Matching-Adjusted Indirect Comparisons of Diroximel Fumarate, Ponesimod, and Teriflunomide for Relapsing Multiple Sclerosis

IntroductionDiroximel fumarate (DRF), ponesimod (PON), and teriflunomide (TERI) are oral disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus PON or TERI.ObjectivesThe objectives of this analysis were to compare DRF versus PON and DRF versus TERI for clinical and radiological outcomes.MethodsWe used individual patient data from EVOLVE-MS-1, a 2-year, open-label, single-arm, phase III trial of DRF (n = 1057), and aggregated data from OPTIMUM, a 2-year, double-blind, phase III trial comparing PON (n = 567) and TERI (n = 566). To account for cross-trial differences, EVOLVE-MS-1 data were weighted to match OPTIMUM's average baseline characteristics using an unanchored matching-adjusted indirect comparison. We examined the outcomes of annualized relapse rate (ARR), 12-week confirmed disability progression (CDP), 24-week CDP, absence of gadolinium-enhancing (Gd+) T1 lesions, and absence of new/newly enlarging T2 lesions.ResultsAfter weighting, we did not observe strong evidence of differences between DRF and PON for ARR [DRF versus PON incidence rate difference (IRD) -0.02; 95% confidence interval (CI) -0.08, 0.04; incidence rate ratio (IRR) 0.92; 95% CI 0.61, 1.2], 12-week CDP [risk difference (RD) -2.5%; 95% CI -6.3, 1.2; risk ratio (RR) 0.76; 95% CI 0.38, 1.1], 24-week CDP (RD -2.7%; 95% CI -6.0, 0.63; RR 0.68; 95% CI 0.28, 1.0), and absence of new/newly enlarging T2 lesions (RD -2.5%; 95% CI -13, 7.4; RR 0.94; 95% CI 0.70, 1.2). However, a higher proportion of DRF-treated patients were free of Gd+ T1 lesions than PON-treated patients (RD 11%; 95% CI 6.0, 16; RR 1.1; 95% CI 1.06, 1.2). Compared with TERI, DRF showed improved ARR (IRD -0.08; 95% CI -0.15, -0.01; IRR 0.74; 95% CI 0.50, 0.94), 12-week CDP (RD -4.2%; 95% CI -7.9, -0.48; RR 0.67; 95% CI 0.38, 0.90), 24-week CDP (RD -4.3%; 95% CI -7.7, -1.1; RR 0.57; 95% CI 0.26, 0.81), and absence of Gd+ T1 lesions (RD 25%; 95% CI 19, 30; RR 1.4; 95% CI 1.3, 1.5). However, DRF and TERI did not appear to differ significantly with respect to absence of new/newly enlarging T2 lesions when based on comparisons using the overall EVOLVE-MS-1 sample (RD 8.5%; 95% CI -0.93, 18; RR 1.3; 95% CI 0.94, 1.6), or in a sensitivity analysis restricted to newly enrolled EVOLVE-MS-1 patients (RD 2.7%; 95% CI -9.1, 14; RR 1.1; 95% CI 0.68, 1.5).ConclusionsWe did not observe differences between DRF and PON for ARR, CDP, and absence of new/newly enlarging T2 lesions, but there was a higher proportion of patients free of Gd+ T1 lesions among DRF-treated patients than PON-treated patients. DRF had improved efficacy versus TERI for all clinical and radiological outcomes, except for absence of new/newly enlarging T2 lesions.

Automated summary

This study compared the differences between Diroximel fumarate (DRF) and ponesimod (PON) as well as DRF and teriflunomide (TERI) in terms of clinical and radiological outcomes. The study found that there was no strong evidence of differences between DRF and PON in the treatment of relapsing multiple sclerosis, but DRF showed improved efficacy compared to TERI.