No Significant Clinical Benefit in Combination Therapy for MS

Disease-modifying therapies (DMTs) have been available for the treatment of relapsing-remitting multiple sclerosis (MS) since 1993. Currently, 9 distinct marketed entities, representing 6 different therapeutic strategies, all immunomodulators, are indicated for this degenerative disease of the central nervous system.

Because it is unlikely that a single therapy will have the desired combination of efficacy sufficient to eliminate all MS disease activity and the short- and long-term safety profiles expected for chronic disease management, a recent study sought to combine 2 therapies for the treatment of MS. The study, CombiRx, sponsored by the National Institutes of Health, was reported online in an accepted article in Annals of Neurology [2013 Feb 19. doi:10.10.1002/ana.23863].

The objective of CombiRx was to determine the benefits of concurrent use of 2 effective MS therapies—interferon beta-1a (IFN) and glatiramer acetate (GA)—because both have good safety, modest efficacy as monotherapy, probable different mechanisms of action, and are currently the most commonly prescribed therapies for relapsing-remitting MS.

The study trial period began in January 2005 and ran through April 2009, with study follow-up closing in April 2012 after the final participant completed a 36-month study period. The trial was conducted at 68 sites, both private practice and academic, in the United States and Canada.

This double-blind, randomized, controlled study involved 1008 participants. Eligible participants were between 18 and 60 years of age, had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5, had a diagnosis of RRMS by Poser or McDonald criteria, and had at least 2 exacerbations in the prior 3 years, where 1 exacerbation could be a magnetic resonance imaging (MRI) change meeting the 2001 McDonald MRI criteria for dissemination in time. The primary end point was reduction in annualized relapse rate (ARR) utilizing a strict definition of relapse.

The study allowed for comparative efficacy analysis between the 2 single agents, GA and IFN, as well as the efficacy of combination therapy compared with each monotherapy. IFN 30 µg was administered intramuscularly weekly and GA 20 mg was administered subcutaneously daily, with matched placebo preparations, for a total of 8 injections per week.

The study found that combination IFN + GA was not superior to either agent alone in lessening confirmed EDSS progression or change in Multiple Sclerosis Functional Composite score over the 36-month study period. GA was significantly better than IFN, reducing the risk of exacerbation by 31%. The primary outcomes assessment comparing the ARR of the combination group was not statistically superior to GA, the better of the 2 single agents, when adjusting for baseline age (P=.27). The combination was, however, significantly better than IFN, reducing the risk of exacerbation by 25% (P=.027 vs P=.022, respectively).

Additionally, there was no difference between groups in time to first exacerbation (P=.19) or proportion of subjects with relapses (protocol defined exacerbations: IFN vs GA, P=.14; IFN+GA vs IFN, P=0.19; IFN+GA vs GA, P=.21).

All 3 treatment groups appeared to be effective in reducing MRI-defined disease activity as measured by enhanced lesion numbers within 6 months of their initiation.

Although the study confirms the safety of combination therapy, there is insufficient clinical efficacy to warrant an endorsement of this combination at this point. The CombiRx study does set a framework for future MS therapeutic studies, and, according to the researchers, the study will continue, charting patient progress well beyond 3 years.