Lemtrada™ Receives FDA Approval for Relapsing Forms of MS

Approval History

Initially, Lemtrada was poised for approval in December 2013. However, on December 30, 2013, Genzyme announced that it had received a Complete Response Letter from the FDA, informing them that the application for their drug was “not ready for approval,” noting possible issues in study design. For full details, please see, “Lemtrada Denied FDA Approval; More Studies Needed.”

In April 2014, Genzyme resubmitted Lemtrada’s application to the FDA for approval, and the application was accepted by the FDA the following month. For more information, please see, “FDA Accepts Resubmitted Lemtrada Application for Review.”

According to a press release issued by Genzyme, “First approved in September 2013 in the European Union, Lemtrada is approved in more than 40 countries. Additional marketing applications for Lemtrada are under review by regulatory agencies around the world.”

An Overview of How Lemtrada Affects the Immune System, Study Results, and Adverse Events

Lemtrada rapidly depletes or suppresses immune system cells (T and B cells) that damage the myelin and nerves of the central nervous system (CNS), a hallmark feature of MS. This injury to the nerves causes the symptoms of MS and may be viewed as lesions on magnetic resonance imaging (MRI) scans. Once these T and B cells are depleted or suppressed, the attack on the nerves of the CNS (those within the brain and spinal cord) may potentially be halted, and a new group of T and B cells is eventually produced by the body. By depleting or suppressing the damaging T and B cells, researchers believe that the immune system may be reset, and the new immune-system cells may behave differently than those that previously attacked the nerves.

In clinical trials, Lemtrada was shown to significantly reduce the relapse rate for individuals with relapsing-remitting MS, as well as significantly reduce the risk of sustained disability accumulation. In a multi-year extension study of the 334 individuals who participated in the original Phase II study (comparing Lemtrada to an approved long-term treatment for MS), Lemtrada reduced the risk for sustained accumulation of disability by 73 percent, while 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.

Adverse events from Lemtrada can include infusion reactions to the medication, an increased risk of infection, and emergent autoimmune diseases. In the two Phase III studies – CARE-MS I and II respectively – approximately 18 percent and 16 percent of Lemtrada patients developed an autoimmune thyroid disorder, and 0.8 percent and 1 percent developed a potentially severe bleeding disorder called immune thrombocytopenic purpura (ITP). In ITP, the blood does not clot as it should, and this can result in internal bleeding.

Risk Evaluation and Mitigation Strategy

According to Genzyme’s press release, “Lemtrada is only available through a restricted distribution program, the Lemtrada REMS (Risk Evaluation and Mitigation Strategy). This program has been developed to ensure that access to Lemtrada in the U.S. is only through certified prescribers, healthcare facilities and specialty pharmacies and to also ensure that patients are enrolled in the REMS program. The program is intended to help educate healthcare providers and patients on the serious risks associated with Lemtrada and the appropriate periodic monitoring required to support the detection of these risks for 48 months after the last infusion. The REMS is based on a developmental risk management program that was successfully implemented in the Phase 2 and Phase 3 trials and allowed for early detection and management of some of the serious risks associated with Lemtrada.”

The press release also states, “The Lemtrada label includes a boxed warning noting a risk of serious, sometimes fatal autoimmune conditions, serious and life-threatening infusion reactions and also noting Lemtrada may cause an increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders.”

Comment from MSAA’s Chief Medical Officer

MSAA’s Chief Medical Officer Dr. Jack Burks believes that Lemtrada, with its ability to reduce relapses and possibly improve disability as well as prevent disease progression, has the potential to be a major contributor in the long-term treatment of MS. According to Dr. Burks, “I am very pleased to see another valuable treatment option approved for individuals with relapsing forms of MS. Efficacy data from Phase II and Phase III FDA trials with Lemtrada were significant and impressive. However, given that adverse events such as thyroid problems, low platelet counts, and infusion reactions were seen in some MS patients, any drug-safety recommendations and monitoring programs put into place by the FDA are vitally important. These types of events may be discovered early and are manageable.”

Additional Information about Lemtrada

Lemtrada is a humanized monoclonal antibody that targets a protein present on the surface of mature lymphocytes, and results 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 is being 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, while 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 study 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 time 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 as 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 II 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” 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. 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.

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 microorganisms 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, and 0.8 percent and 1 percent developed a potentially severe bleeding disorder called immune thrombocytopenic purpura (ITP). In 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 suggest that there is potential for Lemtrada to be a meaningful addition to the presently 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.

The preceding information appeared in MSAA’s annual MS Research Update, which was published in February 2014. The update was written by Stephen Krieger, MD and reviewed by Jack Burks, MD. Individuals may visit the publications section of MSAA’s website to view the most recent edition of the MS Research Update and view specifics about both approved and experimental therapies for MS.

For More Information

Genzyme’s MS One to One® program will provide information about multiple sclerosis, Lemtrada, and other relevant resources. MS One to One® is staffed by MS nurses and trained representatives who can provide support for individuals living with MS, their healthcare providers, family, and loved ones. For more information, please call the MS One to One® line at (855) MSOne2One (1-855-676-6326) Monday through Friday, from 8:30 am to 8:00 pm ET. Information and support are also available at www.MSOnetoOne.com.

Anyone with questions may also contact MSAA’s Client Services Specialists via email, phone, or our online chat feature. Please see the information below for contact details.

Questions may be sent via email to MSquestions@mymsaa.org.
MSAA’s Client Services Specialists may also be reached by calling (800) 532-7667, extension 154. (Please note that MSAA’s Specialists are available during normal business hours, 8:30 am to 5:00 pm ET, Monday through Friday.)
MSAA offers an interactive one-on-one chat feature that allows individuals to ask questions about MS while browsing MSAA’s website.

Written by Susan Wells Courtney
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer