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

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; ENDORSE Study Investigators

doi:10.1007/s40120-023-00475-8

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

Neurol Ther. 2023 Jun;12(3):883-897. doi: 10.1007/s40120-023-00475-8. Epub 2023 Apr 15.

Authors

Lilyana Amezcua^{1

2}, Yang Mao-Draayer^{3

4}, Wendy S Vargas⁵, Rebecca Farber⁵, Sara Schaefer⁶, Filipe Branco⁷, Sarah M England⁷, Nicholas Belviso⁷, James B Lewin⁷, Jason P Mendoza⁷, Sai L Shankar^{8

9}; ENDORSE Study Investigators

Affiliations

¹ Multiple Sclerosis Comprehensive Care Center, University of Southern California, Los Angeles, CA, USA.
² Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Autoimmunity Center of Excellence, Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ Columbia Multiple Sclerosis Center, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Multiple Sclerosis Comprehensive Care Center, UC-Health Neurology Clinic, Fort Collins, CO, USA.
⁷ Biogen, Cambridge, MA, USA.
⁸ Biogen, Cambridge, MA, USA. sai.shankar@biogen.com.
⁹ , 133 Boston Post Road, Weston, MA, 02493, USA. sai.shankar@biogen.com.

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).

Keywords: DMT; Dimethyl fumarate; Efficacy; Multiple sclerosis; Safety; Young adults.

Associated data

ClinicalTrials.gov/NCT00835770
ClinicalTrials.gov/NCT00451451