Search

Background:Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. Objective: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). Methods:Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif (R) Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension. Results:Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%). Conclusion: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit. ClinicalTrials.gov registration numbers:CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The CARE-MS I, CARE-MS II, and CAMMS03409 studies were funded by Sanofi and Bayer HealthCare Pharmaceuticals. Only Sanofi contributed to the conduct of the studies; collection, management, analysis, and interpretation of the data; review of the manuscript. Apart from the Sanofi employees listed as authors, the funders had no role in preparation, approval, and decision to submit the manuscript for publication. Van Wijmeersch, B (reprint author), Hasselt Univ, Fac Med & Life Sci, Campus Hasselt,Martelarenlaan 42, B-3500 Hasselt, Belgium. bart.vanwijmeersch@uhasselt.be

Background: In CARE-MS II (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved health-related quality of life (HRQL) outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients over 2 years. Patients completing CARE-MS II could enter a 4-year extension study (NCT00930553). Objective: The aim of this study is to assess 6-year HRQL outcomes in alemtuzumab-treated CARE-MS II patients, including those with highly active disease (HAD). Methods: During extension, patients could receive additional alemtuzumab for clinical/magnetic resonance imaging (MRI) activity or other disease-modifying therapies per investigator’s discretion. Assessments include Functional Assessment of Multiple Sclerosis (FAMS), 36-Item Short-Form Health Survey (SF-36), and EQ-5D visual analog scale (EQ-VAS). Results: Alemtuzumab-treated patients improved or stabilized all HRQL measures over 6 years with significant improvements from baseline at all time points on EQ-VAS and for up to 5 years on FAMS, SF-36 MCS, and SF-36 PCS. Alemtuzumab-treated patients with HAD showed significant improvements versus baseline at Year 2 on all HRQL measures, and significant improvements versus SC IFNB-1a on SF-36 PCS and EQ-VAS; however, the improvements did not reach the threshold for clinical relevance. Conclusion: Alemtuzumab-treated CARE-MS II patients improved or stabilized HRQL versus baseline over 6 years. This is the first study to show long-term HRQL benefits in patients with HAD.

Background: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. Objective: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. Methods: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. Results: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. Conclusion: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

Funder: Bayer HealthCare Pharmaceuticals, Funder: Sanofi; FundRef: https://doi.org/10.13039/100004339, Background:: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing–remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. Methods:: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN–alemtuzumab), followed by additional, as-needed, alemtuzumab. Results:: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN–alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN–alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. Conclusion:: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. ClinicalTrials.gov identifiers:: NCT00530348; NCT00548405; NCT00930553

Background Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods Patients ( N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. Conclusions The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression. ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

Background: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. Objective: To evaluate infections over 6 years in alemtuzumab-treated patients. Methods: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 μg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. Results: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%–1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. Conclusion: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

Background: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. Objective: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. Methods: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. Results: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. Conclusion: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

Background Individual functional system scores (FSS) of the Expanded Disability Status Scale (EDSS) play a central role in determining the overall EDSS score in patients with early-stage multiple sclerosis (MS). Alemtuzumab treatment improves preexisting disability for many patients; however, it is unknown whether improvement is specific to certain functional systems. Objective We assessed the effect of alemtuzumab on individual FSS of the EDSS. Methods CAMMS223 was a 36-month, rater-blinded, phase 2 trial; treatment-naive patients with active relapsing-remitting MS, EDSS ≤3, and symptom onset within 3 years were randomized to annual courses of alemtuzumab or subcutaneous interferon beta-1a (SC IFNB-1a) 44 μg three times weekly. Results Alemtuzumab-treated patients had improved outcomes versus SC IFNB-1a patients on most FSS at Month 36; the greatest effect occurred for sensory, pyramidal, and cerebellar FSS. Among patients who experienced 6-month sustained accumulation of disability, clinical worsening occurred most frequently in the brainstem and sensory systems. For patients with 6-month sustained reduction in preexisting disability, pyramidal and sensory systems contributed most frequently to clinical improvement. Conclusions Alemtuzumab demonstrated a broad treatment effect in improving preexisting disability. These findings may influence treatment decisions in patients with early, active relapsing-remitting MS displaying neurological deficits. ClinicalTrials.gov Identifier NCT00050778.

Objective: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS). Methods: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II). Results: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a. Conclusions: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS. ClinicalTrials.gov identifier: NCT00530348 and NCT00548405. Classification of evidence: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.

Background: Alemtuzumab is a humanized monoclonal antibody approved in several countries for treatment of relapsing-remitting multiple sclerosis (RRMS). This report summarizes the experience with infusion-associated reactions (IARs) in two phase 3 trials of alemtuzumab in RRMS and examines skilled nursing interventions in IAR prevention and management. Methods: In the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies, patients with RRMS (treatment naive [CARE-MS I] or with inadequate response [defined as at least one relapse] to previous therapy [CARE-MS II]) received intravenous infusions of alemtuzumab 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Patients were monitored for IARs during and after each infusion. An IAR was defined as any adverse event occurring during any infusion or within 24 hours after infusion. Results: The IARs affected 90.1% of patients receiving alemtuzumab. The most common IARs were headache, rash, pyrexia, nausea, and flushing; most were mild to moderate in severity. Management of IARs consisted of infusion interruption or rate reduction, pharmacologic therapies, and continual patient education and support. Medication administration before and during alemtuzumab infusion reduced IAR severity. Forty-five of 972 alemtuzumab-treated patients (4.6%) required interruption of the first treatment course (ie, infusions did not occur on consecutive days); of these, 24 (53.3%) were still able to complete the first and second full treatment courses. Conclusions: Nurses played an invaluable role in the detection and management of IARs in the CARE-MS studies. Best practices for management of IARs associated with alemtuzumab include patient and caregiver education, medication to lessen IAR severity, infusion monitoring, and discharge planning.

Background: Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis. Objective: To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials. Methods: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36). Results: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS. Conclusion: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

Objective:To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.Methods:In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed.Results:Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3–5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1–5: −0.48%, −0.22%, −0.10%, −0.19%, −0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.Conclusions:Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment.Classification of evidence:This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years.

Alemtuzumab, a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes, may be an effective treatment for early multiple sclerosis.In this phase 2, randomized, blinded trial involving previously untreated, early, relapsing-remitting multiple sclerosis, we assigned 334 patients with scores of 3.0 or less on the Expanded Disability Status Scale and a disease duration of 3 years or less to receive either subcutaneous interferon beta-1a (at a dose of 44 microg) three times per week or annual intravenous cycles of alemtuzumab (at a dose of either 12 mg or 24 mg per day) for 36 months. In September 2005, alemtuzumab therapy was suspended after immune thrombocytopenic purpura developed in three patients, one of whom died. Treatment with interferon beta-1a continued throughout the study.Alemtuzumab significantly reduced the rate of sustained accumulation of disability, as compared with interferon beta-1a (9.0% vs. 26.2%; hazard ratio, 0.29; 95% confidence interval [CI], 0.16 to 0.54; P0.001) and the annualized rate of relapse (0.10 vs. 0.36; hazard ratio, 0.26; 95% CI, 0.16 to 0.41; P0.001). The mean disability score on a 10-point scale improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the interferon beta-1a group (P0.001). In the alemtuzumab group, the lesion burden (as seen on T(2)-weighted magnetic resonance imaging) was reduced, as compared with that in the interferon beta-1a group (P=0.005). From month 12 to month 36, brain volume (as seen on T(1)-weighted magnetic resonance imaging) increased in the alemtuzumab group but decreased in the interferon beta-1a group (P=0.02). Adverse events in the alemtuzumab group, as compared with the interferon beta-1a group, included autoimmunity (thyroid disorders [23% vs. 3%] and immune thrombocytopenic purpura [3% vs. 1%]) and infections (66% vs. 47%). There were no significant differences in outcomes between the 12-mg dose and the 24-mg dose of alemtuzumab.In patients with early, relapsing-remitting multiple sclerosis, alemtuzumab was more effective than interferon beta-1a but was associated with autoimmunity, most seriously manifesting as immune thrombocytopenic purpura. The study was not powered to identify uncommon adverse events. (ClinicalTrials.gov number, NCT00050778.)

Pregnancy outcomes in patients in the alemtuzumab MS clinical development program (CAMMS223 and NCT00050778; CARE-MS I and NCT00530348; CARE-MS II and NCT00548405; CAMMS03409 and NCT00930553) were evaluated. Patients received 2 alemtuzumab courses in core studies (baseline, 5 days; 12 months later, 3 days), and optional, as-needed retreatment during extension per investigator discretion. Pregnant/lactating patients were treatment-ineligible but remained on study for safety follow-up. By December 31, 2015, 200 pregnancies occurred in 137/972 alemtuzumab-treated women, including 182 completed with known outcomes, 11 ongoing, and 7 unknown outcomes. Of completed pregnancies, 123 (68%) were live births without congenital abnormalities or birth defects; 39 (21%) spontaneous abortions, 19 (10%) elective abortions, and 1 (0.5%) stillbirth (previously reported). There was no evidence of teratogenicity, and the spontaneous abortion rate was comparable with other MS and general populations. Women are recommended to use effective contraception during alemtuzumab infusion and for 4 months after. Real-world data are currently collected by the International Lemtrada Pregnancy Exposure Registry, a prospective, noninterventional, observational safety study enrolling patients pregnant during or within 4 months of alemtuzumab exposure in ≥19 countries. It will evaluate pregnancy outcomes, including monitoring infants for adverse events for 1 year. UK pregnancy cases can be reported to: Neuroresearch.nurse@srft.nhs.uk; phone 0161-206-0534. Study Support Sanofi and Bayer HealthCare Pharmaceuticals.

Background: Alemtuzumab is a monoclonal antibody directed against CD52 that depletes T and B lymphocytes. Objective: To evaluate the treatment effect of alemtuzumab on low-contrast vision in relapsing–remitting multiple sclerosis (RRMS) patients. Methods: This was a pre-defined exploratory analysis within a randomized, rater-blinded trial (CAMMS223) that was run at 49 academic medical centers in the US and in Europe. Patients with untreated, early, RRMS (McDonald, n = 334) were randomized 1:1:1 to subcutaneous interferon beta-1a (IFNB-1a), or alemtuzumab 12 mg or 24 mg. Visual contrast sensitivity was measured for each eye at baseline and quarterly, with Pelli-Robson charts. Results: The eyes of patients in the pooled alemtuzumab group (versus IFNB-1a) had a greater than 2-fold higher rate of both 3-month and 6-month sustained visual improvement, of at least 0.3 log units (2 triplets, 6 letters) (At 3 months the hazard ratio (HR) = 2.26; CI = 1.19 to 4.31; P = 0.013; and at 6 months the HR = 2.44; CI =1.16 to 5.15; P = 0.019), and they had a lower risk of 3- and 6-month sustained worsening of at least 0.15 log units (1 triplet, 3 letters) (At 3 months the HR = 0.58; CI = 0.38 to 0.89; P = 0.012; and at 6 months HR = 0.55; CI=0.35 to 0.87; P = 0.010). Over the 36-month study period, the eyes of patients in the pooled alemtuzumab group improved in mean contrast sensitivity to a greater extent than those in the IFNB-1a group (0.080 log units versus 0.038 log units; P = 0.0102). Conclusions: Alemtuzumab was associated with a greater chance of improved contrast sensitivity in patients with RRMS and may delay the worsening of visual function. Contrast sensitivity testing was sensitive to treatment effects, even within an active comparator study design. These results support the validity of low-contrast vision testing as a clinical outcome in MS trials.

