Date: 2015-10-08
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Barcelona, Spain
Company: Genzyme (USA - MA), a Sanofi company (France)
Product: Lemtrada® (alemtuzumab)
Action
mechanism: monoclonal antibody. This humanized monoclonal antibody targets the cell-surface glycoprotein CD52, which is often expressed on T- and B-lymphocytes. Preliminary research suggests that alemtuzumab depletes the T- and B-cells that may be responsible for the cellular damage in multiple sclerosis, while potentially sparing other cells of the immune system. Early alemtuzumab research has also suggested a distinctive pattern of lymphocyte reconstitution in patients following treatment.
Disease: multiple sclerosis
Therapeutic area: Autoimmune diseases - Neurodegenerative diseases
Country:
Trial
details: The CARE-MS trials are Phase III, global, randomized clinical trials designed to evaluate whether the investigational MS therapy Lemtrada™ could achieve meaningful efficacy and safety improvements over the approved, active comparator Rebif (subcutaneous interferon beta-1a 44 mcg), a standard treatment for relapsing-remitting MS. The CARE-MS I study evaluated 581 patients naïve to prior MS treatment, except for steroids. The CARE-MS II study evaluated 840 patients who have had at least one relapse occurring while on MS therapy, including standard injectable disease modifying therapies. Genzyme announced publication of results of these studies in The Lancet in November 2012.
In both the trials, Lemtrada™was given as an IV administration a total of eight times over the course of the two-year study. The first treatment course of Lemtrada™ was administered on five consecutive days, and the second course was administered on three consecutive days 12 months later. Rebif 44 mcg was administered by subcutaneous injection three times per week, each week, throughout the two years of study. In the third-year following initial treatment, starting the extension phase of the trials, patients who experienced resumed disease activity were retreated with Lemtrada™ once daily for three days. Patients who took Rebif in the pivotal study phase and crossed over to receive Lemtrada™ in the extension phase received Lemtrada™ once daily for five days and then once daily for three days one year later.
More than 90 percent of the patients who participated in the Phase III pivotal trials enrolled in the extension study. Patients who originally received Lemtrada™ were eligible to receive additional treatment in the extension study if they experienced at least one relapse or at least two new or enlarging brain or spinal lesions.
Latest
news: * On October 8, 2015, Sanofi and its subsidiary Genzyme announced positive new five-year investigational data from the extension study of Lemtrada® (alemtuzumab) for patients with relapsing remitting multiple sclerosis (RRMS). These results will be presented on October 9, 2015 at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Barcelona, Spain. In RRMS patients treated with Lemtrada® in the Phase III pivotal studies, the effects described below observed in the two-year trials were maintained through three additional years in the extension study (years three, four and five). After the initial two courses of treatment in the pivotal studies, which were given at month zero and at month 12, 68 percent of Lemtrada patients from CARE-MS I and 60 percent from CARE-MS II did not receive additional Lemtrada treatment during the following four years, through month 60. •The low annualized relapse rates observed in patients who received Lemtrada in CARE-MS I (0.18) and CARE-MS II (0.27) were maintained from year three (0.19 and 0.22) to year five (0.15 and 0.18). •Through year five, 80 percent and 76 percent of patients who received Lemtrada in CARE-MS I and CARE-MS II, respectively, did not experience worsening of disability progression confirmed over six months as measured by the Expanded Disability Status Scale (EDSS). •Through year five, 33 percent and 43 percent of patients who had some 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 five, patients who received Lemtrada in CARE-MS I and II experienced a slowing of brain volume loss as measured by brain parenchymal fraction on magnetic resonance imaging (MRI). In years three, four and five, the median yearly brain volume loss was -0.20 percent or less, which was lower than what was observed during the two-year pivotal studies. •In each of years three, four and five, most patients had no evidence of MRI disease activity (70 - 72 percent, CARE-MS I; 68 - 70 percent, CARE-MS II). Through year five, the incidence of most adverse events during the extension study was comparable or reduced compared with the pivotal studies. The frequency of thyroid adverse events was highest in year three and declined thereafter. * On