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Lemtrada (alemtuzumab) received FDA approval on November 14, 2014, under fast track designation, for the treatment of patients with relapsing forms of MS.Due to the safety profile, alemtuzumab should generally be reserved for patients who have had an inadequate response to 2 or more drugs indicated for MS.
Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system and can lead to significant disability. An estimated 2.3 million people worldwide have been diagnosed with MS. Most patients are diagnosed between the ages of 20 and 50 years, and MS is reported more frequently in women than in men.1 MS is characterized by relapses or repeated episodes of inflammation within the brain and spinal cord. These relapses injure myelin sheaths that surround and insulate nerves, and nerve cell axons.2 These areas of inflammation and/or scarring appear as visible lesions on magnetic resonance imaging (MRI). Prevention of relapses and delay in progression of disability are the treatment goals for disease-modifying therapies for MS.3
Lemtrada (alemtuzumab) received FDA approval on November 14, 2014, under fast track designation, for the treatment of patients with relapsing forms of MS.4 Due to the safety profile, alemtuzumab should generally be reserved for patients who have had an inadequate response to 2 or more drugs indicated for MS.5 Alemtuzumab was previously marketed as Campath for monotherapy treatment of B-cell chronic lymphocytic leukemia.6,7
Alemtuzumab is a recombinant, humanized IgG monoclonal antibody directed against the cell surface glycoprotein, CD52, located on T and B lymphocytes. Depletion of T and B lymphocytes occurs after each treatment course. The nadir occurs at 1 month, with B-lymphocyte counts recovering at month 6, while T-lymphocyte counts typically remain below baseline 12 months after treatment.5 Its mechanism of action in MS is unknown.
Alemtuzumab is available from specialty pharmacies through the Risk Evaluation and Mitigation Strategy (REMS) program for this drug.5 The REMS program requires enrollment of patients and certification of prescribers, pharmacies, and healthcare facilities due to the risks of autoimmune disorders, serious infusion reactions, and malignancies. The infusion is administered in a facility with equipment and healthcare providers trained to manage anaphylaxis or serious infusion reactions. Required monthly monitoring of complete blood counts and urinalysis begins on treatment initiation and continues for 4 years after the last infusion of alemtuzumab.5,8
Alemtuzumab is administered by intravenous (IV) infusion as 12 mg daily over 4 hours for 5 consecutive days. Twelve months later, a second treatment course of alemtuzumab 12 mg daily for 3 consecutive days is administered. For the first 3 days of each alemtuzumab treatment course, patients must be premedicated with methylprednisolone 1 g IV daily. Additionally, antiviral prophylaxis for herpetic viral infections is initiated on the first day of each treatment course and continued for at least 2 months or until the CD4+ lymphocyte count is 200 cells/mcL or higher, whichever occurs later.5
Alemtuzumab, a first-in-class monoclonal antibody against CD52, is a new treatment option for patients who have had an inadequate response or intolerability to other MS therapies. The approach to MS includes the management of symptoms, treatment of acute relapses, and utilization of disease-modifying therapies to reduce the frequency and severity of relapses and to delay disease and disability progression.2,3 Current disease-modifying therapies for MS include injectable medications such as Copaxone (glatiramer acetate), Avonex, Rebif (interferon beta-1a), Betaseron, Extavia (interferon beta-1b), Plegridy (peginterferon beta-1a), Tysabri (natalizumab), and mitoxantrone. Oral MS drugs include Aubagio (teriflunomide), Gilenya (fingolimod), and Tecfidera (dimethyl fumarate).
Efficacy and safety of alemtuzumab were compared to interferon beta-1a (Rebif) in 2, multicenter, open-label, phase 3, randomized trials in patients with relapsing-remitting MS (RRMS) (CARE-MS I and CARE-MS II).9,10 The CARE-MS I trial enrolled 581 treatment-naïve, high-functioning patients with MS who had a score of 3 or lower on the Expanded Disability Status Scale (EDSS). In the CARE-MS II trial, 840 enrolled patients with EDSS score of 5 or lower had experienced at least 1 relapse while on interferon beta-1a or glatiramer acetate after at least 6 months of treatment.
In both studies, patients were randomized to alemtuzumab infused for 5 consecutive days followed by a treatment course for 3 consecutive days 12 months later or to interferon beta-1a 44 mcg subcutaneously 3 times weekly after an initial dosage titration. All patients received methylprednisolone 1 g intravenously for 3 consecutive days at the initiation of treatment and at month 12.