Here we provide updated pregnancy outcomes in alemtuzumab-treated female patients in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies. Patients received annual treatment courses of alemtuzumab and could enter an extension study (NCT00930553), with as-needed alemtuzumab retreatment (≥1 year apart). Pregnant/lactating patients were treatment-ineligible but remained on study for safety follow-up. As of July 1, 2015, 193 pregnancies occurred in 136 of 972 alemtuzumab-treated female patients; 167 were completed, 16 were ongoing, and 10 had unknown outcomes. Of completed pregnancies, 110 (66%) were live births with no congenital abnormalities or birth defects among 94 patients (at conception: mean age, 31.5 years; mean EDSS, 1.7; mean time since initial MS relapse, 6.6 years; mean time since last MS relapse, 3.5 years; mean time from previous alemtuzumab infusion, 27.9 months). There were 37 (22%) spontaneous abortions, 19 (11%) elective abortions, and 1 (0.6%) previously reported stillbirth. In alemtuzumab MS clinical studies, the most common pregnancy outcome was full-term live birth, with no evidence of teratogenicity to date. The rate of spontaneous abortion with alemtuzumab was comparable with rates observed in other MS patients and general populations. Ongoing surveillance is needed. Study supported by Sanofi Genzyme and Bayer Healthcare Pharmaceuticals.

In patients with relapsing-remitting MS (RRMS) and an inadequate response (≥1 relapse) to prior therapy, alemtuzumab improved Expanded Disability Status Scale (EDSS) functional systems scores (FSS) over 2 years versus subcutaneous interferon beta-1a (CARE-MS II; NCT00548405). Here we assess alemtuzumab9s effect on FSS over 5 years. Patients received alemtuzumab at baseline and Month 12 in the core study. Patients entering an extension (NCT00930553) could receive as-needed alemtuzumab retreatment, or another disease-modifying therapy (DMT), for disease activity. EDSS was evaluated quarterly by blinded raters. 6-month confirmed FSS disability progression was defined as ≥1.0-point increase in an FSS. 393 (93%) alemtuzumab patients entered the extension; 357 (91%) remained on study through 5 years, 60% received no alemtuzumab after Month 12, and 92% received no other DMT. Over 5 years, mean cerebellar, pyramidal, sensory, and cerebral FSS did not exceed baseline; for each FSS, 71%–80% of patients were free from disability progression. Patients who received only 2 courses of alemtuzumab and no other DMT for 5 years generally had lower FSS than other patients. RRMS patients with inadequate response to prior therapy had persistent improvement/stability across multiple FSS over 5 years with alemtuzumab; most patients received no additional treatment since Month 12. Study supported by Sanofi Genzyme and Bayer Healthcare Pharmaceuticals.

Objective To report a case of anti-glomerular basement membrane disease (anti-GBM disease) during alemtuzumab treatment of a relapsing–remitting multiple sclerosis (RRMS) patient. Design Case report. Setting Outpatient neurology research protocol. Patient A 35-year-old white female receiving alemtuzumab for RRMS in a clinical research protocol developed symptoms leading to diagnosis of anti-GBM disease. Main outcome measure Patient response to the treatment of anti-GBM disease and RRMS. Results Early identification and treatment of anti-GBM disease resolved clinical symptoms and preserved renal function. Alemtuzumab treatment of RRMS resolved initial MS symptoms and appears to have controlled active disease to date. Conclusion Close monitoring for potential side effects of alemtuzumab treatment in RRMS resulted in a positive outcome when anti-GBM disease was recognized and treated early.

To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline).Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months.Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab.Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports.This study provides Class III evidence that alemtuzumab is more effective than interferon β-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

In a phase 2 clinical trial of annual alemtuzumab for treatment of relapsing-remitting multiple sclerosis, 6 of 216 patients (2.8%) developed immune thrombocytopenia (ITP). Over mean follow-up of 4.5 years, the incidence rate of ITP was 6.2 (95% confidence interval, 2.3-13.3) per 1000 person-years. Median times from initial and last alemtuzumab exposure to ITP diagnosis were 24.5 and 10.5 months, respectively. Five patients developed severe thrombocytopenia. Four were symptomatic, including fatal intracranial hemorrhage in the index case. Four patients received standard first-line ITP therapy, all of whom responded to treatment within 1 week. All 5 surviving patients achieved complete remission and remained in complete remission without need for ongoing ITP therapy for a median duration of 34 months at last follow-up. A monitoring plan for the early detection of ITP, implemented after presentation of the index case, identified all 5 subsequent cases before serious hemorrhagic morbidity or mortality occurred. In conclusion, we describe a distinctive form of ITP associated with alemtuzumab treatment characterized by delayed presentation after drug exposure, responsiveness to conventional ITP therapies, and prolonged remission. Clinicians should maintain a high level of vigilance and consider routine monitoring for ITP in patients treated with this agent. This trial was registered at www.clinicaltrials.gov as #NCT00050778.

Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability.334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS.322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab.Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis.Genzyme and Bayer Schering Pharma.

Background/objectives Alumtzumab is approved in over 30 countries for relapsing-remitting multiple sclerosis. In the 2-year, phase 3 CARE-MS I study (NCT00530348), Alemtuzumab significantly reduced relapses compared with subcutaneous interferon beta-1a, with manageable safety in treatment-naive patients with active relapsing-remitting multiple sclerosis. Durable efficacy of Alemtuzumab was demonstrated at 3-year follow-up. Here we report results for years 3 and 4 after Alemtuzumab initiation, and for years 1 and 2 after Alemtuzumab initiation in patients initially treated with subcutaneous interferon beta-1a (crossover cohort). Design and methods In CARE-MS I, patients received Alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or subcutaneous interferon beta-1a (44 μg 3 times/week). In the extension study (NCT00930553), patients could receive as-needed Alemtuzumab re-treatment (12 mg/day on 3 consecutive days) ≥1 year apart or other disease-modifying therapy. Crossover patients received 2 Alemtuzumab courses (5 days then 3 days) 12 months apart. Results The extension enrolled 349 (95%) eligible patients from the core study Alemtuzumab arm. Through 4 years, 73% of these patients received only 2 annual courses, while 21% and 5% received 1 or 2 additional courses, respectively; Conclusions Most patients receiving Alemtuzumab during the core study required no re-treatment during the 2-year extension period; few sought alternative therapies or withdrew from the study. Among crossover patients, most received both treatment courses and remained in the study.

Treatment of early relapsing-remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath [registered trade mark]) significantly reduced the risk of relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-801)]. Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years. In contrast, those treated with interferon β-1a steadily accumulated disability. Here, by post hoc subgroup analyses of the CAMMS223 trial, we show that among participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. This suggests that disability improvement after alemtuzumab is not solely attributable to its anti-inflammatory effect. So we hypothesized that lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair. Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor. Analysis by reverse transcriptase polymerase chain reaction of cell separations showed that the increased production of ciliary neurotrophic factor and brain-derived neurotrophic factor after alemtuzumab is attributable to increased production by T cells. Media from these post-alemtuzumab peripheral blood mononuclear cell cultures promoted survival of rat neurones and increased axonal length in vitro, effects that were partially reversed by neutralizing antibodies against brain-derived nerve growth factor and ciliary neurotrophic factor. This conditioned media also enhanced oligodendrocyte precursor cell survival, maturation and myelination. Taken together, the clinical analyses and laboratory findings support the interpretation that improvement in disability after alemtuzumab may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the central nervous system.

In the 2-year, phase 3 CARE–MS II study (NCT00548405) of relapsing-remitting multiple sclerosis (RRMS) patients with inadequate efficacy response to prior therapy, alemtuzumab demonstrated superior efficacy and quality-of-life (QoL) improvements versus subcutaneous interferon beta-1a, with manageable safety. Here, QoL outcomes are examined in alemtuzumab-treated patients at Year 3 in an ongoing extension study (NCT00930553). 393 of 435 alemtuzumab 12 mg-treated patients entered the extension study; 80 received as-needed alemtuzumab retreatment during Year 3. Mean Functional Assessment of multiple sclerosis total score (scale 0–176) improved from baseline to year 3 (119.1 vs 124.8; P

