression during the study. No difference between the groups was seen at the end of the core study, nor was a difference seen at the end of years 4 and 6, when MRI was done.

This allowed them also to do a post hoc analysis for disease activity–free status, he noted, "which we decided was an important assessment to do."

In the core study, the combination was superior to either individual agent in disease activity–free status, driven primarily by activity on MRI, Dr. Lublin said. "At year 6, the trend is the same against GA — it's significant against interferon — but you can see it's changing over time," he said. "Not surprising. With disease activity–free state all you can do is fail as time goes farther and farther along, but we think this is an important metric moving forward, which is why we did it and why we put it in the publication. Because as we get down to really low exacerbation rates, we have to start thinking about other outcome measures that are a bit more sensitive," he said.

Safety endpoints were not different from those reported last year, he said. There were 4 deaths, none thought to be related to the study treatments. Serious adverse events were evenly divided between groups, and the investigators didn't identify any combination-related toxicities.

In conclusion, he said, "all 3 study arms performed exceedingly well, no matter which relapse definition you used. These are spectacular results for agents we've been using for a long, long time in terms of reductions in annualized relapse rate."

Imaging Results

In a separate presentation here, Jerry Wolinsky, MD, professor of neurology and director of the MRI Research Center and Multiple Sclerosis Research Group at the University of Texas Medical School at Houston, reviewed the imaging results in the trial out to 7 years.

He reported data showing that the attenuation of gadolinium enhancement was rapidly evident in all 3 groups and remained from month 12 through the core extension. "The combination of interferon and GA was more effective in reducing combined unique activity throughout the study, leading to the largest proportion of subjects remaining free of new detected lesion formation in the 4 and 6-year cohorts in particular," Dr. Wolinsky.

Little change occurred from baseline in T2 hyperintense, T1 hypointense component lesion volumes or total lesion volumes over the follow-up, he noted, and "the rates of brain atrophy stabilized over the first 12 months of the trial and remained quite low — unanticipatedly low overall afterwards.

"Over the entire trial, the combination therapy resulted in higher proportions of patients in a disease activity–free state compared to either single arm, driven in large part by the MRI results," he concluded.

During the discussion, an audience member pointed out that although GA was superior to interferon in reducing relapse rate, interferon was superior to GA in reducing the number of active lesion and total lesion volume.

"The answer is I think these drugs do have different mechanisms of action," Dr. Wolinsky replied. "I'm not sure that we have yet been able to tease out some of the effects of the different mechanisms of action, on what a lesion on one drug or another means, relative to clinical outcome."

However, he noted, the differences between the monotherapy groups are small, "and I think one needs to pay careful attention to that."

Fundamental Clinical Question

In an editorial published with the main trial results, Stephen L. Hauser, MD, Department of Neurology chair at University of California, San Francisco, and editor-in-chief of Annals of Neurology, along with Annals editors Andrew Josephson, MD, and S. Claiborne Johnston, MD, PhD, conclude that, "in the end, CombiRx was essentially a negative study, with the combination therapy doing no better than monotherapy in reducing MS relapse rate over 3 years."

They speculate that perhaps interferon-β1a neutralized the benefit of GA, or alternatively, that the combination might be effective in the same subset of patients with MS, such as those with less aggressive disease, and therefore their effect would not be additive. "Given the suggestive MRI data, we should also leave open the possibility that with a longer period of observation, differences favoring the combination could become apparent."

The larger significance of the CombiRx trial may be in the continued follow-up of these patients, the editorialists suggest.

"Nine different agents, belonging to six different classes of drugs, are now FDA-approved for MS, and at least four others are poised for possible approval in the next couple of years. For clinicians, the fundamental clinical question has changed from 'is there a treatment that really works?' to 'how can we select the most effective and safest treatment for this individual patient?' Answering this question with evidence represents one of the great challenges that we face," they write.

The phase 3 clinical trials used to support approval by the US Food and Drug Administration "provide only very partial help in this regard, as these trials provide only 2 or at most 3 year snapshots of MS disease activity whereas disability evolves much more slowly, usually over decades.

"Here is where the true power of CombiRx may well emerge. With continued follow-up of the cohort over additional years, and hopefully decades, and as correlations with MRI metrics and molecular biomarkers are revealed, this study offers the chance to develop a uniquely complete view of the 'new' long-term natural history of MS, to assess how it is modified by first-generation therapies, and perhaps to begin to predict individual disease trajectories and the likelihood of a therapeutic response," the editorialists conclude.

"If successful towards these ends, CombiRx then emerges as a model for the sort of serious long-term assessment that the field deeply needs, and one that both government and industry funders should strive to emulate — perhaps in partnership — for other therapies, not only in MS but across the clinical neurosciences."

CombiRx was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Lublin has received personal compensation for consulting from Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono Inc., Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, sanofi-aventis, Acorda, Questcor, Roche, Celgene, Abbott, Johnson & Johnson, Revalesio, Coronado Bioscience, and GenFL. He has received compensation from Elsevier for serving as co-chief editor of Multiple Sclerosis and Related Diseases. Dr. Wolinsky has received personal compensation for activities with Bayer Pharmaceuticals Corp, Genzyme Corp, Hoffman LaRoche, Janssen Pharmaceutical, Novartis, sanofi-aventis, and Teva/Teva Neuroscience as a consultant. He has received (royalty or license fee or contractual rights) payments from the University of Texas and research support from Clayton Foundation of Research and the National Institutes of Health.

American Academy of Neurology 65th Annual Meeting. Abstracts S1.002, S1.003. Presented March 19, 2013.

Ann Neurol. Published online March 11, 2013. Abstract