On November 14, 2014, the US Food and Drug Administration (FDA) approved alemtuzumab (Lemtrada™) for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS) who have had an inadequate response to interferon-β or other disease-modifying therapies. However, alemtuzumab is not recommended for all patients with RRMS. In fact, owing to its safety profile and long-term impact on patients’ lifestyles, alemtuzumab is recommended only for persons with 2 or more previous RRMS therapeutic failures. Side effects and disease risks associated with the drug include serious, sometimes fatal autoimmune conditions (related to the drug’s powerful mechanism of action), including immune thrombocytopenia (a bleeding condition) and antiglomerular basement membrane disease (a condition that affects the kidneys). Patients with RRMS who take alemtuzumab are also required to participate in a Risk Evaluation and Mitigation Strategy (REMS) program to educate them about required health monitoring, which includes monthly blood tests for a minimum of 5 years (ie, 4 years of monthly and quarterly monitoring after the patient’s last infusion). Serious life-threatening reactions and an increased risk of malignancies (including thyroid cancer, melanoma, and blood cancers) are also possible. In clinical studies, autoimmune thyroid disorders occurred in 34% of alemtuzumab-treated patients.
Why would anyone willingly assume such risks? The answer may be found in the vision behind the alemtuzumab’s development, as well as in the results of the clinical trials of the drug.
Development of alemtuzumab has spanned more than 35 years — dating back to CAMPATH-1, CAMPATH-1M, and CAMPATH-1H — and in 2001 the drug received FDA approval to treat B-cell lymphocytic leukemia. Alemtuzumab is a monoclonal antibody that binds to CD52, a cell surface antigen present at high levels on T and B lymphocytes, and at lower levels on natural killer cells, monocytes, and macrophages. Its precise therapeutic mechanisms in multiple sclerosis (MS) treatment may involve immunomodulation through the depletion and repopulation of lymphocytes. These potential immunomodulatory effects may include alterations in the number, proportion, and properties of some lymphocyte subsets after treatment, but the precise effects in MS remain unknown. By 1994, research teams led by Waldmann and Compston were convinced that alemtuzumab could prevent inflammatory T cells from entering the brain and spinal cord, prevent relapses, and reduce the frequency of MS attacks. Waldmann and Compston’s observations of patients with RRMS shaped their belief that earlier treatment would lead to improved outcomes, and in 2013 resulted in the European approval of alemtuzumab for the treatment of RRMS. In December 2013, however, the FDA declined approval of alemtuzumab for the treatment of RRMS, citing poor study design due to lack of a placebo control and double-blinding in the phase 3 studies. In May 2014, alemtuzumab was resubmitted for reconsideration with fresh data analyses from the phase 3 trials. The drug was awarded FDA approval 6 months later.
Alemtuzumab is administered intravenously as 4-hour infusions, in 2 treatment courses given in the hospital. The first course comprises 5 consecutive days of treatment, and the second course, administered 12 months later, comprises 3 consecutive days of treatment. After completion of the second course, in clinical studies 70% of patients sustained efficacy over 3 years and were able to stop therapy completely. When alemtuzumab (Lemtrada™) was compared with Rebif® (interferon β-1a), a competitor in clinical studies, patients taking alemtuzumab had 50% fewer relapses. One of the phase 3 studies also suggested that Lemtrada significantly reduced worsening of disability by 42% over Rebif. These results may demonstrate why, despite its worrisome side effect profile, for some patients the potential benefits of alemtuzumab strongly outweigh the risks.
Contributed by William Yarnall, RPh, CCP
Medical Writer, Connexion Healthcare