In the 2-year, phase 3 CARE-MS studies of alemtuzumab in patients with relapsing-remitting multiple sclerosis, infusion-associated reactions (IARs) were the most common adverse events. Here we report on IARs during 4-year follow-up. Patients who were treatment-naive (CARE-MS I; NCT00530348) or with inadequate efficacy response to prior therapy (CARE-MS II; NCT00548405) received 2 annual courses of alemtuzumab 12 mg, and as-needed retreatment in an extension study (NCT00930553). Patients received methylprednisolone on the first 3 days of each course. IARs were any adverse event occurring between start of infusion and within 24 hours after end of infusion. 742/811 alemtuzumab-treated patients entered extension. Over 4 years, 70.4% received only 2 initial treatment courses; 22.6% and 6.1% received 3 and 4 courses, respectively. IARs were most frequent in Course 1 (84.7%) versus Courses 2 (68.5%), 3 (65.7%), and 4 (71.1%); frequency decreased on infusion Days 2 and 3 versus Day 1. IARs were predominantly mild to moderate; none led to study withdrawal or death. Serious IAR incidence was 3.1%. Most common IARs were skin disorders (predominantly rash), headache, pyrexia, and nausea. One confirmed anaphylaxis and one non-anaphylactoid hypotension event resolved with treatment. Effective IAR management included premedication, infusion monitoring, symptomatic treatment, and infusion interruption/adjustment.

Background/objectives Alemtuzumab is approved in over 30 countries for relapsing-remitting multiple sclerosis. In the 2-year, phase 3 CARE-MS II study (NCT00548405), alemtuzumab had superior efficacy over subcutaneous interferon beta-1a and manageable safety over 2 years; follow-up at Year 3 showed durable efficacy of alemtuzumab. Here we report results for years 3 and 4 after alemtuzumab initiation, and for years 1 and 2 after alemtuzumab initiation in patients initially treated with subcutaneous interferon beta-1a (crossover cohort). Design and methods In CARE-MS II, patients with active relapsing-remitting multiple sclerosis who relapsed on prior therapy received 2 courses of alemtuzumab (12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later) or subcutaneous interferon beta-1a (44 ?g 3 times/week). In the extension study (NCT00930553), alemtuzumab-treated patients could receive as-needed re-treatment (12 mg/day intravenously on 3 consecutive days) ?1 year apart or other disease-modifying therapy. Crossover patients received 2 alemtuzumab courses (5 days then 3 days) 12 months apart. Results The extension enrolled 393 (93%) eligible patients from the core study alemtuzumab arm. Through 4 years, 68% received the first 2, but no additional courses; 24% and 7% received 1 or 2 additional courses, respectively; 5% received another disease-modifying therapy during the extension. Twenty-five patients (6%) discontinued study, none from adverse events. Among former interferon beta-1a patients, 146 (83%) entered the extension; 131 (90%) received 2 alemtuzumab courses. Seven extension withdrawals (5%) occurred in crossover patients, 1 from an adverse event. Efficacy and safety data will be reported. Conclusions Most patients receiving alemtuzumab in the core study required no re-treatment during the first 2 extension years; few received alternative therapies or withdrew from study. Among crossover patients, most received both treatment courses and remained in the study.

Objective: Evaluate the effect of alemtuzumab on relapse and disability versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients who have relapsed on prior therapy. Background Alemtuzumab was significantly more effective than SC IFNB-1a in two clinical trials with treatment-naive RRMS patients. Treatment options are limited for RRMS patients experiencing disease activity during therapy, and few controlled studies have been conducted to determine their appropriate management. Design/Methods: CARE-MS II is a 2-year rater-blinded trial with RRMS patients who have relapsed during prior therapy. Alemtuzumab treatment was 12 mg/day (or 24 mg/day in an exploratory cohort) by intravenous administration for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly throughout the study. Entry criteria included 18-55 years of age, MS symptom onset within 10 years, and Expanded Disability Status Scale (EDSS) score ≤5. Primary endpoints include relapses adjudicated by an independent panel and time to sustained accumulation of disability assessed by blinded evaluators. Results: 840 patients from 180 centers in 23 countries were randomized. Baseline characteristics (mean) were: age 35 years; disease duration 3.9 years; EDSS 2.7; with 1.6 and 2.7 relapses in 1 and 2 years prior to study entry, respectively. The most common prior MS therapies were interferon-beta (78.6%) or glatiramer acetate (32.5%); less than 5% of patients had received other prior MS therapy (some patients received more than one therapy). Conclusions: Database lock and study analysis will occur in late 2011. The principal efficacy and safety results will be presented. ®Rebif is a registered trademark of EMD Serono, Inc. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Twyman has received personal compensation for activities with Genzyme Corporation as a consultant, speaker and participant on advisory boards. Dr. Twyman has received research support from Genzyme Corporation. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Miller has received personal compensation for activities with Allergan, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Forest, Novartis, Sanofi Aventis, and Teva as a speaker. Dr. Miller has received research support from Allergan, Biogen Idec, Genzyme, Elan, Teva, Novartis, Ono, Sanofi Aventis, EMD Serono, and Roche-Genetech. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

