Lemtrada™ (alemtuzumab) is a prescription medication approved by the Food and Drug Administration (FDA) in November 2014 for treating adults with relapsing forms of multiple sclerosis (MS). Lemtrada is a humanized monoclonal antibody directed that causes depletion of lymphocytes (white blood cells). It was originally approved, at a significantly higher dose, for the treatment of B-cell chronic lymphocytic leukemia. Its ability to target immune cells led investigators to test its potential as a treatment for relapsing MS. Lemtrada is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.
“The FDA approval of Lemtrada is a significant milestone for people living with relapsing MS in the United States,” said Dr. Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. “We are pleased that the voices of the MS community have been recognized and that people with relapsing MS will now have access to a new, needed treatment option.”
Alemtuzumab is a monoclonal antibody that targets CD52, a protein abundant on T and B cells. Circulating T and B cells are thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab depletes circulating T and B lymphocytes after each treatment course. Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes.
The FDA approval of Lemtrada is based on two pivotal randomized Phase III open-label rater-blinded studies comparing treatment with Lemtrada to Rebif® (high-dose subcutaneous interferon beta-1a) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II).
Lemtrada is given by intravenous infusion – for 5 consecutive days initially and for 3 consecutive days one year later. The prescribing information includes a boxed warning about the potential for serious or life-threatening autoimmune disorders, infusion reactions and malignancies. Lemtrada will only be available from certified prescribers, and patients will be enrolled in a Risk Evaluation and Mitigation Strategy (REMS) program to ensure that ongoing periodic monitoring will be maintained to detect potential problems.
FDA screening and monitoring recommendations:
The FDA recommends that before starting treatment:
- Determine whether the individual has been vaccinated for varicella zoster virus, and if not, tested for antibodies and vaccinated if needed 6 weeks prior to beginning treatment with Lemtrada.
- Thyroid function tests such as thyroid stimulating hormone level should be obtained before treatment and every 3 months until 48 months after the last infusion.
- Full blood count with differential should be obtained prior to treatment and monthly thereafter until 48 months after the last infusion.
- Serum creatinine levels should be obtained prior to treatment and monthly thereafter until 48 months after the last infusion.
- Urinalysis with urine cell counts be obtained prior to treatment and monthly thereafter until 48 months after the last infusion.
- Skin exam should occur at start of treatment and yearly thereafter to monitor for melanoma.
- People with active infections should consider delaying treatment until the infection is controlled.
- People should not have live-virus vaccines after a course of Lemtrada.
Care-MS I Study:
In a 2 year, rater-masked, randomized controlled phase 3 trial, adults aged 18–50 years with previously untreated relapsing-remitting multiple sclerosis was undertaken. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Co-primary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug.
In the CARE-MS I study, data were evaluated for 563 people with early, active relapsing-remitting MS, who had never received disease-modifying therapy to treat their MS and were randomly assigned to receive Lemtrada or Rebif. After two years the relapse rate for those on Lemtrada was reduced by 55% compared to those on Rebif. Also after two years, 8% of those on Lemtrada experienced an increase (worsening) in their EDSS score (a standard scale of physical disability) compared to 11 % on Rebif – a difference that was not statistically significant. After two years 78% of those on Lemtrada remained relapse-free, which was significantly more than the 59% who remained relapse-free on Rebif.
- 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab.
- 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events) corresponding to a 54.9% improvement with alemtuzumab.
- Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group.
- 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group.
- 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious.
- Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a.
- 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a.
- By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group.
- Two patients in the alemtuzumab group developed thyroid papillary carcinoma.
Care-MS II Study:
In a 2 year, rater-masked, randomised controlled phase 3 trial enrolled adults aged 18–55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Co-primary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug.
