Endocrine and multiple sclerosis outcomes in patients with autoimmune thyroid events in the alemtuzumab CARE-MS studies

Background Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. Objective Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. Methods Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. Results Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves’ disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves’ disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. Conclusion Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients

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

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 safety signals were observed over 9 years that were unique to the HAD populations. ClinicalTrials.gov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656

The Effect of a Polysaccharide-Based Multinutrient Dietary Supplementation Regimen on Infections and Immune Functioning in Multiple Sclerosis

Multiple sclerosis (MS) is a progressive neurodegenerative disease associated with increased infection rates, chronic inflammation, and premature death. Optimization of nutritional status via dietary supplementation may improve immune function in people suffering from MS and lead to decreased rates of infection. Fifteen individuals with a diagnosis of relapsing-remitting MS for an average of 12.4 years (SD =7.4; R = 2, 25) were enrolled in a one-year open-label clinical trial. Participants consumed a broad-spectrum dietary supplement regimen containing polysaccharides, phytochemicals, antioxidants, vitamins, and minerals three times per day. The occurrence of infections and a panel of cytokines, growth factors, and T- and B-cell subsets were assessed at baseline and 12 months. Seven female and 8 male participants with an average age of 51.3 years (SD =7.2; R = 38, 65) completed the study. At the end of the intervention, participants had fewer total infections (M = 7.9, SD =8.1 at baseline and M = 2.5, SD =4.3 at 12-month follow-up). At 12 months, IL-2, TNF-α, EGF, and CD95 + CD34+ significantly increased, while IL-1β significantly decreased. No major adverse effects were reported; only mild gastrointestinal intolerance was reported in four cases. A decreased occurrence of infection was observed in MS patients treated with 12 months of a polysaccharide-based multinutrient dietary supplement. Significant changes were also noted in several key biomarkers that would be physiologically favorable to the MS population. Thus, the results of this study suggest an immunomodulatory effect of the dietary supplement regimen studied

sj-docx-1-mso-10.1177_20552173221142741 - Supplemental material for Endocrine and multiple sclerosis outcomes in patients with autoimmune thyroid events in the alemtuzumab CARE-MS studies

Supplemental material, sj-docx-1-mso-10.1177_20552173221142741 for Endocrine and multiple sclerosis outcomes in patients with autoimmune thyroid events in the alemtuzumab CARE-MS studies by Colin M. Dayan, Beatriz Lecumberri, Ilaria Muller, Sashiananthan Ganesananthan, Samuel F. Hunter, Krzysztof W. Selmaj, Hans-Peter Hartung, Eva K. Havrdova, Christopher C. LaGanke, Tjalf Ziemssen, Bart Van Wijmeersch, Sven G. Meuth, David H. Margolin, Elizabeth M. Poole, Darren P. Baker and Peter A. Senior in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p

Ofatumumab versus Teriflunomide in Multiple Sclerosis

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.)