Efficacy and Safety of Alemtuzumab Through 9 Years of Follow-up in Patients with Highly Active Disease: Post Hoc Analysis of CARE-MS I and II Patients in the TOPAZ Extension Study

Abstract

Background Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously. Objectives In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm. Methods Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition. Results In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was − 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9. Conclusions Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No sa...

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial

“…Long-term safety and efficacy follow-up continue in the subsequent 5-year long-Term follow-up study for multiple sclerOsis Patients who have completed the AlemtuZumab extension study (TOPAZ; NCT02255656). 43 …”

Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies

“…Details on the rater-blinded, active-controlled CARE-MS trials and subsequent extension studies have been published previously [6,7,[9][10][11][12][13]. After C 30 days of clinical stability, patients were randomized to receive either two courses of alemtuzumab 12 mg/day (given as intravenous [IV] infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later) or SC IFNB-1a 44 lg three times per week after dose titration.…”

Oral pulsed therapy of relapsing multiple sclerosis with cladribine tablets – expert opinion on issues in clinical practice

“…Lorscheider et al 20 proposed a diagnostic definition of SPMS based on the EDSS value and preceding relapses: SPMS is present if a patient has at least a 1-point worsening from a previous EDSS ≤5. 5 (or a 0.5-point EDSS worsening from a previous EDSS ≥6.0) confirmed over ≥3 months in the absence of relapses, with a minimum EDSS score of ≥4 and a pyramidal FS score of ≥2. Transitional MS according to Kleiter et al 21 implies: MS disease duration ≥ 4 years; EDSS 3.0 to 5.0; relapse-independent increase of disability by ≥0.5 points over the previous year or ≥1 point over the previous 2 years; MRI with ≥1 cortical lesion(s) OR evidence of cortical atrophy and/or smoldering lesions; disease activity during previous 2 years with ≥1 clinical relapse or ≥1 new or enlarging T2 lesion on MRI.…”

“…While mouse experiments reveal teratogenicity of cladribine upon intraperitoneal administration of dosages ≥5 mg/kg, 4 no signal of teratogenicity emerged from the limited pregnancy data in the oral cladribine clinical trial program with the approved dose. 5 According to the current summary of product characteristics of cladribine tablets, 11 pregnancy must be ruled out in females of childbearing age prior to the initiation of treatment with oral cladribine in years 1 and 2. Dual-method contraception (i.e.…”

“…However, broad adoption of alemtuzumab has been limited by its considerable risks including the development of severe secondary autoimmune diseases. 5 In 2017, oral cladribine was licensed in the European Union as the first oral pulsed therapy.…”