In a comparative effectiveness study published in JAMA, cladribine (Mavenclad; EMD Serono) demonstrated superior performance over sphingosine-1-phosphate receptor modulators (S1Ps) in reducing disability progression among treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) over a 25-month period. The findings suggest cladribine may offer greater short-term protection against disability progression compared to traditional S1P treatments.
The research involved 475 pairs of treatment-naive individuals, totaling 950 participants with a mean age of 34.7 years, predominantly female (72.2%). Data was collected from 108 MS centers across Italy, with the primary outcome focusing on no evidence of disease activity (NEDA-3) and its subcomponents. Secondary analyses evaluated disability accrual classified into progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW). Cox proportional hazards models were applied to compare outcomes while controlling for visit frequency and MRI frequency.
Carla Tortorella, MD, PhD, a neurologist at the University of Bari, led the study, which revealed comparable outcomes between cladribine and S1Ps for primary and secondary endpoints. Notably, patients treated with cladribine experienced a significantly lower risk of worsening disability compared to those on S1Ps (11.4% versus 14.7%; hazard ratio 0.64; 95% confidence interval 0.42–0.96; p = 0.03).
In terms of comparative effectiveness, cladribine outperformed S1Ps in NEDA-3 loss (44.4% vs 52.2%), relapse rates (15.2% vs 16.0%), and MRI activity (31.3% vs 34.8%). Sensitivity analyses confirmed these findings in various subgroups, including patients younger than 40 and those diagnosed per the 2017 McDonald Criteria.
Among the 950 participants, treatment discontinuation occurred in 86 patients (18.1%) receiving cladribine, compared to 102 patients (20.5%) receiving S1PRMs, with no significant difference. A total of 188 patients switched therapies, largely escalating to monoclonal antibodies or de-escalating to moderate-efficacy disease modifying therapies (DMT), but no between-group differences were observed. Data on subsequent DMTs were missing for 37 patients who discontinued S1PRMs.
The study noted several limitations, including its observational design with nonrandomized treatment allocation and potential residual confounding despite matching. Selection bias may also affect results, given that a larger number of eligible patients treated with S1PRMs were excluded compared to those receiving cladribine. Factors like adherence and tolerability were not measured, potentially influencing outcomes, and variations in data collection could compromise accuracy. There was no prespecified primary outcome, and no adjustments for multiple comparisons were conducted, suggesting findings should be interpreted cautiously.
Researchers emphasized that while cladribine showed a lower risk of disability worsening compared to S1PRMs, it was noted that “beyond 36 months, cladribine was associated with higher risk of relapse and loss of NEDA-3 status.” This “novel finding requires careful consideration,” as NEDA-3, despite its widespread adoption, may not fully represent the severity or impact of disease activity and should be measured alongside other therapeutic effectiveness indicators.
Cladribine’s long-term efficacy has been previously investigated; a single-center, real-world cohort study indicated that cladribine was both safe and well-tolerated for a two-year period in older patients transitioning from a previous DMT. These comprehensive findings were recently presented at the 2024 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, highlighting cladribine’s promising role in MS treatment.
Original Source: https://www.neurologylive.com/view/cladribine-more-effective-than-s1p-receptor-modulators-treating-relapsing-remitting-ms-study-shows
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Publish Date: 2025-11-16 01:34:00
