Interferon beta and Glatiramer Acetate: Equivalent for the Treatment of MS?
Abstract & Commentary
By Susan Gauthier, DO, MS, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gaulthier reports no financial relationships relevant to this field of study.
Synopsis: In an MRI-based study, interferon beta-1b failed to show superiority over glatiramer acetate for the treatment of multiple sclerosis.
Source: Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNb-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 2009;72:1976-1983.
Standard initial treatment for patients with relapsing-remitting multiple sclerosis (RRMS) or those at risk for developing RRMS, patients with a clinically isolated syndrome (CIS), is one of four FDA-approved injectable immunomodulatory agents. The current treatment options include two formulations of interferon beta-1a, high- and low-dose, one formulation of interferon beta-1b (IFNb-1b), and glatiramer acetate (GA). Efficacy of each of these treatments, compared to placebo, has been clearly demonstrated in their separate phase III trials; however, comparative data amongst these agents has been lacking. Cadavid and colleagues reported on the BECOME study, where the following hypothesis was tested: Given the effect of interferon therapy on the blood brain barrier, IFNb-1b should more effectively suppress new inflammatory activity on the brain MRI as compared to GA.
The BECOME study was a two-year comparative study of IFNb-1b and GA for which patients received monthly MRIs within the first year, with an option for the same in the second year. The study was powered to assume a superiority of IFNb-1b, so seventy-five RRMS and CIS patients were randomized to receive either IFNb-1b or GA. The primary outcome was the number of combined active lesions (CALs) per scan over the first year; this included the total number of contrast-enhancing lesions plus new non-enhancing T2-hyperintense lesions. The MRI protocol was distinct as compared to previous studies in that it used a 3 Tesla MRI, triple-dose gadopentetate dimeglumine, and extended post-injection delays (40 minutes after first injection and 20 minutes after second). The baseline clinical characteristics were similar between the two groups, and although the number of baseline contrast-enhancing lesions was higher in the IFNb-1b group, the difference did not reach significance. The rate of compliance for monthly scans within the first nine months of the study was reported to be 94% in the IFNb-1b group and 82% in the GA group. Eighty percent of the IFNb-1b group remained in the study for the full two years, whereas 90% of the GA group was retained.
There were a total of 2,443 CALs over the 24-month study, with 90.3% enhancing and 9.7% non-enhancing new T2-hyperintense lesions; interestingly, 44% of the contrast-enhancing lesions were persistently enhancing. There was no difference in the primary outcome between the two groups; the IFNb-1b-treated patients had 0.63 CALs per monthly scan, and there were 0.58 CALs in the GA-treated patients. Nearly 80% of patients from both treatment groups developed new lesions over the course of 24 months. Although the study was not powered to detect a clinical difference, the annualized relapse rate between the two treatment groups was similar. Relapse rate was not related to baseline contrast-enhancing lesions, but was correlated to the monthly cumulative number of new contrast-enhancing lesions.
Commentary
The BECOME study is the last of three recent comparative trials of interferon therapy and GA to be published; however, as the other studies were powered to determine a difference in clinical events, this study was powered to assess a difference in MRI activity. The development of new inflammatory lesions on MRI is an accepted biomarker for MS and is widely used in phase II clinical trials. Similar to REGARD and BEYOND, BECOME failed to meet the primary outcome of interferon superiority over GA.1,2 Importantly, none of these studies were powered to determine equality of these treatments; as a result, the only accurate conclusion that can be drawn is that interferon therapy does not appear to be superior. In both the REGARD and BEYOND studies, the MRI data partially favored interferon therapy; however, the MRI protocol in BECOME was uniquely created to improve the visualization of inflammatory lesions, thus a comparison of the MRI results between studies would not be appropriate. The significance of BECOME lies in a few take-away points. These include: 1.) the validation of MRI as a disease biomarker (correlation of new lesions with relapse rate); 2.) contrast-enhanced lesions can persistently enhance (1/3 for up to 3 months); and 3.) MRI breakthrough activity is common within the first two years on either IFNb-1b or GA (80% of patients). Given the results of these recent studies, patient tolerance should be a primary factor in making treatment decisions. Last, physicians should recognize that all four drugs are only partially effective and as a class should be considered as only the first step in managing patients with MS.
References
1. Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the Rebif vs. Glatiramer Acetate in Relapsing MS Disease REGARD study): A multicentre, randomized, parallel, open-label trial. Lancet Neurol 2008;7: 903-914.
2. O'Connor P, Arnason B, Comi G, et al. Interferon beta-1b 500 mcg, interferon beta-1b 250 mcg and glatiramer acetate: Primary outcomes of the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose (BEYOND) Study. Neurology 2008;71:153-154.
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