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Purpose of Review: Current high-efficacy disease-modifying therapies for multiple sclerosis (MS) primarily target adaptive immune cells in peripheral tissues, controlling focal inflammation (acute relapses and magnetic resonance imaging [MRI] activity). However, there is a need for new, safe therapies that address disease progression and disability accumulation in relapsing and progressive MS. The CD40/CD40L pathway, which regulates adaptive and innate immunity, is implicated in MS pathogenesis, making it a potential therapeutic target. Early clinical trials of anti-CD40L antibodies showed encouraging efficacy in autoimmune indications but were discontinued due to thromboembolic risk. Recent therapeutic advancements now allow researchers to leverage this pathway while reducing safety risks. Recent Findings: Frexalimab is a humanized anti-CD40L immunoglobulin-G1 monoclonal antibody, Fc-engineered to overcome thromboembolic risk. It is the first second-generation anti-CD40L antibody being investigated in MS. In a randomized-controlled phase 2 trial, frexalimab was well-tolerated, showing rapid and sustained reduction in disease activity (assessed by MRI) while preserving lymphocyte levels. Summary: Recent clinical findings strengthen the rationale for targeting CD40L in MS, supporting further development of anti-CD40L antibodies as potential high-efficacy, non-lymphocyte-depleting MS therapy. Further research is needed to understand the role of this pathway in MS pathogenesis and explore CD40L inhibition to address neuroinflammation and neurodegeneration, where unmet medical needs exist. [ABSTRACT FROM AUTHOR]

Background: Cladribine, a selective immune reconstitution therapy, is approved for the treatment of adult patients with highly active multiple sclerosis (MS). Objectives: Provide experience with cladribine therapy in a real-world setting. Methods: This is a registry-based retrospective observational cohort study. First, using data from the Czech nationwide registry ReMuS, we analysed patients who initiated cladribine from September 1, 2018 to December 31, 2021. Second, we analysed a subgroup of patients who initiated cladribine between September 1, 2018 to June 30, 2020, thus possessing a follow-up period of at least 2 years. We evaluated demographic and MS characteristics including disease-modifying therapies (DMTs) before and after cladribine administration, relapses, Expanded Disability Status Scale (EDSS), and adherence. Results: In total, 617 patients (335 with follow-up of at least 2 years) started cladribine therapy in the study period (mean age 37.0, mean disease duration 8.4 years, 74.1% females). In most cases, cladribine was administered as a second-line drug, a total of 80.7% had been escalated from a platform DMT. During 2 years before cladribine initiation, the average annualised relapse rate (ARR) was.67. Following cladribine initiation, the ARR decreased to.28 in the first year and.22 in the second year. Overall, across the entire two-year treatment period, 69.0% of patients were relapse-free and the average ARR was.25. As for EDSS development, the median baseline EDSS was 2.5 and remained stable even after 24 months. The adherence to treatment ranged of around 90%. Conclusion: This nationwide study confirms the efficacy of cladribine in real-world settings, especially in patients who are not treatment-naïve. In addition, the study shows an exceptionally high adherence rate, a finding that underscores the invaluable role of cladribine, but also the value of registry-based studies in capturing real-world clinical practice. [ABSTRACT FROM AUTHOR]

Early intervention with high-efficacy disease-modifying therapy (HE DMT) may be the best strategy to delay irreversible neurological damage and progression of multiple sclerosis (MS). In European healthcare systems, however, patient access to HE DMTs in MS is often restricted to later stages of the disease due to restrictions in reimbursement despite broader regulatory labels. Although not every patient should be treated with HE DMTs at the initial stages of the disease, early and unrestricted access to HE DMTs with a positive benefit–risk profile and a reasonable value proposition will provide the freedom of choice for an appropriate treatment based on a shared decision between expert physicians and patients. This will further optimize outcomes and facilitate efficient resource allocation and sustainability in healthcare systems and society. [ABSTRACT FROM AUTHOR]

Background Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic resonance imaging, ultimately leading to a high risk for rapid disability accumulation. The treatment approach for high-risk patients is evolving into a model of individualized therapy in which early initiation of high-efficacy disease-modifying therapy (DMT), which I refer to as “early and strong” therapy, is viewed as a rational strategy to prevent the irreversible damage that occurs at disease onset and early in the disease course. This approach uses an individualized benefit-risk assessment to match the level of DMT efficacy with the patient's risk of disease progression and balances it against the risk of drug-related adverse events. It also includes consideration of the patient's risk tolerance and desire for a high-efficacy treatment. This paper discusses the rationale for early treatment, and summarizes the available clinical data on high-efficacy and moderately-high efficacy DMTs in patients with high-risk RRMS. Methods Literature searches were conducted using search terms “aggressive RRMS”, “highly active RRMS”, and “severe RRMS” alone and in conjunction with the terms “natalizumab”, “fingolimod”, “alemtuzumab”, “mitoxantrone”, and “cyclophosphamide”. Studies of drug efficacy in these high-risk populations were reviewed. Results Subgroup analyses of pivotal trials of natalizumab, fingolimod, and alemtuzumab were available, as well as an independent study of mitoxantrone and a pilot study of cyclophosphamide. In each study, DMT reduced relapses versus either placebo, active comparator, or baseline relapse rate. Conclusion Data for the high-efficacy DMTs natalizumab and alemtuzumab, and the moderately high-efficacy DMT fingolimod, suggest they are effective in this patient population. Further studies are warranted, and clinical trial data to inform treatment decisions for this high-risk group represent a significant unmet need. [ABSTRACT FROM AUTHOR]