Alemtuzumab, a monoclonal antibody that targets CD52 on T and B lymphocytes, has received approval in Canada for the treatment of adults aged 18-64 years with relapsing-remitting MS who have had an inadequate response to interferon-beta or other disease-modifying
therapies.
The drug is administered by IV infusion at a dose of 12 mg/day x 5 days, followed one year later by 12 mg/day x 3 days. The recommended duration of the infusion is approximately 4 hours.
Before treatment initiation, patients must be evaluated for active or latent tuberculosis, and for hepatitis B and C. A baseline brain MRI with gadolinium is advised. Pre-treatment with corticosteroids (IV methylprednisolone 1 g/day x 3 days) immediately prior to the infusion is recommended to reduce the risk of transient worsening of MS due to cytokine release (Moreau et al. Brain 1996;119[Pt 1]:225-237). Pre-treatment with antihistamines and/or antipyretics may also be considered to reduce the risk of infusion reactions. Antiviral prophylaxis should be administered on day 1 of the infusion and continued for at least one month due to the risk of herpesvirus infection/reactivation. An ECG is also recommended prior to each treatment course due to a risk of cardiac arrhythmia.
Following treatment initiation, blood tests (CBC with differential, serum creatinine) and urinalysis (with urine cell counts) should be obtained monthly for at least four years after the last infusion. Women should be screened annually for human papillomavirus (HPV). Thyroid function (e.g. TSH) should be determined at baseline and every three months thereafter, and close monitoring for autoimmune thyroid disease is advised. Alemtuzumab is not recommended in women planning to become pregnant or during breastfeeding.
Approval of alemtuzumab (Lemtrada) was based on the results of two phase III studies (CARE-MS I, CARE-MS II) and a phase II study (CAMMS223). In CARE-MS I, alemtuzumab and subcutaneous interferon-beta-1a 44 mcg three times/week were compared in 563 treatment-naïve RRMS patients (Cohen et al. Lancet 2012;380:1819-1828). At two years, the proportion of patients who experienced a relapse was 21.8% with alemtuzumab versus 40.1% with IFNb; this corresponded to a 54.9% reduction. There was no significant difference in sustained accumulation of disability (SAD; 8% vs. 11%).
In CARE-MS II, two doses of alemtuzumab (12 and 24 mg) were compared to IFNb 44 mcg three times/week in 628 RRMS patients; the 24-mg arm was subsequently halted due to low recruitment (Coles et al. Lancet 2012;380:1829-1839). Subjects had been previously treated with at least one disease-modifying or other therapy (immunoglobulin, azathioprine) for a mean of three years. Compared to CARE-MS I, subjects in CARE-MS II were slightly older (35-36 years vs. 33 years), had greater disability (mean EDSS 2.7 vs. 2.0), and a longer duration of MS (4.6 vs. 2.1 years), although baseline disease activity (relapses in prior year, number of Gd+ lesions) was similar. At two years, the proportion of patients experiencing a relapse was 34.5% with alemtuzumab compared to 51.5% with IFNb. It should be noted that a majority of subjects in the IFNb arm had demonstrated a prior inadequate response to IFNb, which may explain the high event rate (201 events in 202 patients, 99.5%) in this group. In contrast to CARE-MS I, the proportion of patients with SAD was significantly lower with alemtuzumab compared to IFNb (12.7% vs. 19.8%) in CARE-MS II.
The Canadian label includes warnings about the risks of autoimmunity and infections, including progressive multifocal leukoencephalopathy (PML). The most common secondary autoimmunity seen with alemtuzumab was thyroid disease. In the five-year follow-up of the phase II trial, the incidence of thyroid disorders was 30% compared to 4% with IFNb (Coles et al. Neurology 2012;78:1069-1078). The estimated incidence of immune thrombocytopenia (ITP) is 1% (Cohen 2012). ITP typically occurred 14-36 months after drug exposure. The phase II trial was suspended following the report of three cases of ITP, including one death (CAMMS 223 investigators. N Engl J Med 2008;359:1786-1801). The label also cautions about nephropathies (e.g. Goodpasture’s disease), with an estimated incidence of 0.3%.
The warning about infections was based on the use of higher doses of alemtuzumab in patients without MS. The incidence of serious infections in CARE-MS II was 4% (Cohen 2012). While alemtuzumab has profound effects on T and B cell populations, the drug has a lesser effect on the innate immune system (NK cells, dendritic cells, macrophages), which may preserve some degree of immunocompetence (Freedman et al. J Clin Cell Immunol 2013;4; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3869402/). However, the risk of herpesvirus infection or reactivation appears to be high, with an incidence of 16% in both CARE-MS trials (vs. 2-4% with IFNb) despite antiviral prophylaxis.
The risk of PML is not known. There have been no PML cases in MS trials of alemtuzumab, but cases have been reported in patients receiving alemtuzumab for other conditions. A Canadian analysis published in 2011 of Canadian, World Health Organization and Medline databases reported 14 PML cases associated with alemtuzumab (compared to 32 for natalizumab and 114 for rituximab at that time) (Keene et al. Can J Neurol Sci 2011;38:565-571). The Canadian product monograph states that PML has been reported in patients with B cell chronic lymphocytic leukemia, but the PML frequency in patients treated with alemtuzumab was no greater than the background frequency. Regular monitoring for signs and symptoms suggestive of PML is recommended. An ECG is required prior to each treatment course.
The most common adverse effect with alemtuzumab is infusion reactions (notably headache, rash, pyrexia, nausea and skin reactions), which occurred in 82% of patients in clinical trials despite pre-treatments. Infusions reactions were generally mild to moderate; reactions were severe in 9% of patients. Serious reactions (e.g. cardiac arrhythmias, pyrexia, urticaria and hypotension) occurred in 3% of patients.
In Canada, alemtuzumab is indicated as a second- or third-line agent. In contrast, the European Medicines Agency approved the drug in September 2013 for adult RRMS patients with active disease, so it could conceivably be used as a first-line agent. In the U.S., the Food and Drug Administration rejected the application altogether, stating that there was insufficient evidence from adequate and well-controlled studies to demonstrate that the benefits of alemtuzumab outweigh the risks.
Comment
Dr. François Grand’Maison: Alemtuzumab is a very effective drug with considerable potential toxicity, which for the most part is manageable. Although it is a welcome addition to our armamentarium against MS, it is not appropriate for everyone. Its mechanism of action in MS is uncertain but the theoretical resetting of the immune system is very appealing. Therefore, it may be particularly beneficial in patients with highly active disease at onset. Another situation where alemtuzumab may be valuable is after 18-24 months of natalizumab therapy in JC virus antibody-positive patients because of the high risk of PML, especially if fingolimod is contraindicated. At present, fingolimod is the number one choice following natalizumab.
The FDA rejected the alemtuzumab application because of the single-blinded design of the trials. It can be argued that the considerable side effects or infusion/injection reactions of the drugs would inevitably unmask the blind. The FDA may be asking for an impossible trial.