Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE

Abstract

Introduction: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported.

Methods: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0-2 /DMF for years 3-9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed.

Results: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0-2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6-0.8 and 0.9-2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was -1.32% (range -1.60% to -1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 10⁹/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation.

Conclusions: Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS.

Trial registration: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).

Keywords: delayed-release dimethyl fumarate; efficacy; multiple sclerosis; newly diagnosed; safety.

Figure 1.

Patient populations for safety, efficacy, and lymphocyte analysis. DMF, dimethyl fumarate; BID, twice daily; TID, three times daily; MRI, magnetic resonance imaging; PBO, placebo.

Figure 2.

Linear mixed-effect model of lymphocyte reconstitution after DMF discontinuation in patients with mild to moderate lymphopenia. ALC, absolute lymphocyte count; DMF, delayed-release dimethyl fumarate; LLN, lower limit of normal.

Figure 3.

(a) Adjusted ARR by yearly interval for the DMF/DMF and PBO/DMF groups in the overall ENDORSE population over 9 years (ENDORSE 7 years). Adjusted ARR is shown for all patients treated with DMF continuously (DMF/DMF), and for patients treated with PBO in years 0–2 in DEFINE/CONFIRM followed by DMF in years 3–9 in ENDORSE (PBO/DMF). Based on negative binomial regression, except for years 4–5, 5–6, 6–7, 7–8, and 8–9, which are based on Poisson regression, adjusted for baseline EDSS score (⩽2, ⩾2.0), baseline age (<40, ⩾40 years), region, and number of relapses in the year before DEFINE/CONFIRM study entry. (b) Adjusted ARR by yearly interval during treatment with PBO (years 0–2 in DEFINE/CONFIRM) and DMF (years 3–9 in ENDORSE) in the overall ENDORSE population. ARR was defined as the total number of relapses divided by the number of patient-years in the study, using a negative binomial regression model, except for years 4–5, 5–6, 6–7, 7–8, and 8–9, which are based on Poisson regression, adjusted for age, number of relapses in the year prior to study entry, baseline EDSS score and region. (c) Proportion of patients in the overall ENDORSE population with baseline EDSS score ⩽3 and 24-week confirmed progression to EDSS score ⩾4 over 384 weeks. CDP was defined as ⩾1-point worsening if baseline score was ⩾1; thus, only patients with EDSS score ⩽3 were included. Kaplan-Meier estimate. ARR, annualized relapse rate; BL, baseline; CDP, confirmed disability progression; CI, confidence interval; DMF, delayed-release dimethyl fumarate; EDSS, Expanded Disability Status Scale; PBO, placebo.

Figure 4.

(a) Adjusted ARR by yearly interval for the DMF/DMF and PBO/DMF groups of newly diagnosed patients over 9 years (ENDORSE 7 years). Adjusted ARR is shown for newly diagnosed patients treated with DMF continuously (DMF/DMF), and for newly diagnosed patients treated with PBO in years 0–2 in DEFINE/CONFIRM followed by DMF in years 3–9 in ENDORSE (PBO/DMF). Based on negative binomial regression, except for years 4–5, 5–6, 6–7, 7–8, and 8–9, which are based on Poisson regression, adjusted for baseline EDSS score (⩽2, ⩾2.0), baseline age (<40, ⩾40 years), region, and number of relapses in the year before DEFINE/CONFIRM study entry. (b) Adjusted ARR during treatment with PBO (years 0–2 in DEFINE/CONFIRM) and DMF (years 3–9 in ENDORSE) in newly diagnosed patients. ARR was defined as the total number of relapses divided by the number of patient-years in the study, using a negative binomial regression model, except for years 4–5, 5–6, 6–7, 7–8, and 8–9, which are based on Poisson regression, adjusted for age, number of relapses in the year prior to study entry, baseline EDSS score and region. (c) Proportion of newly diagnosed patients with baseline EDSS score ⩽3 and 24-week confirmed progression to EDSS score ⩾4 over 384 weeks. CDP was defined as ⩾ 1-point worsening if baseline score was ⩾ 1; thus, only patients with EDSS score ⩽ 3 were included. Kaplan-Meier estimate. ARR, annualized relapse rate; BL, baseline; CDP, confirmed disability progression; CI, confidence interval; DMF, delayed-release dimethyl fumarate; EDSS, Expanded Disability Status Scale; PBO, placebo.