The CARE-MS II study was a two-year trial comparing Lemtrada to the standard subcutaneous dosing of Rebif. Data were evaluated for 628 people with relapsing-remitting MS who had already been treated with another MS therapy but had experienced at least one relapse on that previous therapy. After two years, the annual relapse rate for those on Lemtrada was 0.26 compared to 0.52 for those on Rebif, representing a 49% lower risk of relapses. In addition, on average fewer people on Lemtrada had an increase (worsening) in their EDSS score compared to those on Rebif (13% for Lemtrada vs. 21% for Rebif) – a 42% difference that was statistically significant. After two years, 65% of those on Lemtrada remained relapse-free compared to 47% on Rebif, which was also statistically significantly.
- 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses.
- 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events) corresponding to a 49.4% improvement with alemtuzumab.
- 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group.
- 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group corresponding to a 42% improvement in the alemtuzumab group.
- For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.
Additional Data Presented At ECTRIMS 2016 MS Conference : 6 Years Of Data
After the initial two courses of treatment in the CARE-MS trials, which were given at month zero and at month 12, 64 percent of Lemtrada patients from CARE-MS I and 55 percent from CARE-MS II did not receive additional Lemtrada treatment during the following five years, through month 72.
- The low annualized relapse rates observed in patients who received Lemtrada in the Phase III studies CARE-MS I (0.16) and CARE-MS II (0.28) remained consistent throughout the extension (0.12 and 0.15 at year six.)
- Through year six, 77 percent and 72 percent of patients who received Lemtrada in CARE-MS I and CARE-MS II, respectively, did not experience worsening of six-month confirmed disability as measured by the Expanded Disability Status Scale (EDSS).
- Through year six, 34 percent and 43 percent of patients who had disability before receiving Lemtrada in CARE-MS I and CARE-MS II, respectively, had improvement in EDSS score confirmed over at least six months as compared with pre-treatment baseline.
- Through year six, patients who received Lemtrada in CARE-MS I and II experienced a slowing of brain atrophy as measured by brain parenchymal fraction on magnetic resonance imaging (MRI). In years three through six, the median yearly brain volume loss was -0.20 percent or less, which was lower than what was observed in the Lemtrada-treated patients during the two-year pivotal studies (CARE-MS I: -0.59 percent in year one; -0.25 percent in year two; CARE-MS II: -0.48 percent in year one; -0.22 percent in year two).
- In each of years three, four, five and six, most patients had no evidence of MRI disease activity, defined as no new gadolinium-enhancing T1 lesions and no new or enlarging T2 lesions (66 – 72 percent, CARE-MS I; 68 – 70 percent, CARE-MS II).
Prescribing information for Lemtrada includes a boxed warning about the potential for serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia (a rare bleeding condition) and anti-glomerular basement membrane disease (which impacts the kidneys). It also warns about serious and life-threatening infusion reactions (reactions occurring during or more than 24 hours after the administration of the medication), increased risk of malignancies (including thyroid cancer, melanoma, and blood cancers). Autoimmune thyroid disorders occurred in 34% of people treated with Lemtrada in clinical studies.
The most common side effects noted in people who have taken Lemtrada:
- Nasal congestion
- Urinary tract infection
- Upper respiratory tract infection
- Herpes viral infection
- Thyroid gland disorders
- Fungal infections
- Pain in joints, extremities and back
- Sore mouth and throat
- Tingling and /or dizziness
- Abdominal pain
As an organization whose vision is to create a world free of multiple sclerosis, the Society strives to live by a set of core values which guide our work and our actions on a daily basis. We are passionate in our commitment to people affected by MS. We strive to improve quality of life while searching for the cure. We are leaders in the vision of a world free of MS. Through creativity and hard work, we accelerate the pace of scientific discovery, promote quality health care, stimulate community resources and services, advocate for favorable government policies, and are the world’s best source of information about multiple sclerosis. We are honest and straightforward in all that we do. We treat everyone with dignity and respect. We act responsibly with resources entrusted to us. We are accountable and act in accordance with these values. We set high standards of performance and service delivery, and work toward excellence in everything we do. We advance the interests of people affected by multiple sclerosis through individual and team achievements. We recognize our volunteers and staff as our most valued resources. We encourage collaboration across organizational boundaries.
National Multiple Sclerosis Society Lemtrada Video:
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