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Open Access 15-04-2023 | Multiple Sclerosis | ORIGINAL RESEARCH

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies

Authors: Lilyana Amezcua, Yang Mao-Draayer, Wendy S. Vargas, Rebecca Farber, Sara Schaefer, Filipe Branco, Sarah M. England, Nicholas Belviso, James B. Lewin, Jason P. Mendoza, Sai L. Shankar, the ENDORSE Study Investigators

Published in: Neurology and Therapy | Issue 3/2023

Abstract

Introduction

Dimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population.

Methods

Randomized patients received DMF 240 mg twice daily or placebo (PBO; years 0–2 DEFINE/CONFIRM), then DMF (years 3–10; continuous DMF/DMF or PBO/DMF; ENDORSE); maximum follow-up (combined studies) was 13 years. This integrated post hoc analysis evaluated safety and efficacy of DMF in a subgroup of young adults aged 18–29 years.

Results

Of 1736 patients enrolled in ENDORSE, 125 were young adults, 86 treated continuously with DMF (DMF/DMF) and 39 received delayed DMF (PBO/DMF) in DEFINE/CONFIRM. Most (n = 116 [93%]) young adults completed DMF treatment in DEFINE/CONFIRM. Median (range) follow-up time in ENDORSE was 6.5 (2.0–10.0) years. Young adults entering ENDORSE who had been treated with DMF in DEFINE/CONFIRM had a model-based Annualized Relapse Rate (ARR; 95% CI) of 0.24 (0.16–0.35) vs. 0.56 (0.35–0.88) in PBO patients. ARR remained low in ENDORSE: 0.07 (0.01–0.47) at years 9–10 (DMF/DMF group). At year 10 of ENDORSE, EDSS scores were low in young adults: DMF/DMF, 1.9 (1.4); PBO/DMF, 2.4 (1.6). At ~ 7 years, the proportion of young adults with no confirmed disability progresion was 81% for DMF/DMF and 72% for PBO/DMF. Patient-reported outcomes (PROs) (SF-36 and EQ-5D) generally remained stable during ENDORSE. The most common adverse events (AEs) in young adults during ENDORSE were MS relapse (n = 53 [42%]). Most AEs were mild (n = 20 [23.3%], n = 7 [17.9%]) to moderate (n = 45 [52.3%], n = 23 [59.0%]) in the DMF/DMF and PBO/DMF groups, respectively. The most common serious AE (SAE) was MS relapse (n = 19 [15%]).

Conclusion

The data support a favorable benefit-risk profile of DMF in young adults, as evidenced by well-characterized safety, sustained efficacy, and stable PROs.

Clinical Trial Information

Clinical trials.gov, DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770).

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Conradsson D, Ytterberg C, von Koch L, Johansson S. Changes in disability in people with multiple sclerosis: a 10-year prospective study. J Neurol. 2018;265(1):119–26. https://doi.org/10.1007/s00415-017-8676-8.CrossRefPubMed

Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Prim. 2018;4(1):43. https://doi.org/10.1038/s41572-018-0041-4.CrossRefPubMed

Kobelt G, Thompson A, Berg J, et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler. 2017;23(8):1123–36. https://doi.org/10.1177/1352458517694432.CrossRefPubMedPubMedCentral

Scalfari A, Lederer C, Daumer M, et al. The relationship of age with the clinical phenotype in multiple sclerosis. Mult Scler. 2016;22(13):1750–8. https://doi.org/10.1177/1352458516630396.CrossRefPubMed

Tremlett H, Devonshire V. Is late-onset multiple sclerosis associated with a worse outcome? Neurology. 2006;67(6):954–9. https://doi.org/10.1212/01.wnl.0000237475.01655.9d.CrossRefPubMed

Ziemssen T, Albrecht H, Haas J, et al. Descriptive analysis of real-world data on fingolimod long-term treatment of young adult RRMS patients. Front Neurol. 2021;12:637107. https://doi.org/10.3389/fneur.2021.637107.CrossRefPubMedPubMedCentral

Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology. 2002;59(12):1922–8. https://doi.org/10.1212/01.wnl.0000036907.37650.8e.CrossRefPubMed

McKay KA, Hillert J, Manouchehrinia A. Long-term disability progression of pediatric-onset multiple sclerosis. Neurology. 2019;92(24):e2764–73. https://doi.org/10.1212/WNL.0000000000007647.CrossRefPubMedPubMedCentral

Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler. 2018;24(2):96–120. https://doi.org/10.1177/1352458517751049.CrossRefPubMed

10.

Chalmer TA, Baggesen LM, Norgaard M, et al. Early versus later treatment start in multiple sclerosis: a register-based cohort study. Eur J Neurol. 2018;25(10):1262-e110. https://doi.org/10.1111/ene.13692.CrossRefPubMed

11.

Mills EA, Begay JA, Fisher C, Mao-Draayer Y. Impact of trial design and patient heterogeneity on the identification of clinically effective therapies for progressive MS. Mult Scler. 2018;24(14):1795–807. https://doi.org/10.1177/1352458518800800.CrossRefPubMedPubMedCentral

12.

Biogen. Tecfidera prescribing information. 2022. https://www.tecfidera.com/content/dam/commercial/multiple-sclerosis/tecfidera/pat/en_us/pdf/full-prescribing-info.pdf. Accessed 6 July 2022.

13.

Gold R, Arnold DL, Bar-Or A, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: final ENDORSE study results. Mult Scler. 2022;28(5):801–16. https://doi.org/10.1177/13524585211037909.CrossRefPubMed

14.

Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97. https://doi.org/10.1056/NEJMoa1206328.CrossRefPubMed

15.

Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107. https://doi.org/10.1056/NEJMoa1114287.CrossRefPubMed

16.

Cohan SL, Moses H, Calkwood J, et al. Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: a multicenter retrospective observational study (STRATEGY). Mult Scler Relat Disord. 2018;22:27–34. https://doi.org/10.1016/j.msard.2018.02.028.CrossRefPubMed

17.

Salter A, Lancia S, Cutter G, et al. Characterizing long-term disability progression and employment in NARCOMS registry participants with multiple sclerosis taking dimethyl fumarate. Int J MS Care. 2021;23(6):239–44. https://doi.org/10.7224/1537-2073.2020-109.CrossRefPubMedPubMedCentral

18.

Berger T, Brochet B, Brambilla L, et al. Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC. Mult Scler J Exp Transl Clin. 2019;5(4):2055217319887191. https://doi.org/10.1177/2055217319887191.CrossRefPubMedPubMedCentral

19.

Kresa-Reahl K, Repovic P, Robertson D, et al. Effectiveness of delayed-release dimethyl fumarate on clinical and patient-reported outcomes in patients with relapsing multiple sclerosis switching from glatiramer acetate: RESPOND, a prospective observational study. Clin Ther. 2018;40(12):2077–87. https://doi.org/10.1016/j.clinthera.2018.10.011.CrossRefPubMed

20.

Repovic P, Robertson D, Kresa-Reahl K, et al. Effectiveness of dimethyl fumarate in patients with relapsing multiple sclerosis switching after suboptimal response to glatiramer acetate, including patients with early multiple sclerosis: subgroup analysis of RESPOND. Neurol Ther. 2021;10(1):169–82. https://doi.org/10.1007/s40120-020-00223-2.CrossRefPubMed

21.

Gold R, Arnold DL, Bar-Or A, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study. Mult Scler. 2017;23(2):253–65. https://doi.org/10.1177/1352458516649037.CrossRefPubMed

22.

Ford CC, Johnson KP, Lisak RP, et al. A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients. Mult Scler. 2006;12(3):309–20. https://doi.org/10.1191/135248506ms1318oa.CrossRefPubMed

23.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52. https://doi.org/10.1212/wnl.33.11.1444.CrossRefPubMed

24.

Longbrake EE, Mao-Draayer Y, Cascione M, et al. Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity. Mult Scler. 2021;27(6):883–94. https://doi.org/10.1177/1352458520937282.CrossRefPubMed

25.

Wu Q, Wang Q, Mao G, et al. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J Immunol. 2017;198(8):3069–80. https://doi.org/10.4049/jimmunol.1601532.CrossRefPubMed

26.

Kopp TI, Blinkenberg M, Petersen T, Sorensen PS, Magyari M. Long term effect of delayed treatment on disability in patients with paediatric onset multiple sclerosis: a prospective Danish cohort study. Mult Scler Relat Disord. 2020;40:101956. doi: https://doi.org/10.1016/j.msard.2020.101956.

27.

Waubant E, Chabas D, Okuda DT, et al. Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol. 2009;66(8):967–71. https://doi.org/10.1001/archneurol.2009.135.CrossRefPubMed

28.

Dahlke F, Arnold DL, Aarden P, et al. Characterisation of MS phenotypes across the age span using a novel data set integrating 34 clinical trials (NO.MS cohort): age is a key contributor to presentation. Mult Scler. 2021;27(13):2062–76. https://doi.org/10.1177/1352458520988637.CrossRefPubMedPubMedCentral

29.

Gartner J, Chitnis T, Ghezzi A, et al. Relapse rate and MRI activity in young adult patients with multiple sclerosis: a post hoc analysis of phase 3 fingolimod trials. Mult Scler J Exp Transl Clin. 2018;4(2):2055217318778610. https://doi.org/10.1177/2055217318778610.CrossRefPubMedPubMedCentral

30.

Tremlett H, Zhao Y, Joseph J, Devonshire V, Neurologists UC. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79(12):1368–74. https://doi.org/10.1136/jnnp.2008.145805.CrossRefPubMed

31.

Weideman AM, Tapia-Maltos MA, Johnson K, Greenwood M, Bielekova B. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577. https://doi.org/10.3389/fneur.2017.00577.CrossRefPubMedPubMedCentral

32.

Vermersch P SM, Levin S, Alroughani R, Deiva K, Pozzilli C, Lyons J, Mokliatchouk O, Pultz J, N'Dure F, Liu S, Badwan R, Branco F, Hood-Humphrey V, Franchimont N, Hanna J, Maghzi A-H. Effect of dimethyl fumarate versus interferon β-1a in patients with pediatric-onset multiple sclerosis: the CONNECT randomized clinical trial. JAMA Network Open. 2022 (in press).

Title: Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies
Authors: Lilyana Amezcua
Yang Mao-Draayer
Wendy S. Vargas
Rebecca Farber
Sara Schaefer
Filipe Branco
Sarah M. England
Nicholas Belviso
James B. Lewin
Jason P. Mendoza
Sai L. Shankar
the ENDORSE Study Investigators
Publication date: 15-04-2023
Publisher: Springer Healthcare
Keywords: Multiple Sclerosis
Dimethyl Fumarate
Published in: Neurology and Therapy / Issue 3/2023
Print ISSN: 2193-8253
Electronic ISSN: 2193-6536
DOI: https://doi.org/10.1007/s40120-023-00475-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies

Abstract

Introduction

Methods

Results

Conclusion

Clinical Trial Information

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

Clinical Trial Information

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