Lemtrada® (alemtuzumab, formerly Campath)
FDA-Approved Medications: Administered by Intravenous (IV) Infusion
Companies: Genzyme, a Sanofi company, and Bayer HealthCare Pharmaceuticals
- Administered in one course yearly by intravenous infusion over three-to-five consecutive days
- Lemtrada is approved in relapsing types of MS
Lemtrada is a humanized monoclonal antibody that targets a protein present on the surface of mature lymphocytes, resulting in a rapid depletion/suppression of T and B cells. This agent has been approved for the treatment of B-cell leukemia, although since 2012, it has been developed solely for MS.
A Phase II study of 334 individuals with early, active RRMS compared Lemtrada to high-dose Rebif (44 mcg) in RRMS. In this three-year safety and efficacy trial, Lemtrada was more effective than Rebif at reducing the relapse rate and the risk for six-month sustained accumulation of disability in patients with RRMS.
In a multi-year extension study of the 334 individuals who participated in the original Phase II study, Lemtrada yielded a 73-percent reduction in risk for sustained accumulation of disability. Additionally, 77 percent of Lemtrada- treated patients were relapse-free.
A five-year assessment showed that 87 percent were free of sustained disability accumulation, 72 percent were relapse-free, and 65 percent were free of clinical-disease activity. These data indicate that Lemtrada’s treatment effect is durable; it halts clinical-disease activity in a significant proportion of RRMS patients through five years – even though many of those patients did not require subsequent re-treatment with the drug.
Lemtrada has since successfully completed two Phase III trials: CARE-MS I and II. The CARE-MS I study18 compared the clinical and MRI results of treatment with Lemtrada, to treatment with subcutaneous Rebif (interferon beta-1a) in patients with RRMS who had not received prior treatment with any disease-modifying therapies. Rebif was given according to the regular dosing of three-times per week, while Lemtrada was given intravenously for five days, and then a second course one year later for three days. CARE-MS I was a multicenter international trial. Data were collected for each patient during a two-year period from the time of the first infusion.
The ARR (annual relapse rate) was 0.18 (or slightly less than one relapse every five years) for Lemtrada-treated patients. This was compared with 0.39 (or slightly less than one relapse every two-and-a-half years) for Rebif-treated patients. This means that Lemtrada reduced the ARR by 55 percent compared to Rebif. Individuals taking Lemtrada had a 59-percent reduction in severe relapses requiring steroid treatment. These clinical data were supported by MRI outcomes. Through year two, fewer Lemtrada patients developed new gadolinium-enhancing lesions (areas of active inflammation and myelin damage in the brain) than Rebif-treated patients (15.2 percent versus 27.2 percent).
CARE-MS II19 is the third study to compare Lemtrada with Rebif. It was designed to evaluate the effect of Lemtrada on relapse and disability as compared to Rebif in people with RRMS who had relapsed on prior therapy – people for whom a first-line injectible medication was insufficient. The study design was otherwise the same as that in CARE-MS I. The co-primary efficacy endpoints were the ARR and time to six-month sustained accumulation of disability as measured by the Expanded Disability Status Scale (EDSS).
Relapse data showed that 65 percent of patients treated with Lemtrada were relapse-free at two years, as compared to 47 percent with Rebif. These data also showed a 49-percent reduction in relapse rate as compared to Rebif. The group treated with Lemtrada showed a decrease in the mean disability score, versus a slight worsening of disability in those treated with Rebif. Approximately 29 percent of patients treated with Lemtrada experienced a six-month sustained improvement in disability, as compared to 13 percent with Rebif.
In addition to the new goal of identifying improvement in disability achieved by some participants in clinical trials, looking at the percent of patients who are “disease-activity free” (also referred to as having “no evidence of disease activity,” or NEDA) during a clinical trial is another important aspirational goal of our increasingly powerful therapies for MS. Along these lines, subsequent analyses of the Lemtrada clinical trial data were presented in 2013.20
In a subset of patients with highly active disease in the CARE-MS II trial (patients with multiple relapses and enhancing MRI lesions in the year prior to enrolling in the trial), 24 percent of individuals treated with Lemtrada were free of disease activity at the end of the two-year study, while none of these study participants treated with Rebif (interferon beta-1a) achieved that outcome.
