Alemtuzumab, a humanised monoclonal antibody, as possible alternative therapy to interferon beta 1a in people with RRMS

Background

Multiple sclerosis is a progressive disease of the central nervous system where the person's own body destroys the coating that protects nerves. The disease may go into remission (where the symptoms reduce or stop) and then relapse (where the symptoms return). This is called relapsing-remitting multiple sclerosis (RRMS). Medicines called monoclonal antibodies (such as alemtuzumab) could be a possible alternative immunotherapy (treatment to stimulate the immune system) to interferon beta treatment (one of the usual treatments) in people with RRMS. In this review, we aimed to compare the benefits, side effects and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS.

Study characteristics

We searched medical databases and found three studies involving 1694 participants (CAMMS223, CARE-MS I and CARE-MS II). CAMMS223 involved people with previously untreated, early RRMS. Participants received either subcutaneous (under the skin) interferon beta 1a (at a dose of 44 μg) three times per week or annual intravenous (into a vein) courses of alemtuzumab (at a dose of either 12 mg per day or 24 mg per day) for 36 months. CARE-MS I enrolled adults aged 18 to 50 years with previously untreated RRMS. Participants received annual intravenous courses of alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg three times per week for 24 months. CARE-MS II enrolled adults aged 18 to 55 years with RRMS and at least one relapse while on interferon beta or glatiramer (another medicine that alters the immune response) treatment. Participants received subcutaneous interferon beta 1a 44 μg three times per week, annual intravenous courses of alemtuzumab 12 mg per day or annual intravenous courses of alemtuzumab 24 mg per day for 24 months. The evidence is current to 1 February 2017.

Key results

The review of trials found that, compared with subcutaneous interferon beta 1a three times per week, annual intravenous cycles of alemtuzumab probably reduces the proportion of participants who experience relapse, may reduce the proportion of participants who experience disability worsening and development of new T2 lesions on MRI. In one study, alemtuzumab 24 mg leads to slightly better EDSS scores when compared with interferon beta 1a.

The rates of adverse events were similarly high for both treatments. The most frequently reported adverse events for both treatments were infusion-associated reactions, infections and autoimmune events. The use of alemtuzumab requires careful monitoring so that potentially serious adverse events can be treated early and effectively.

Quality of the evidence

The quality of the body of evidence obtained for each outcome is mainly low except for the number of participants experiencing at least one relapse for which the quality of evidence was moderate.

Authors' conclusions: 

Annual intravenous cycles of alemtuzumab at a dose of 12 mg per day probably reduces the proportion of participants who experience relapse, may reduce the proportion of participants who experience disability worsening and development of new T2 lesions on MRI over 2 to 3 years in comparison with subcutaneous IFN beta-1a 44 μg three times per week. Annual intravenous cycles of alemtuzumab at a dose of 24 mg per day may reduce the proportion of participants who experience relapse and disability worsening over 3 years in comparison with subcutaneous IFN beta-1a 44 μg three times per week. An average reduction of 0.8 EDSS units with alemtuzumab compared with interferon beta-1a was observed at a dose of 24 mg per day in one study.

The rates of adverse events were similarly high for both treatments. The most frequently reported adverse events for both treatments were infusion-associated reactions, infections and autoimmune events. The use of alemtuzumab requires careful monitoring so that potentially serious adverse events can be treated early and effectively.

Read the full abstract...
Background: 

Alemtuzumab is a humanised monoclonal antibody that alters the circulating lymphocyte pool, causing prolonged lymphopenia, thus remoulding the immune repertoire that accompanies homeostatic lymphocyte reconstitution. It has been proved more effective than interferon (IFN) 1a for the treatment of relapsing-remitting multiple sclerosis (RRMS).

Objectives: 

To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS to prevent disease activity.

Search strategy: 

We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register (1 February 2017) which, among other sources, contains records from CENTRAL, MEDLINE, Embase, CINAHL, LILACS, PEDRO and the trial registry databases Clinical Trials.gov and WHO International Clinical Trials Registry Platform for all prospectively registered and ongoing trials.

Selection criteria: 

All double-blind, randomised, controlled trials comparing intravenous alemtuzumab (12 mg per day or 24 mg per day on five consecutive days during the first month and on three consecutive days at months 12, 24, 36) versus subcutaneous IFN beta 1a (Rebif), 22 μg or 44 μg three times per week, or IFN beta 1a (Avonex) by intramuscular injection 30 μg once a week, in people of any gender and age with RRMS.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane.

Main results: 

We included three trials involving 1694 participants. All trials compared alemtuzumab 12 mg per day or 24 mg per day versus IFN beta 1a for treating RRMS. In CAMMS223, participants received either subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab (at a dose of 12 mg per day or 24 mg per day) for 36 months. In CARE-MS I and CARE-MS II, participants received subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab 12 mg per day for 24 months. All three studies were at risk of performance bias and attrition bias, one study was 'unclear' risk in selection bias.

Compared with interferon beta 1a, alemtuzumab given at a dose of 12 mg per day probably reduces the risk of relapse (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.52 to 0.70, moderate quality evidence), may reduce the risk of worsening disability (RR 0.60, 95% CI 0.45 to 0.79, low quality evidence) and the risk of developing new T2 lesions on magnetic resonance imaging (RR 0.75, 95% CI 0.61 to 0.93, low quality evidence) after 24 and 36 months' follow-up. Mean Expanded Disability Status Scale (EDSS) scores may be similar between the treatment regimens (mean difference (MD) -0.35, 95% CI -0.73 to 0.03, low quality evidence).

At a dose of 24 mg per day alemtuzumab may reduce relapse (RR 0.38, 95% CI 0.23 to 0.62, low quality evidence), worsening disability (RR 0.42, 95% CI 0.21 to 0.84, low quality evidence). The effects on EDSS scores when compared with interferon beta 1a at three years are uncertain due to the very low quality of evidence (MD -0.83, 95% CI -1.17 to -0.49).

All three trials reported adverse events and serious adverse events. The risk of experiencing an adverse event in either alemtuzumab 12 mg or interferon groups may be similar (RR 1.03, 95% CI 0.98 to 1.08, low quality evidence). The risk of serious adverse events is probably similar between treatments (RR 1.03, 95% CI 0.82 to 1.29, moderate quality evidence). The risk of any adverse event may be similar between alemtuzumab 24 mg and interferon (RR 1.02, 95% CI 0.96 to 1.08, low quality evidence). The risk of serious adverse events is probably similar between treatments (RR 0.95, 95% CI 0.70 to 1.31, moderate quality evidence).

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