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

by Selleckchem | Jul 24 2023

Introduction: Diroximel 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.

Objectives: The objectives of this analysis were to compare DRF versus PON and DRF versus TERI for clinical and radiological outcomes.

Methods: We 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.

Results: After 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).

Conclusions: We 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.

Comments:

The study compares the effectiveness of three oral disease-modifying therapies—Diroximel fumarate (DRF), Ponesimod (PON), and Teriflunomide (TERI)—for the treatment of relapsing multiple sclerosis. However, it's important to note that no randomized trials directly compared DRF versus PON or TERI. Therefore, the analysis utilized individual patient data from the EVOLVE-MS-1 trial for DRF and aggregated data from the OPTIMUM trial for PON and TERI.

The objectives of the analysis were to compare DRF versus PON and DRF versus TERI in terms of clinical and radiological outcomes. The outcomes examined included the annualized relapse rate (ARR), confirmed disability progression (CDP) at 12 weeks and 24 weeks, absence of gadolinium-enhancing (Gd+) T1 lesions, and absence of new/newly enlarging T2 lesions.

After weighting the EVOLVE-MS-1 data to match the average baseline characteristics of the OPTIMUM trial, the analysis did not find strong evidence of differences between DRF and PON for ARR, 12-week CDP, 24-week CDP, and absence of new/newly enlarging T2 lesions. However, a higher proportion of DRF-treated patients were free of Gd+ T1 lesions compared to PON-treated patients.

When comparing DRF with TERI, DRF showed improved effectiveness in terms of ARR, 12-week CDP, 24-week CDP, and absence of Gd+ T1 lesions. However, there was no significant difference between DRF and TERI in terms of absence of new/newly enlarging T2 lesions when considering the overall EVOLVE-MS-1 sample or in a sensitivity analysis restricted to newly enrolled EVOLVE-MS-1 patients.

In conclusion, the analysis suggests that DRF and PON have similar efficacy for the measured outcomes, except for a higher proportion of patients free of Gd+ T1 lesions in the DRF group. DRF appears to be more effective than TERI in terms of all clinical and radiological outcomes, except for absence of new/newly enlarging T2 lesions. It's important to note that these findings are based on indirect comparisons due to the lack of head-to-head randomized trials between these treatments.