Should We Use Combination Therapy for Multiple Sclerosis?
Abstract & Commentary
By Susan Gauthier, DO, MS, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Gauthier reports she receives research support from EMD Serono, Biogen Idec, and Novartis Pharmaceuticals, and is on the speakers bureau for Biogen Idec and Teva Neurosciences.
Synopsis: The combination of interferon beta 1a (30 mcg IM weekly) and glatiramer acetate was not more effective on annualized relapse rate in multiple sclerosis compared to either treatment alone.
Source: Lublin F, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 2013;73:327-340.
There are multiple FDA-approved treatments for multiple sclerosis (MS), but the injectables, interferon beta (both 1a and 1b) and glatiramer acetate (GA), have been available for more than a decade. The injectables are known to be partially effective and patient compliance remains difficult. Therefore, several new oral agents have arrived on the market with varying levels of effectiveness and safety. Injection therapy with interferon or GA for MS continues to have the most favorable short- and long-term safety profiles; thus, an attempt to improve efficacy through a combination of these medications was of great interest and was the driving force behind the recently published CombiRx study. Given that both interferon beta 1a (IFN) and GA are likely to have different mechanisms of action, there was an expected benefit from the combination over and above each of these drugs used as monotherapy.
The CombiRx study was a three-arm, randomized, double-blind, placebo-controlled study with a 2:1:1 randomization of the combination of IFN+GA or each individual agent with matching placebo. Participants were in the core study for a minimum of 3 years and up to 7 years in an extension phase. Inclusion criteria required two relapses within the past 3 years, and a new lesion on MRI could qualify for a relapse. The primary outcome was annualized relapse rate (ARR). Secondary outcome measures included progression on clinical disability scores (EDSS, MSFC) and a composite MRI score (gad+, T2, T1 lesions, and atrophy measure). The study was powered to compare the combination of IFN+GA to the better of the two monotherapy groups, and the sample size allowed for a comparative efficacy analysis between IFN and GA. The superior of the two monotherapies was GA (0.16 vs 0.11, P = 0.022); however, the combination of IFN+GA was not superior to GA (P = 0.27) alone. There were no differences between any of the groups on clinical progression (EDSS or MSFC) or on the composite MRI score. Differences in individual lesion counts were noted among the groups, wherein the combination of IFN+GA was superior to the nominal winner, IFN, in reducing the number of enhancing lesions (P = 0.01) and combined unique lesion activity (CUA, the sum of new enhanced, unenhanced, and enlarged lesion, P < 0.0001) over the course of 3 years. The effect on brain atrophy was similar among all three groups, and, interestingly, the pattern of tissue loss was very similar among all treatment arms with the majority occurring in the first year (average of all subjects 2.7%), followed by 0.7% in year 2 and 0.01% in last year. Disease activity-free status (DAFS) — which is defined as no relapses, no EDSS progression, and no new CUA — did not differ among the two monotherapy treatment arms; however, the combination of IFN+GA was superior to both (GA: P < 0.0001, IFN: P = 0.0004). There were no safety issues identified during the study.
Unfortunately, the combination of IFN+GA did not show superiority on ARR but did show a benefit on overall DAFS. The use of DAFS as an outcome measure in clinical trials (or as a goal for standard of care treatment) is controversial within the field, given its dependence on MRI. However, given the low ARR in this and other modern clinical trials, which has yet to be fully understood, the role of the MRI as a sensitive marker of continued disease activity might need to be reconsidered. The state of true remission, based on imaging modalities, is accepted within many other disease fields, but in the field of MS, a tolerance for MRI disease activity still exists. This tolerance is due, in part, from the lack of a cross-sectional relationship between lesions and disability, the so-called clinical-MRI paradox of MS, and because the safety profiles of the more efficacious drugs are complicated. Since combination therapy failed to show superiority on the standard clinical measures, it is difficult to conceive of this moving into our current treatment algorithm. Of great importance, this study highlighted an overall low ARR and clinical progression rates as well as very low measures of atrophy (within second and third year) among patients treated with IFN and GA monotherapy, suggesting that many patients can receive an effective clinical and potentially neuroprotective benefit from these drugs. Therefore, considering the favorable long-term safety profile of injectable therapy, these treatments remain strong viable options.