April 23, 2015, Genzyme, a Sanofi company, announced that new magnetic resonance imaging (MRI) data from the Lemtrada® (alemtuzumab) clinical development program will be presented at the 67th American Academy of Neurology (AAN) Annual Meeting. In relapsing remitting multiple sclerosis (RRMS) patients treated with Lemtrada® in the Phase III pivotal studies, MRI effects observed in the two-year trials were maintained through two additional years in the extension study (years three and four). After the initial two courses of treatment in the pivotal studies, which were given at month zero and at month 12, approximately 70 percent of Lemtrada® patients did not receive additional Lemtrada® treatment during the following three years, through month 48. The Phase III trials of Lemtrada were randomized, two-year pivotal studies comparing treatment with Lemtrada to high-dose subcutaneous interferon beta-1a (Rebif®) in patients with RRMS who had active disease and were either new to treatment (CARE-MS I) or who had an inadequate response to another therapy (CARE-MS II). Through year four, the adverse event profile of Lemtrada ® was consistent with that observed during the pivotal studies. The new data being presented at AAN include: The rate of brain atrophy, as measured by brain parenchymal fraction (BPF), decreased progressively over four years among Lemtrada patients in CARE-MS I. Among CARE-MS II Lemtrada patients, the rate of brain atrophy decreased progressively over three years and remained low in year four. In both studies, the median yearly brain volume loss was less than -0.20% in years three and four, which was lower than what was observed during the two-year pivotal studies. Safety results from the second year of the extension study were previously reported. No new risks were identified. The most common side effects of Lemtrada are rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. Other serious side effects associated with Lemtrada include autoimmune thyroid disease, autoimmune cytopenias, infections and pneumonitis. A risk management program incorporating education and monitoring helps support early detection and management of these identified risks. * On September 11, 2014, Genzyme, a Sanofi company, announced positive interim results from the second year of the extension study of Lemtrada™ (alemtuzumab) for multiple sclerosis. In this analysis, relapse rates and sustained accumulation of disability remained low among patients who had previously received Lemtrada in either of the Phase III CARE-MS I and CARE-MS II studies. In these pivotal studies, Lemtrada™ was given as two annual courses, at the start of the study and 12 months later. Approximately 70 percent of patients who received Lemtrada™ in the pivotal studies did not receive further treatment with Lemtrada through the second year of the extension study. No new safety signals were identified. These data have been presented at the European Committee for Research and Treatment in Multiple Sclerosis (ECTRIMS) meeting in Boston. Extension Study Results: The Phase III trials of Lemtrada™ were randomized, two-year pivotal studies comparing treatment with Lemtrada to high-dose subcutaneous interferon beta-1a (Rebif®) in patients with relapsing-remitting multiple sclerosis who had active disease and were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). * On March 21, 2013, Genzyme, a Sanofi Company, has announced interim results from the first year of the extension study of Lemtrada™ (alemtuzumab), being developed for the treatment for multiple sclerosis. In this analysis of the first year of the extension study, relapse rates and sustained accumulation of disability remained low among patients who had previously received Lemtrada™ in either of the Phase III CARE-MS I and CARE-MS II studies. In these pivotal studies, Lemtrada™ was given as two annual courses, at the start of the study and 12 months later. More than 80 percent of patients did not receive further treatment with Lemtrada™ during the first year of the extension study. These interim results are from the first year of the extension study for patients who previously received Lemtrada™ in the two-year studies. Findings stated below are based on patients who enrolled in the extension study: • More than half of patients (67 percent in CARE-MS I and 55 percent in CARE-MS II) who received Lemtrada™ in the pivotal trials and enrolled in the extension study were still relapse-free through the first year of the extension study.
In CARE-MS I and II, treatment with Lemtrada significantly reduced the risk of developing new lesions compared to interferon beta-1a. In the extension study, most of the Lemtrada-treated patients from CARE-MS I and II were free of new lesions and MRI activity in years three and four (approximately 70%).
More than 90 percent of the patients who were treated with Lemtrada™ in the Phase III trials enrolled in the extension study. These patients were eligible to receive additional treatment with Lemtrada™ in the extension study if they experienced at least one relapse or at least two new or enlarging brain or spinal cord lesions.
The following interim results are from the second year of the extension study for patients who previously received Lemtrada in the two-year pivotal studies:
• In year four, the annualized relapse rates for patients who received Lemtrada™ in CARE-MS I and CARE-MS II were 0.14 and 0.23, respectively. These rates were comparable to the annualized relapse rates for those patients who received Lemtrada in the pivotal trials.
• Through year four, 74 percent of patients in CARE-MS I and 66 percent in CARE-MS II had improved or stable disability as measured by the Expanded Disability Status Scale (EDSS).
• Through year four, 83 percent and 76 percent of patients who received Lemtrada in the pivotal trials, respectively, did not experience six-month sustained accumulation of disability – meaning they did not experience a worsening of their disability that persisted for six continuous months in the four years of observation.
• Approximately 70 percent of patients treated with Lemtrada in the pivotal studies did not receive a third course of treatment in years three and four.
Safety results from the second year of the extension study were reported. No new risks were identified. As previously reported, there were two deaths in the extension study. One was from sepsis and the other was presumed accidental and deemed unrelated to study treatment. Over four years, approximately 2 percent of patients treated with Lemtrada™ in the pivotal trials developed immune thrombocytopenia (ITP), all of whom responded to treatment. Patient monitoring for autoimmune disorders is incorporated in all Genzyme-sponsored trials of Lemtrada™.
The most common side effects of Lemtrada™ are infusion associated reactions (headache, rash, pyrexia, nausea, fatigue, urticaria, insomnia, pruritus, diarrhea, chills, dizziness, and flushing), infections (upper respiratory tract and urinary tract), and thyroid disorders. Autoimmune conditions (including immune thrombocytopenia, other cytopenias, glomerulonephritis and thyroid disease) and serious infections can occur in patients receiving Lemtrada. A comprehensive risk management program incorporating education and monitoring will help support early detection and management of these identified risks.
• In the first year of the extension phase, the annualized relapse rate for patients who received Lemtrada™ in the pivotal trials was 0.24 and 0.25, comparable to the annualized relapse rate for those patients in CARE MS I and CARE-MS II, respectively.
• Through year three, 72.4 percent of patients in CARE MS I and 70.0 percent in CARE MS II had improved or stable disability as measured by EDSS.
• At three years, 88 percent and 80 percent of patients who received LEMTRADA in the pivotal trials, respectively, did not experience six-month confirmed sustained accumulation of disability.
• More than 80 percent of patients treated with Lemtrada™ in the pivotal studies did not receive a third course of treatment within a year of entering the extension study.
Safety results from the first year of the extension study were reported for patients who received Lemtrada™ in the Phase III pivotal studies. No new risks were identified. The frequency and type of common and serious adverse events in the first year of the extension study were generally similar to those in the Phase III pivotal studies. The most common adverse events during this period of time were infections, including predominantly mild to moderate upper respiratory and urinary tract infections. There were two deaths. One, as previously reported, was from sepsis. The other death was presumed accidental and deemed unrelated to study treatment.
The cumulative incidence of autoimmune thyroid disease over three years was 29.9 percent, as expected based on the Phase II study experience. Additionally, over three years, approximately 1 percent of patients developed immune thrombocytopenia (ITP) and 0.3 percent developed nephropathy, all of whom responded to treatment. These cases were detected early through routine monitoring. Patient monitoring for autoimmune disorders is incorporated in all Genzyme-sponsored trials of LEMTRADA.
Genzyme’s applications to market Lemtrada™ for the treatment of MS are currently being reviewed by the European Medicines Agency and the FDA. The company expects action on both applications this year.
