Results of a large randomized trial have shown that the combination interferon beta-1a and Gatiramer Acetate was not more effective than either agent alone on the primary endpoint of reduction in annualized relapse rate in patients with relapsing-remitting Multiple Sclerosis (MS).

“All 3 study arms performed exceedingly well, no matter which relapse definition was used,” principal investigator Fred Lublin, MD, professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mt. Sinai Medical Center in New York City concluded.

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 magnetic resonance imaging (MRI), endpoints that were presented separately by 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.

Combination therapy also resulted in a higher proportion of patients achieving disease activity–free status, largely driven by these latter findings on MRI.

“From a clinical point of view, with these 2 agents, there wasn’t much advantage to combining,” Dr. Lublin told Medscape Medical News. However, “from an MRI and disease activity, there was, in the sense that if you want to eliminate all disease activity, we showed you could eliminate more of it by combining.”

While the cost implications of that are unclear, the 7 subcutaneous and 1 intramuscular injections of combined treatment per week was well tolerated by patients. The results were presented here at the American Academy of Neurology’s 64th Annual Meeting. The study was funded by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS).

“CombiRx was a unique collaboration between NIH, academic institutions, practicing neurologists, Pharma and biotech, the largest test thus far of the potential for combining immunotherapies in early relapsing-remitting MS,” Dr. Lublin concluded. “It provides the longest controlled clinical, MRI and biomarker dataset of any MS trial.”

Potential for Combination Therapy

Drugs shown effective for treatment of MS on their own may be additive or synergistic when used together, particularly if they have different presumed mechanisms of action, Dr. Lublin noted. The CombiRx investigators sought to examine whether interferon beta-1a and Gatiramer Acetate used together might be more effective than either alone. Teva and Biogen Idec provided the study drugs free of charge but did not fund the trial.

CombiRx was a 3-year, double-blind, multicenter trial that randomly assigned 1008 patients with relapsing-remitting MS to receive Gatiramer acetate plus placebo (25%), interferon beta-1a plus placebo (25%), or a combination of both active drugs (50% of patients). The primary endpoint was the annualized relapse rate over the 3 years, comparing the combination with the best single-agent group.

Eligible patients had relapsing-remitting MS, had 2 or more relapses in the previous 3 years, had an Expanded Disability Status Scale (EDSS) score of 5.5 or less, and were naive to either of the treatments used. Eighty-one percent of patients completed 36 months of follow-up, “a very good retention rate for an MS study,” Dr. Lublin noted. Most MS trials report after 24 months of follow-up.

The investigators used 3 different definitions of exacerbations, and all were determined centrally. Each of these definitions has been used in previous MS trials, he noted, so the investigators used all 3 to glean as much information as possible.

• Protocol-defined exacerbation: A new or worsening symptom lasting longer than 24 hours, in the absence of fever or metabolic derangement, seen within 7 days of onset and associated with a change in EDSS score of .5 or 2 points in 1 functional system, or a 1-point change in 2 functional systems.
• Non–protocol-defined exacerbation: As above but seen outside of the 7-day window after onset.
• Suspect exacerbation: Not associated with a change in EDSS but considered by investigators to nevertheless be an exacerbation.

“The first thing to note is that annualized relapse rates are extremely low whichever definition you use,” Dr. Lublin noted. The rates seen in the trial translate to an attack every 6 to 10 years, Dr. Lublin noted, “so those are very encouraging results in terms of the efficacy.”

American Academy of Neurology’s 64th Annual Meeting:
Abstract# PL02.003. Presented April 27, 2012.
Abstract# IN3-2.003. Presented April 24, 2012.

Second, the combination group “was not significantly better than the better of the 2 treatment arms.

A-No differences between any of the treatment groups were seen in percentage of patients relapsing over 36 months, or the time to first relapse, he noted.

Similarly, the percentage of patients with 6-month EDSS progression did not differ by treatment group, Dr. Lublin noted, “but we came up with an interesting observation. That is, those individuals entering the study with an EDSS of 0, meaning nothing abnormal on the neurologic examination, had a 9-fold increased risk of going on to confirmed progression than those with an EDSS of greater than 0. We’ve not seen this sort of data before and we’re studying it now to see what was driving those changes.”

B-Change on the Multiple Sclerosis Functional Composite did not differ between groups. Among those who were free of any clinical disease activity, including relapses or change in EDSS, there was still no difference between groups, Dr. Lublin said.

“However, when you go to a full definition of disease activity free status, meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions, you now see that the combination group is significantly better than either of the 2 treatment groups using both definitions for exacerbation,” he said. “This is being driven by the MRI data shown earlier this week,” he said, referring to Dr. Wolinsky’s presentation.

In terms of safety, 4 patients died: 3 in the primary portion of the study and 1 in the extension. Seizure secondary to MS resulted in death in the interferon plus Gatiramer group, a pulmonary embolus occurred in the interferon group, and 1 overdose leading to anoxic brain injury and death occurred in the interferon group.

In all, there were 190 serious adverse events in 136 patients, but with no difference between the treatment groups, Dr. Lublin noted. “We’re still characterizing them, but there was no evidence thus far of any combined toxicity from combining the agents.”

Extension Phase
“A longer-term extension phase of the CombiRx study will address if the observed differences that we’ve seen at this point in MRI and the disease activity free status findings predict later clinical differences,” he concluded.
They also plan to look at 2-year data using all 3 definitions of relapse and validate disability definitions, as well as develop models of progressive disease.