Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis: Final Update 1 Report [Internet]

Excerpt

Purpose: We compared the effectiveness and safety of disease-modifying drugs for the treatment of multiple sclerosis: Glatiramer acetate (Copaxone^®), interferon beta-1a (Avonex^®, Rebif^®), interferon beta-1b (Betaseron^®, Extavia^®), mitoxantrone (Novantrone^®), and natalizumab (Tysabri^®).

Data Sources: We searched Ovid MEDLINE^® and the Cochrane Library and the Database of Abstracts of Reviews of Effects through December 2009. For additional data we also hand searched reference lists, government web sites and dossiers submitted by pharmaceutical companies.

Review Methods: Study selection, data abstraction, validity assessment, grading the strength of the evidence, and data synthesis were all carried out according to standard Drug Effectiveness Review Project review methods.

Results: In patients with relapsing remitting multiple sclerosis, little difference in relapse outcomes were found between interferon beta-1a SC (Rebif^®) and interferon beta-1b (Betaseron^®), while interferon beta-1a IM (Avonex^®) was less effective than interferon beta-1a SC (Rebif^®) and interferon beta-1b (Betaseron^®) based on 4 fair-quality head-to-head trials. Direct evidence from 5 fair-quality head-to-head trials was conflicting on disease progression outcomes between the interferons. Pooled analysis of direct and indirect trial data found no difference between the interferons on changes in disability and no difference between interferon beta-1a SC (Rebif^®) and interferon beta-1a IM (Avonex^®) on disease progression but did find interferon beta-1b (Betaseron^®) to be superior to interferon beta-1a IM (Avonex^®) on disease progression (relative risk, 0.48; 95% CI, 0.27 to 0.86). There was no difference in relapse or disease progression between glatiramer and interferon beta-1a SC (Rebif^®) or interferon beta-1b (Betaseron^®) based on 2 head-to-head trials. Evidence is insufficient to make any judgments regarding effectiveness in primary progressive or secondary progressive multiple sclerosis.

Evidence suggested that all 3 interferon beta-1 products and glatiramer reduced the probability of converting from clinically isolated syndrome to clinically definite multiple sclerosis over 2 to 5 year periods.

Interferon beta-1a IM (Avonex^®) appeared to have the lowest immunogenicity, with rates of development of neutralizing antibodies of 2% to 8.5%, starting around 9 months of treatment. With interferon beta-1a SC (Rebif^®) antibodies occurred later with rates of immunogenicity between 12% and 46%, and with interferon beta-1b SC (Betaseron^®) neutralizing antibodies appeared as early as 3 months in 30% to 40% of patients. Evidence for interferon beta-1b SC (Betaseron^®) and interferon beta-1a SC (Rebif^®) indicated that consistent positive neutralizing antibody status with high titer increased relapse rates, by one-half to two-thirds, during longer periods of follow-up. This difference was not seen with follow-up of 2 years or less, and there was inadequate evidence to conclude that there is an impact on disease progression.

No difference was found in withdrawal rates among beta interferons in head-to-head trials. Transaminase elevations were common with all beta interferon products, with little difference in rates of occurrence. There was a lower rate of depression in patients taking interferon beta-1a (Rebif^®) compared with the other interferons based on limited trial data. Interferon beta-1a IM (Avonex^®) was associated with the highest rates of flu-like syndrome compared with the other beta interferons. Interferon beta-1b SC (Avonex^®) was associated with the lowest rates of injection site reactions whereas interferon beta-1b SC (Betaseron^®) and interferon beta-1b SC (Rebif^®) had similar rates. Significant long-term concerns included progressive multifocal leukoencephalopathy in patients receiving natalizumab >12 months, lipoatrophy with prolonged use of glatiramer, and permanent amenorrhea in older women receiving higher total dose of mitoxantrone.

There was some evidence that response to beta interferons and glatiramer differs in men and women, but there was no evidence that this difference favors one product over another. Evidence is insufficient to make conclusions about the safety of these drugs in pregnancy. A post hoc subgroup analysis of a head-to-head trial of interferon beta-1a products (Avonex^® and Rebif^®) found that African-American patients experienced more exacerbations and were less likely to be exacerbation-free compared with white patients over the course of the study.

Conclusion: There was fair evidence that interferon beta-1a IM (Avonex^®) is less effective than interferon beta-1a SC (Rebif^®) and interferon beta-1b (Betaseron^®) for preventing relapse in patients with relapsing remitting multiple sclerosis. On other outcomes and in other populations, direct evidence is either lacking or shows few differences in effectiveness or safety among the disease-modifying drugs used to treat multiple sclerosis.