Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study

Alemtuzumab; Disease-modifying therapy; Multiple sclerosisAlemtuzumab; Teràpia modificadora de la malaltia; Esclerosi múltipleAlemtuzumab; Terapia modificadora de la enfermedad; Esclerosis múltipleBackground and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants (‘alemtuzumab-only’) could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab (‘IFN-alemtuzumab’). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5–7 years (11–13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3–13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15–0.20] and IFN-alemtuzumab (0.14; 0.11–0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11–13 years, and most participants did not require more than one additional course.The TOPAZ study as well as writing and editorial support for this article were funded by Sanofi

Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial

BACKGROUND: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. METHODS: The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. RESULTS: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). CONCLUSIONS: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome

Brain health: time matters in multiple sclerosis

publisher: Elsevier articletitle: Brain health: time matters in multiple sclerosis journaltitle: Multiple Sclerosis and Related Disorders articlelink: http://dx.doi.org/10.1016/j.msard.2016.07.003 content_type: article copyright: © 2016 Oxford PharmaGenesis Ltd. Published by Elsevier B.V

Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing–remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound

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

Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings.

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

Prevalence of Grey Matter Pathology in Early Multiple Sclerosis Assessed by Magnetization Transfer Ratio Imaging

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability

2021 MAGNIMS–CMSC–NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD

OBJECTIVE: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. METHODS: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. RESULTS: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. CONCLUSION: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy

$\textbf{Objective}$: Evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting multiple sclerosis (RRMS). $\textbf{Methods}$: Alemtuzumab-treated patients in CARE-MS I (NCT00530348) received treatment courses at Months 0 and 12; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included 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). $\textbf{Results}$: Most alemtuzumab-treated patients (95.1%) who completed CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in Years 3, 4, and 5 (0.19, 0.14, 0.15). Over Years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, 62.4%) had annual NEDA in Years 3, 4, and 5. Median yearly BVL improved over Years 2–4, and remained low in Year 5 (Year 1–5: –0.59%, –0.25%, –0.19%, –0.15%, –0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at Year 3 and subsequently declined. $\textbf{Conclusions}$: Based on these data, alemtuzumab has the potential to provide durable efficacy through 5 years in the absence of continuous treatment. $\textbf{Classification of Evidence}$: This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in RRMS patients.Supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals