Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world

Abstract

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, preexisting disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

Keywords: alemtuzumab; long-term efficacy; long-term safety; mechanism of action; multiple sclerosis; real-world experience.

Figure 1.

Through Year 6 of the CARE-MS extension, in cohorts of patients entering from (a) CARE-MS I and (b) CARE-MS II, the majority of patients received no further alemtuzumab after their second course.^, CARE-MS, Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis; DMT, disease-modifying therapy; MRI, magnetic resonance imaging.

Figure 2.

(a, b) The 6-month CDW and (c, d) 6-month CDI through 6 years in patients from CARE-MS I and II.^, Number at risk is the number of patients who remained on study and who had yet to experience CDW. For CDI analyses, number at risk is the number of patients with baseline EDSS of ⩾2.0, who remained on study, and who had yet to experience CDI. CARE-MS, Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis; CDI, confirmed disability improvement; CDW, confirmed disability worsening; EDSS, Expanded Disability Status Score

Figure 3.

Median annual change in brain volume, measured by BPF, in alemtuzumab-treated patients enrolled in the extension from CARE-MS I (a) or II (b). BPF, brain parenchymal fraction; CARE-MS, Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis; Y, year.

Figure 4.

Change from baseline in FAMS score (a, b) and SF-36 PCS (c,d) score in CARE-MS I and II patients with and without 6-month CDI.^, *Significant change from baseline, p < 0.05; †Significant difference between groups, p < 0.05. CARE-MS, Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis; CDI, confirmed disability improvement; FAMS, Functional Assessment of Multiple Sclerosis; PCS, Physical Component Summary; SF-36, 36-Item Short-Form Survey; Y, year.