June 25, 2014
Health Canada approves Lemtrada™ for the management of relapsing-remitting MS
Health Canada has recently approved Lemtrada™ (alemtuzumab) as a disease-modifying therapy for adults with relapsing-remitting multiple sclerosis (RRMS) who have been unresponsive or intolerant to interferon beta or other disease-modifying therapies. The approval followed the completion of two phase III clinical trials called CARE-MS I and CARE-MS II.
Clinical trials design (study population, dose, and route of administration)
Both CARE-MS I and CARE-MS II studies were phase 3 clinical trials that took place over 2 years and involved participants with active relapsing-remitting MS (RRMS).
This study recruited 581 participants aged 18-50 years who were all treatment-naive, meaning they did not take any medication prior to receiving alemtuzumab. Eligible participants were randomly assigned to receive either alemtuzumab or interferon beta-1a (IFNβ-1a) – a standard MS treatment used as a comparator in this study. Alemtuzumab was administered intravenously at a dose of 12mg/day for five consecutive days, followed by three consecutive days of infusions one year later. IFNβ-1a was administered via under-the-skin injections 3 times a week for two years at a dose of 44µg. To determine the efficacy (ability to produce in effect) of alemtuzumab in comparison to IFNβ-1a, the study investigators measured changes in annual relapse rate and disability progression.
This study recruited 840 participants aged 18-55 years who experienced an inadequate response to treatment with IFNß-1a or glatiramer acetate. Eligible participants were randomly assigned to receive one of the following:
- IFNβ-1a at a dose of 44µg 3 times a week for two years
- intravenous alemtuzumab at a dose of 12 mg/day for five days, followed by three additional infusions one year later
- intravenous alemtuzumab at a dose of 24 mg/day for 5 days, followed by 3 additional infusions one year later - this part of the study was discontinued to accelerate recruitment in the other two groups
To determine the efficacy of alemtuzumab after prior treatment with interferon or glatiramer acetate, in comparison to IFNβ-1a, the study investigators measured changes in annual relapse rate and disability progression in people who received alemtuzumab versus IFNβ-1a. A number of secondary measures were observed in the CARE-MS II study, including:
- Proportion of relapse-free patients
- Change from baseline in expanded disability status scale (EDSS)
- Disability progression as measured by change from baseline in multiple sclerosis functional composite (MSFC)
- Changes in lesion volume as indicated on MRI
Clinical trial results
Results of the study showed that, in people with RRMS who were treatment-naïve, alemtuzumab reduced the annualized relapse rate by 56% versus IFNβ-1a (Rebif ®). As well, 78% of people treated with alemtuzumab were relapse-free at the two year mark, compared with 59% of people treated with IFNβ-1a. Eleven percent of treatment-naïve participants who received IFNβ-1a had sustained accumulation of disability compared with 8% of participants treated with alemtuzumab.
Results of the study showed that, in people with RRMS who were unresponsive or intolerant to treatment with interferon beta-1a or glatiramer acetate, alemtuzumab reduced the annual relapse rate by 49% versus IFNβ-1a. As well, 65% of people treated with alemtuzumab were relapse-free at the two year mark, compared with 47% of people treated with IFNβ-1a. The risk of sustained accumulation of disability was reduced by 42%.
Imaging data collected from the study showed that lesion volume decreased after treatment with alemtuzumab and IFNβ-1a, but the decrease did not differ between groups. Further analysis revealed that alemtuzumab reduced the number of people who developed new lesions compared with IFNβ-1a. Treatment with alemtuzumab also reduced brain volume loss compared with IFNβ-1a.
Summary of results
Overall in both studies, treatment with alemtuzumab reduced relapses compared with IFNβ-1a, and more people were relapse-free after two years in the alemtuzumab group than in the IFNβ-1a group. In CARE-MS I, the rate of sustained accumulation of disability did not differ between the alemtuzumab and IFNβ-1a treatment groups. In CARE-MS II, which involved people who were previously treated with other disease-modifying therapies for MS, treatment with alemtuzumab significantly reduced the risk of sustained accumulation of disability compared with IFNβ-1a.
The safety profile of alemtuzumab observed in these trials was consistent with that from previous studies. Adverse events were higher in the alemtuzumab group, including mild-to- moderate infusion-associated reactions, infections and autoimmune disorders. Because autoimmune adverse events can develop up to five years after infusion of alemtuzumab, some cases may not have been captured during this two year study. As a result, a four year extension study is now taking place to continue follow-up with study participants. The occurrence of serious adverse events was similar for both treatment groups.
Lemtrada™ is manufactured by Genzyme Canada. Lemtrada™ joins Tysabri® (natalizumab) as the second monoclonal antibody treatment approved for MS in Canada. Monoclonal antibodies are artificially produced in the lab to target a very specific molecule in the body. In the case of Lemtrada, the target is the CD52 molecule found on the surface of T and B cells, which are white blood of the immune system. By attaching onto these molecules, Lemtrada has the ability to prevent them from becoming active and entering the central nervous system to cause damage to myelin.
Lemtrada™ is administered via infusion into a vein. Each infusion takes approximately four hours. For the first treatment course, individuals receive one infusion per day for five days. One year later, individuals receive one infusion per day for three days. Each infusion delivers 12 mg of Lemtrada. There is no treatment between the two courses.
Lemtrada™ may cause serious infection and autoimmune side effects, such as: immune thrombocytopenic purpura (ITP, or low platelets), thyroid disorders, and kidney disease. Common side effects which often occur during or shortly after a single infusion or treatment course include: headache, dizziness; rash, hives, itching; fever; nausea, vomiting; and difficulty sleeping. Most people treated with Lemtrada™ will experience side effects at the time of the infusion or within 24 hours after the infusion. Most infusion-associated reactions are mild but some serious reactions are possible, such as: fever, hives, irregular heartbeat, nausea, chest discomfort or low blood pressure. Occasionally allergic reactions are possible.
Alemtuzumab continues to provide evidence of efficacy in treating relapsing-remitting MS, however its efficacy should be weighed against its potentially serious, but manageable, adverse effects. Selecting an MS therapy should be done in consultation with a neurologist. For more information about Lemtrada please speak with your physician or contact Genzyme Canada’s patient support program, MS One to One at 1-855-MS1-2ONE (1-855-671-2663).
Full drug information with FAQ will be available on the MS Society website shortly
Cohen JA et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380:1819-28.
Coles AJ et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380; 1829-39.