Three-year follow-up data from the CARE-MS II extension study presented in 2014 demonstrated21 that Lemtrada has a durable treatment effect. Eighty percent of individuals with RRMS who received two yearly courses of the drug in the CARE-MS II trial did not need to receive a third course of treatment. Seventy percent of EDSS scores were stable or improved at year three, compared to the baseline measurement upon entry into the trial.
Several safety concerns have been raised by the above studies, including infusion reactions to the medication, and an increased risk of infection and emergent autoimmune diseases in patients treated with Lemtrada. All three studies showed a modest increase in the incidence of infections, though no opportunistic infections occurred. (These types of infections are a result of micro-organisms found in the body that only infect a person when the immune system has been weakened.) No treatment-related fatalities were reported in the Phase III studies.
In the CARE-MS I and II studies respectively, approximately 18 percent and 16 percent of Lemtrada patients developed an autoimmune thyroid disorder. At the 2014 American Academy of Neurology meeting, further data was presented: Four-year follow-up data from the ongoing CARE-MS extension study found that in years zero to four, 35 percent of individuals receiving Lemtrada experienced a thyroid adverse event. None of these events resulted in discontinuation of treatment with Lemtrada, and most of the thyroid-related adverse events were treated with conventional treatment. The incidence of events peaked at month 36 and decreased thereafter.
In the CARE-MS studies, approximately 1 percent of subjects developed a potentially severe bleeding disorder called immune thrombocytopenic purpura (ITP). With ITP, the blood does not clot as it should, and this can result in internal bleeding. It is important that patients treated with Lemtrada commit to monthly lab and self-monitoring because, if not detected and treated, ITP can have grave consequences. When addressed promptly, ITP caused by drug treatments such as Lemtrada, responds readily to treatment. A program to monitor for the development of thyroid issues and immune thrombocytopenia was successful in early detection of these known complications from Lemtrada in the clinical trials.
With the side effects and adverse events in mind, the significant reduction in relapses with Lemtrada compared with Rebif was a deciding factor in the FDA’s consideration of Lemtrada as an addition to the available treatment options for RRMS. In June 2012, the parent company announced that Lemtrada was submitted to both the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for approval.
In September 2013, the EMA granted marketing authorization for Lemtrada for the treatment of multiple sclerosis. In Europe, the drug is indicated for the treatment of adult patients who have relapsing-remitting MS with active disease defined by clinical or imaging features.
In November 2013, the FDA held a meeting to discuss Lemtrada. Despite raising concerns over the drug’s safety as well as study design, the FDA’s advisory committee voted to recommend the drug for approval. Unlike the EMA’s decision, the committee recommended that the treatment be approved only as a second-line therapy, when other disease-modifying therapies fail or are not tolerated well by a patient.
However, in December 2013, Lemtrada was initially denied FDA approval. After a period of detailed reconsideration of the data, the FDA decided to approve Lemtrada for use in the United States in November 2014. Because of its safety profile, the FDA indicated that use of Lemtrada should generally be reserved for people who have had an inadequate response to two or more MS therapies.
The prescribing information for Lemtrada includes a boxed warning about the potential for serious, sometimes fatal, autoimmune conditions based on the data described earlier, including thyroid conditions, immune thrombocytopenia (ITP), and an immune condition that impacts the kidneys. Patients need to be aware of the potential for serious and even life-threatening infusion reactions on the days the medication is administered, and an increased risk of malignancies in the long-term.
Patients electing to be treated with Lemtrada need to take preventative antiviral medications and undergo careful monitoring, including blood and urine tests every month for 48 months after the last dose is given, as well as annual skin exams, as part of the Lemtrada REMS (Risk Evaluation and Mitigation Strategy) program.