Figure 5.

Patients with (a) no new T1 hypointense or (b) no new/newly enlarging T2 hyperintense lesions, calculated by comparing with previous visit with visit for patients who had non-missing data from weeks 48–240 in the ENDORSE magnetic resonance imaging cohort for patients with five consecutive scans. Data after patients switched to alternative multiple sclerosis medications were excluded. ^aIncludes patients from the PBO/DMF and GA/DMF groups in years 1–2 of ENDORSE. ^bIncludes patients from the PBO/DMF and GA/DMF groups in years 2–3 of ENDORSE. ^cIncludes patients from the PBO/DMF and GA/DMF groups in years 3–4 of ENDORSE and patients in the DMF/DMF group in years 1–2 of ENDORSE. ^dIncludes patients from the PBO/DMF and GA/DMF groups in years 4–5 of ENDORSE and patients in the DMF/DMF group in years 2–3 of ENDORSE. ^eIncludes patients from the PBO/DMF and GA/DMF groups in years 5–6 of ENDORSE and patients in the DMF/DMF group in years 3–4 of ENDORSE. ^fIncludes patients from the PBO/DMF and GA/DMF groups in years 6–7 of ENDORSE and patients in the DMF/DMF group in years 4–5 of ENDORSE. DMF, delayed-release dimethyl fumarate; GA, glatiramer acetate; PBO, placebo.

Figure 6.

Number of (a) new T1 hypointense and (b) new/newly enlarging T2 hyperintense lesions, comparing with previous visit with visit for patients who had non-missing data from weeks 48–240 in the ENDORSE magnetic resonance imaging cohort for patients with five consecutive scans. Data after patients switched to alternative multiple sclerosis medications were excluded. Number of patients reporting lesions is shown for each time point. ^aIncludes patients from the PBO/DMF and GA/DMF groups in years 1–2 of ENDORSE. ^bIncludes patients from the PBO/DMF and GA/DMF groups in years 2–3 of ENDORSE. ^cIncludes patients from the PBO/DMF and GA/DMF groups in years 3–4 of ENDORSE and patients in the DMF/DMF group in years 1–2 of ENDORSE. ^dIncludes patients from the PBO/DMF and GA/DMF groups in years 4–5 of ENDORSE and patients in the DMF/DMF group in years 2–3 of ENDORSE. ^eIncludes patients from the PBO/DMF and GA/DMF groups in years 5–6 of ENDORSE and patients in the DMF/DMF group in years 3–4 of ENDORSE. ^fIncludes patients from the PBO/DMF and GA/DMF groups in years 6–7 of ENDORSE and patients in the DMF/DMF group in years 4–5 of ENDORSE. For reference, the annual mean (SD) number of new T1 hypointense lesions for DMF-treated patients in DEFINE/CONFIRM at 2 years was 0.9 (2.8) compared with 3.1 (4.9) for PBO-treated patients; mean (SD) number of new/newly enlarging T2 hyperintense lesions for DMF-treated patients in DEFINE/CONFIRM at 2 years was 1.7 (4.4) compared with 8.2 (11.9) for PBO-treated patients. DMF, delayed-release dimethyl fumarate; GA, glatiramer acetate; PBO, placebo; SD, standard deviation; SE, standard error.

Figure 7.

PBVC by year of DMF treatment. Adjusted yearly PBVC change from previous year compared with the annual summary from the DMF/DMF group in the ENDORSE MRI cohort. All patients treated with DMF BID continuously from DEFINE/CONFIRM and ENDORSE were included due to sample size restrictions. Data after patients switched to alternative multiple sclerosis medications were excluded. Adjusted mean, standard error, treatment group difference and 95% CI from an analysis of covariance model adjusted for region and baseline T2 lesion volume. Number of patients with an MRI is shown for each time point. BID, twice daily; CI, confidence interval; DMF, delayed-release dimethyl fumarate; MRI, magnetic resonance imaging; PBVC, percentage brain volume change.