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Background: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide., Objective: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension., Methods: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension., Results: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p  = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p  = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p  = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group., Conclusion: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Kumaran Deiva: consulting fees and travel grants from Biogen, Merck, Novartis Pharmaceuticals, Roche, and Sanofi. Tanuja Chitnis: consulting fees from Biogen, Novartis Pharmaceuticals, Roche Genentech, and Sanofi; research support from National Institutes of Health, National MS Society, U.S. Department of Defense, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Novartis Pharmaceuticals, Octave Bioscience, Genentech, and Tiziana Life Sciences. Brenda Banwell: consulting fees from Novartis Pharmaceuticals, Roche, Sanofi, and UCB; non-remunerated advisory input for Biogen, EMD Serono, Novartis Pharmaceuticals, and Teva. Ludwig Kappos: Dr Kappos’ institution (University Hospital Basel) has received in the past 3 years and used exclusively research support, steering committees, advisory boards, and consultancy fees from AbbVie, Actelion, AurigaVision AG, Biogen, Celgene, Desitin, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Japan Tobacco, Merck, Minoryx, Novartis, Roche, Sanofi, Santhera, Senda, Shionogi, Teva, and Wellmera; speaker fees from Celgene, Janssen, Merck, Novartis, and Roche; support for educational activities from Biogen, Desitin, Novartis, Sanofi, and Teva; license fees for Neurostatus products and grants from European Union, Innosuisse, Novartis, Roche Research Foundation, Swiss MS Society, and Swiss National Research Foundation. Douglas L Arnold: consulting fees from Alexion, Biogen, Celgene, Eli Lilly and Company, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi, and Shionogi; equity interest in NeuroRx. Kivilcim Gücüyener: no competing interests. Stephane Saubadu: employee of Sanofi, with ownership interest. Wenruo Hu: employee of Sanofi, with ownership interest. Myriam Benamor: employee of Sanofi, with ownership interest. Annaig Le-Halpere: employee of Sanofi, with ownership interest. Philippe Truffinet: employee of Sanofi, with ownership interest. Marc Tardieu: research support from Novartis Pharmaceuticals and Sanofi.

Background: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis., Methods: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab., Results: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches., Conclusions: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The phase 3 TERIKIDS study demonstrated efficacy and manageable safety for teriflunomide versus placebo in children with relapsing multiple sclerosis (RMS)., Objective: Evaluate plasma neurofilament light chain (pNfL) concentrations in TERIKIDS., Methods: Patients received placebo or teriflunomide (14 mg adult equivalent) for up to 96 weeks in the double-blind (DB) period. In the open-label extension (OLE), all patients received teriflunomide until up to 192 weeks after randomization. pNfL was measured using single-molecule array assay (Simoa ® NF-light ™ )., Results: Baseline mean age was 14.5 years; 69.4% were female. Baseline geometric least square mean pNfL levels were similar for teriflunomide ( n  = 78) and placebo ( n  = 33) patients (19.83 vs 18.30 pg/mL). Over the combined DB and OLE periods, pNfL values were lower for teriflunomide versus placebo (analysis of variance p  < 0.01; Week 192: 10.61 vs 17.32 pg/mL). Observed between-group pNfL differences were attenuated upon adjustment for gadolinium (Gd)-enhancing or new/enlarged T2 lesion counts at DB Week 24. Higher baseline pNfL levels were associated with shorter time since first MS symptom onset, higher baseline Gd-enhancing lesion counts and T2 lesion volume, and increased hazard of high magnetic resonance imaging activity or clinical relapse during the DB period., Conclusion: Teriflunomide treatment was associated with significantly reduced pNfL levels in children with RMS., Clinicaltrials.gov Identifier: NCT02201108.

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor., Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD)., Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics., Results: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants., Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Background: Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis., Methods: The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10-17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing., Findings: Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39-1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29-0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13-0·51; p<0·0001). Adverse events occurred in 96 (88%) patients in the teriflunomide group and 47 (82%) patients in the placebo group; serious adverse events occurred in 12 (11%) patients in the teriflunomide group and 6 (11%) patients in the placebo group. Nasopharyngitis, upper-respiratory-tract infection, alopecia, paraesthesia, abdominal pain, and increased blood creatine phosphokinase were more frequent with teriflunomide than with placebo. During the double-blind phase, four patients in the teriflunomide group had pancreatic adverse events (two with acute pancreatitis and two with pancreatic enzyme elevation), of which three events led to treatment discontinuation., Interpretation: No significant difference in time to first confirmed clinical relapse was found, possibly because more patients than expected switched from the double-blind to the open-label treatment period because of high MRI activity. Key secondary imaging analyses and a prespecified sensitivity analysis of probability of relapse or high MRI activity suggest that teriflunomide might have beneficial effects in children with relapsing multiple sclerosis by reducing the risk of focal inflammatory activity., Funding: Sanofi., Competing Interests: Declaration of interests TC reports consulting fees (Bayer and Novartis), advisory boards (Biogen, Novartis, Roche-Genentech, and Sanofi), research support (Mallinckrodt, Novartis, Serono, and Verily), and speaker fees (Medscape). BB reports consulting fees (Novartis and UCB), non-remunerated advisory input (Biogen Idec, EMD Serono, Novartis, Sanofi, and Teva Neuroscience), and speaker fees (Medscape). LK's institution (University Hospital Basel) has received in the past 3 years and has used exclusively for research support steering committees, advisory boards, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and XenoPort), speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, and Teva), support of educational activities (Bayer HealthCare, Biogen Idec, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva), licence fees (Neurostatus products), and grants (Biogen, Merck, Novartis, Roche, the Swiss Multiple Sclerosis Society, Innoswiss, the Swiss National Research Foundation, the European Union, and Roche Research Foundations). DLA reports consultant fees (Acorda Therapeutics, Biogen, Celgene, Genentech, GeNeuro, F Hoffmann-La Roche, Merck, Novartis, Roche, Sanofi, Teva, and Wave Life Sciences), financial support for research activities (Biogen Idec Canada, Immunotec, Novartis Canada, and Novartis Global Medical Affairs), and personal compensation (NeuroRx Research). KD reports consulting fees and travel grants (Merck, Novartis, and Sanofi). SS, WH, MB, AL-H, and PT are employees of Sanofi, with ownership interest. MT reports research support (Novartis and Sanofi Genzyme). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)