Pharmacology

Alemtuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody that is directed against the 21-28 kDa cell surface glycoprotein CD52.

Pharmacodynamics. The beneficial effects of alemtuzumab have been observed clinically, but there is no adequate explanation of its mechanism of action. Treatment with alemtuzumab targets the CD52-bearing T lymphocytes for destruction. The role of high expression of CD52 on T cells in the pathogenesis of multiple sclerosis is not clear, but these cells are rendered susceptible to alemtuzumab-mediated cell lysis, which suppresses neuroinflammatory responses in multiple sclerosis. Depletion of T cells high in CD52 might be of importance in the development of secondary autoimmune disease after alemtuzumab treatment.

Immunomodulatory effects of alemtuzumab may occur through the depletion and repopulation of lymphocytes, increase in regulatory T-cell subsets, and rapid cell cycling of repopulating T cells with enhanced T-cell apoptosis (07).

MRI studies show a decrease of brain parenchymal fraction, as a measure of brain atrophy, in alemtuzumab-treated patients over 2 years indicating a neuroprotective effect, but it is not certain if it reflects an anti-inflammatory action that limits the collateral damage to neurons or is indicative of primary neuroprotective activity associated with increased lymphocytic delivery of neurotrophins to the central nervous system (11).

Pharmacokinetics. Classical biotransformation studies have not been conducted for alemtuzumab, but some features of the pharmacokinetics of alemtuzumab are as follows:

Pharmacogenetics. Incidence of immune thrombocytopenic purpura increases during treatment with alemtuzumab. A phase 4 study examining DNA extracted from peripheral blood to assess the genetic association of preidentified candidate single-nucleotide polymorphism to alemtuzumab-induced immune thrombocytopenic purpura in relapsing multiple sclerosis patients has been completed (NCT03784898). The results have not been published.

Routes of administration. Alemtuzumab is administered by intravenous infusion.

A phase 1, exploratory, randomized, open-label, 2-arm study is in progress to characterize the pharmacodynamics, pharmacokinetics, safety, and tolerability of alemtuzumab 12 mg administered subcutaneously or intravenously in patients with progressive multiple sclerosis (NCT02583594).

Clinical trials

According to a systematic review of randomized clinical trials in patients with relapsing-remitting multiple sclerosis, alemtuzumab 12 mg was better than subcutaneous interferon beta-1a for the following outcomes assessed at 24 months: relapse-free survival, sustained disease progression-free survival, and new or enlarging T2-hyperintense lesions on MRI (17).

Patients treated with alemtuzumab in phase 3 clinical trials showed improvements in physical, mental, and emotional quality of life, which were significantly greater than in those treated with subcutaneous interferon beta-1a on both disease-specific and general measures of quality of life (01).

Data from extension studies of alemtuzumab on patients with active relapsing-remitting multiple sclerosis who received treatment courses at baseline and 12 months later provide evidence for durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses (09). Retrospective chart review of 71 consecutive patients with relapsing-remitting multiple sclerosis who were treated with alemtuzumab from 2015 to 2018 showed that efficacy remains high in the real-world clinical practice (03).

Indications

Alemtuzumab is indicated for the treatment of patients with relapsing forms of multiple sclerosis and is mostly used in patients who have had an inadequate response to 2 or more drugs indicated for the treatment of multiple sclerosis.

Off-label uses

Alemtuzumab is used off-label in kidney transplantation as induction and antirejection therapy.

Contraindications

Goals and duration of treatment

A 3-year real-world study of alemtuzumab treatment of patients with relapsing-remitting multiple sclerosis showed improvement of disability as well as remission of disease activity, clinically and on MRI, in a significant proportion of patients (16). A retrospective study has shown that for multiple sclerosis patients under treatment with natalizumab who have ongoing disease activity and require a switch to another disease-modifying treatment, alemtuzumab has advantages over fingolimod for reduction of disease activity as well as progression of disability (15). A 6-year follow-up of patients in clinical trials has shown that conversion rate to secondary progressive multiple sclerosis was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression (10).

Dosing

The recommended dosage is 12 mg of alemtuzumab infused for 5 consecutive days in the first course and for 3 days in the second course 1 year later.

Special considerations

Treatment during COVID-19 pandemic. Use of immunosuppressant drugs during COVID-19 pandemic is controversial. Alemtuzumab is an immunosuppressive drug that induces lymphocytes depletion and a study was done on multiple sclerosis patients to determine its interaction with COVID-19. Results suggest that patients receiving alemtuzumab showed very mild symptoms of COVID-19 and the authors speculate that immune reconstitution induced by treatment may induce positive changes in the immune system in the defense against SARS-CoV2 (13). There is a report of a young woman who had COVID-19 a few days after alemtuzumab infusion with blood counts showing intense immunosuppression but she had a mild infection and recovered within 2 weeks (05).

Pediatric. The safety and effectiveness of alemtuzumab in pediatric patients less than 17 years of age have not been established. A multicenter, open-label, single-arm, before and after switch study is ongoing to evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis with disease activity on prior disease-modifying therapy (NCT03368664).

Geriatrics. No specific studies have been conducted to investigate the pharmacokinetics of alemtuzumab in geriatric patients.

Pregnancy. The use of alemtuzumab in women of childbearing age who desire pregnancy or are not on reliable birth control is not recommended because of potential risks to the fetus (12). Antibodies, including anti-CD52 and autoantibodies, may be transferred from the mother to the fetus during pregnancy, and placental transfer of antithyroid antibodies may result in neonatal Graves’ disease.

Interactions

No formal drug interaction studies have been conducted with alemtuzumab using the recommended dose in patients with multiple sclerosis.

Adverse effects

Mild to moderate infusion-related reactions -- headache, rash, pyrexia, and nausea -- are the most common adverse events, affecting over 90% of patients, and are assumed to be due to the rapid release of the cytokines resulting from target cell lysis and consecutive inflammatory responses (18). These can be prevented by concomitant corticosteroids, antihistamines, and antipyretic drugs.

Alemtuzumab may cause serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia and anti-glomerular basement membrane disease. Complete blood counts with differential, serum creatinine levels and urinalysis with urine cell counts are recommended at periodic intervals for 48 months after the last dose of alemtuzumab. Alemtuzumab-related secondary autoimmune disorders involving thyroid are frequent and affect the risk-benefit ratio. Standard ThyAb-testing for antithyroid-peroxidase and antithyroglobulin antibodies at baseline is a biomarker of increased risk for clinically manifest thyroid secondary autoimmune disorders and should therefore be used in clinical decisions to initiate treatment with alemtuzumab (19).

Infections, mainly of mild-to-moderate severity, were recorded as adverse events in more than 70% of patients in phase 2/3 clinical trials of alemtuzumab. Recommended preventive measures include prophylaxis against herpes virus and tuberculosis, papillomavirus screening, and Listeria-free diet (04).

Intracerebral hemorrhage following alemtuzumab is likely due to hypertension that may occur during the infusion of the drug, and mean systolic blood pressure increases of 20 mmHg or more, or more than 20% throughout the infusion period, are an indication of the need of admission to a hospital for close observation (02).