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

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Abstract

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.

Clinical Trials Registration

EVOLVE-MS-1 (ClinicalTrials.gov identifier: NCT02634307); OPTIMUM (ClinicalTrials.gov identifier: NCT02425644).

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Acknowledgements

Editorial support for the preparation of this manuscript, including copyediting, formatting, and drafting of the figures, was provided by Excel Medical Affairs (Fairfield, CT, USA), under the direction of the authors; funding was provided by Biogen.

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Authors and Affiliations

  1. Biogen, Cambridge, MA, USA

    Tammy Jiang, Changyu Shen & James B. Lewin

  2. Center of Clinical Neuroscience, Carl Gustav Carus University Hospital, Dresden, Germany

    Tjalf Ziemssen

  3. Hope Neurology MS Center, Knoxville, TN, USA

    Sibyl Wray

  4. Biogen, Upplands-Väsby, Sweden

    Karin Söderbärg

  5. Biogen, Baar, Switzerland

    Ivan Božin

  6. University of Ottawa, Ottawa, ON, Canada

    Mark S. Freedman

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Correspondence to Tammy Jiang.

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Funding

EVOLVE-MS-1 and the current analysis were sponsored by Biogen.

Conflicts of interest

T.J., C.S., K.S., J.B.L., and I.B. are employees of and hold stock/stock options in Biogen. T.Z. received personal compensation for consulting services and speaker honoraria from Bayer, Biogen Idec, Novartis, Sanofi, Synthon, and Teva, and financial support for research activities from Bayer, Biogen Idec, Novartis, Sanofi Aventis, and Teva. S.W. received consulting fees from and served on advisory boards for Biogen, Celgene, and EMD Serono; received research support from Biogen, Celgene, EMD Serono, Genentech-Roche, Novartis, Receptos, Sanofi-Genzyme, and TG Therapeutics; and served on speaker bureaus for Biogen, Celgene, EMD Serono, Genentech-Roche, and Sanofi-Genzyme. M.S.F. received research/educational grants from Sanofi-Genzyme; received honoraria/consultation fees from Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), EMD, Hoffman La-Roche, Janssen (J&J), Merck Serono, Novartis, Quanterix, Sanofi-Genzyme, and Teva Canada Innovation; served on advisory boards/boards of directors for Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), Celestra, Hoffman La-Roche, Janssen (J&J), McKesson, Merck Serono, Novartis, and Sanofi-Genzyme; and participated in speakers bureau for Sanofi-Genzyme and EMD Serono.

Availability of data and material

EVOLVE-MS-1 was registered with ClinicalTrials.gov (NCT02634307). Study data will be shared in accordance with applicable regulations and laws.

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Author contributions

Data analysis was performed by Tammy Jiang and Ivan Bozin. The first draft of the manuscript was written by Tammy Jiang. Tammy Jiang, Tjalf Ziemssen, Sibyl Wray, Changyu Shen, Karin Söderbärg, James B. Lewin, Ivan Bozin, and Mark S. Freedman reviewed and revised drafts of the manuscript, and approved the final version.

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Jiang, T., Ziemssen, T., Wray, S. et al. Matching-Adjusted Indirect Comparisons of Diroximel Fumarate, Ponesimod, and Teriflunomide for Relapsing Multiple Sclerosis. CNS Drugs 37, 441–452 (2023). https://doi.org/10.1007/s40263-023-01002-x

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