In both trials, the coprimary endpoints were annualized relapse rate (ARR) and rate of sustained accumulation of disability over 6 months (SAD). Alemtuzumab demonstrated reductions in ARR in both studies of patients with RRMS over 2 years compared to interferon beta-1a. SAD results were inconsistent, with only the CARE-MS II trial favoring alemtuzumab over interferon beta-1a.
Abbreviations: ARR, annualized relapse rate; SAD, sustained accumulation of disability over 6 months
Source: Refs 9,10
Both studies evaluated MRI outcomes, specifically percent change in T2 hyperintense lesion volume (lesion burden). Both treatments reduced lesion volume, but the difference between the 2 groups was not significant.
Extension studies of CARE-MS I and CARE-MS II with alemtuzumab are ongoing. A total of 73% and 68% of the alemtuzumab-treated patients from the CARE-MS I and CARE-MS II studies, respectively, did not require additional doses of alemtuzumab through year 4.11,12
Most common adverse reactions consisted of infusion reactions, rash, headache, pyrexia, and nasopharyngitis.5,9,10 One-third of patients experienced thyroid disorders including hyperthyroidism and hypothyroidism. Serious autoimmune adverse effects included immune thrombocytopenia (2%), glomerular nephropathies (0.3%), and autoimmune cytopenias (0.5%).
Questions remain about potential bias introduced by the open-label study design. FDA Peripheral and Central Nervous System Drugs Advisory Committee reviewed alemtuzumab in November 2013. FDA presented concerns with the larger attrition rate of interferon-assigned patients who withdrew from the study prior to the first dose and the use of baseline EDSS scores obtained after patients knew their assigned randomized treatment.13,14 Relapse reporting and EDSS testing processes were subject to potential bias by the patient and the treating neurologist despite use of a blinded EDSS rater. In November 2013, FDA Advisory Committee voted 11 to 6 (1 abstention) that the clinical trials were inadequate; however, the committee did support that alemtuzumab provided substantial evidence of effectiveness in relapsing MS with a vote of 12 to 6.15
Alemtuzumab offers another alternative for patients who have had an inadequate response, contraindication, or are intolerant to the other MS therapies. Alemtuzumab will likely be a third- or fourth-line agent. Annual treatment courses may be perceived as a possible advantage to a patient who would like to avoid routine medication administration; however, there is a risk of serious, unpredictable adverse events in the setting of the long duration of action and lack of an antidote. Questions remain about the risks of autoimmune disorders and the risk of malignancies.
Current wholesale acquisition cost (WAC) and average wholesale price (AWP) for the 2-year treatment course of alemtuzumab are $158,000 and $189,600, respectively.16
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Care of MS patients includes the management of symptoms, treatment of acute relapses, and utilization of disease-modifying therapies to reduce the frequency and severity of relapses and delay disease and disability progression. American Academy of Neurology 2002 guidelines recommend glatiramer acetate or interferon beta products for RRMS.2 Guidelines for MS have not yet addressed the role of the newer agents for relapsing forms of MS.2,3,17,18
In July 2014, after a comprehensive review of current evidence, MS Coalition recommended that patients with relapsing MS be treated with a disease-modifying therapy as soon as possible after diagnosis, and that therapy be continued indefinitely unless there are intolerable adverse effects, inadequate adherence, suboptimal response, or the availability of a more appropriate regimen.3 The MS Coalition did not state a preference for any one medication or class of medications. Patient-specific medication selection should be based on route and frequency of delivery, side-effect profile, contraindications, and occurrence of clinical relapse or MRI changes while on therapy.
Alemtuzumab reduced the relapse rate in patients with MS compared to interferon beta-1a. Inconsistent results were observed with the effect of alemtuzumab on the sustained accumulation of disability over 6 months. Questions remain about the open-label clinical trials and the potential impact bias may have had on the results. Patients and providers must weigh the risk of serious adverse effects including autoimmune disorders, infusion reactions, and malignancy against the benefits of efficacy with alemtuzumab. With an increasing number of options for the treatment of relapsing MS, the place in therapy for each disease-modifying agent is not straightforward. Individual treatment decisions will likely consider the risks and benefits of each therapy, physician experience, patient comorbidities, administration, and patient preferences.3
Dr Rawlings is the manager of pharmacy and therapeutics with the Drug Intelligence Department at Catamaran.