Glatiramer acetate 20mg powder and solvent for solution for injection vials

BackgroundRegenerative strategies in progressive multiple sclerosis (MS) pose a significant unmet need. Combining immunomodulatory treatment with remyelinating interventions to target the complex underlying pathogenesis appeals as the next frontier in MS therapeutic developments. Therefore, it is important to identify which disease-modifying treatments (DMT) with proremyelinating properties are most promising for future use in combination treatments. This systematic review provides an overview of preclinical and clinical research on remyelination, focusing on the effects of currently available FDA and EMA-approved DMT.MethodsThe search was conducted in accordance with the "Synthesis without meta-analysis" (SWiM) reporting guideline. The protocol was registered at PROSPERO prior to the search.ResultsFifty-seven articles on preclinical research, three randomized controlled trials (RCTs), 29 non-randomized clinical studies, and eight reviews were included. Preclinical research suggested neuroprotective properties of various DMT. However, convincing evidence of true remyelination, either by influencing oligodendrocyte lineage cells in cell cultures or histological analysis in vivo, could only be found in studies investigating glatiramer acetate, teriflunomide, Fingolimod, Siponimod, Ponesimod, and alemtuzumab. Clinical trials using surrogate markers of myelin repair, such as advanced imaging and electrophysiological techniques, demonstrated promising results with glatiramer acetate, Fingolimod, Siponimod, natalizumab, alemtuzumab, and ocrelizumab. However, we found insufficient proof to claim that changes in these surrogate markers can be explained by remyelination alone.ConclusionsFuture proof-of-concept clinical trials investigating remyelinating agents in MS should consider combining outcome measures into composite endpoints. Furthermore, research efforts should be dedicated to novel biomarkers to assess repair mechanisms in MS.

Abstract licence: CC BY-NC-ND

BackgroundTarget trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data.MethodsThis multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment.Results14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions.ConclusionThe combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS.

Abstract licence: CC BY-NC