Objective: Compare alemtuzumab and interferon beta-1a (IFNB-1a) on top-line clinical efficacy and safety outcomes in the phase 3 pivotal study: CARE-MS I. Background Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool. Design/Methods: CARE-MS I was a 2-year, randomized, rater-blinded, active-comparator, trial comparing alemtuzumab to IFNB-1a in active, treatment-naive relapsing-remitting MS (RRMS) patients. Alemtuzumab treatment was 12mg/day iv for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44 mcg SC 3-times weekly for 24 months. Primary efficacy endpoints were relapse rate and time to 6-month sustained accumulation of disability (SAD). Results: 581 patients from 98 centers in 16 countries were randomized 2:1 to alemtuzumab or IFNB-1a. Mean age was 33; mean EDSS was 2; mean time since first episode was 2 years. Alemtuzumab reduced relapse rate by 55% compared to IFNB-1a (p Conclusions: Alemtuzumab significantly reduces the relapse rate in RRMS patients compared to an active comparator. Effect on disability accumulation was not significantly different, possibly due to the very low incidence of disability accumulation in the sample overall. The safety profile for alemtuzumab was consistent with previous studies. These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Brinar has nothing to disclose. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Stojanovic has nothing to disclose. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.

Objective: Compare alemtuzumab and subcutaneous interferon beta-1a (IFNB-1a) on relapse outcomes from a phase 3 trial in patients with relapsing-remitting multiple sclerosis (RRMS). Background Over 2 years, alemtuzumab reduced the rate of relapse by 55% compared with IFNB-1a (p Design/Methods: CARE-MS I was a 2-year, randomized, rater-blinded, global trial comparing the efficacy and safety of alemtuzumab to subcutaneous IFNB-1a in active, treatment-naive RRMS patients. Alemtuzumab treatment was 12mg/day intravenously for 5 days at study start and 3 days one year later. IFNB-1a treatment was 44mcg SC 3-times weekly for 24 months. Relapse rate was a co-primary endpoint. Relapse events were required to last at least 48 hours, required objective signs on exam as assessed by blinded raters, and were adjudicated by an independent relapse adjudication committee. Results: Annualized relapse rate was 0.18 (95% CI: 0.13, 0.23) for alemtuzumab-treated patients compared with 0.39 (95% CI: 0.29, 0.53) for IFNB-1a-treated patients (55% reduction, p Conclusions: Alemtuzumab significantly reduces relapses in RRMS patients compared with high-dose, high-frequency IFNB-1a. These results suggest the potential for alemtuzumab to be a meaningful addition to treatment options for RRMS, if approved. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Fox has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, Pfizer Inc, and Teva Neuroscience. Dr. Fox has received personal compensation in an editorial capacity for Neura. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Brinar has nothing to disclose. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavruex has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavruex has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Stojanovic has nothing to disclose. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neurosciences, GlaxoSmithKline, Nasvax, Xenoport and Genzyme Corporation as consulting and/or speaking activities. Dr. Weiner has received research support from Merck Serono. Dr. Lake has received personal compensation for activities with Genzyme as an employee. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Biogen Idec as an employee.Dr. Panzara holds stock and/or stock options in Biogen Idec. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.