Background

DMF is a well-established therapy for relapsing forms of multiple sclerosis (RMS); data from ENDORSE, an extension to phase 3 studies DEFINE and CONFIRM, has enabled >10 years follow-up.

Objectives

We report safety/efficacy of DMF in patients with RMS treated with DMF and followed for 13 years in ENDORSE (NCT00835770) (2 years DEFINE/CONFIRM, and >10 years ENDORSE).

Methods

Incidence of serious AEs (SAEs), discontinuations due to AEs, annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg BID: placebo (PBO)/DMF (PBO, years 0–2 /DMF, years 3–10) or continuously (DMF/DMF). Efficacy outcomes were assessed in patients up to 10 years due to sample size considerations. For lymphocyte analysis, data from first DMF exposure were analysed for patients in DEFINE/CONFIRM/ENDORSE.

Results

At 23 January 2020, 1736 patients enrolled/received ≥1 dose DMF. Of 1736 patients, 760 completed. Patients were followed for a median (min,max) of 6.76(0.04,10.98) years in ENDORSE, and 2 years in DEFINE/CONFIRM. Overall, 551 (32%) patients experienced SAEs; most were MS relapse and fall. There was one case of PML in this study. There was no increased incidence of other infections or serious infections. Sixteen percent (n=282) patients discontinued due to AEs; 2% relapse, 2% disease progression, and 4% GI disorders. ALC decreased over the first 48 weeks, and then remained generally stable for the majority of the study. The proportion of patients with other AEs of special interest (including opportunistic infection, malignancy, and serious herpes zoster) was similar regardless of ALC. For patients continuously treated (n=501), overall ARR remained low (0.141[95% CI, 0.119,0.167]), while for PBO/DMF patients (n=249) ARR decreased after initiating DMF (ARR 0–2 years, 0.330[95% CI, 0.266,0.408]; ARR overall, 0.149[95% CI, 0.116,0.190]). Overall, 60% of DMF/DMF and 66% of PBO/DMF patients remained relapse-free; 20% and 17% of patients had 1 relapse, respectively. Walking abilities were maintained throughout the study; the number of patients with EDSS scores ≤3.5 was 413/479(86%) DMF/DMF (179/217[82%] PBO/DMF) at Year 2, and 173/226(77%) DMF/DMF (67/90[74%] PBO/DMF) at Year 10. Seventy-two percent and 73% of DMF/DMF and PBO/DMF patients, respectively, had no 24-week confirmed disability progression over 10 years.

Conclusions

These safety and efficacy data in patients followed for 13 years, support DMF as a long-term option for patients with RMS.

Background

Diroximel fumarate (DRF) is an oral fumarate recently approved in the United States for relapsing forms of multiple sclerosis (MS). DRF demonstrated favorable gastrointestinal (GI) tolerability in clinical studies of MS patients (pts). Discontinuations due to GI adverse events (AEs) were low (0.7%) in an open-label 2-year study. In a randomized study versus dimethyl fumarate (DMF), fewer pts reported GI AEs (35%, 88/253 DRF vs 49%,123/251 DMF) and GI AEs leading to discontinuation (0.8% DRF vs. 4.8% DMF); GI AEs were less frequently reported as moderate/severe for DRF (23%, 20/88) vs DMF (40%, 49/123). It is important to characterize DRF persistence in a real-world setting and effectiveness across different patient types and geographies.

Objectives

To describe the novel design of the DRF EXPERIENCE (EXPloring diroximEl fumarate Real-world experIENCE) Study Initiative.

Methods

A Phase IV DRF study should collect data on meaningful real-world outcomes, including treatment persistence, real-world tolerability, and clinical effectiveness, including cognitive changes, to align with evolving treatment goals. As DRF was designed to reduce treatment burden, impact on quality of life should also be assessed. Country-specific nuances due to unique healthcare environments, ethnicity, and cultural considerations diminish the utility of a single-study design.

Results

The DRF EXPERIENCE Study Initiative uses a novel design comprising 4 individual studies, each conducted in different regions but anchored by a core protocol to characterize the early experience in pts initiating DRF per routine care. The core protocol defines a set of required assessments for each study, but also allows flexibility to include others that address country-specific research questions. The primary objective is to characterize persistence to DRF at 1 year. Core protocol assessments include relapse, disability, cognitive changes, and pt-reported Neuro-QoL. Each study will enroll ~200 pts; the pooled total sample size of ~800 will improve ability for subgroup analyses. Pts will be followed for 2 years and include those newly initiating a disease modifying therapy (DMT) or switching from previous DMTs (including prior DMF).

Conclusions

The DRF EXPERIENCE Study Initiative uses a novel design to characterize the improved GI tolerability profile and effectiveness of DRF in MS pts in the real-world and will be informative to providers and patients when considering MS treatment goals together with the burden of therapy.

Supported by: Biogen

Background

Diroximel fumarate (DRF) is a novel oral fumarate for relapsing forms of multiple sclerosis (MS). DRF is converted to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). Oral administration of DRF 462mg and DMF 240mg produce bioequivalent MMF exposure and are therefore expected to exhibit comparable efficacy and safety profiles. DRF has an improved gastrointestinal (GI) tolerability profile compared to DMF.

Objectives

To report interim safety, tolerability, and efficacy outcomes in DRF-treated patients from EVOLVE-MS-1 and to assess GI tolerability in a subgroup of patients who received DMF prior to DRF.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, 96-week study assessing DRF safety, tolerability, and efficacy in adults with relapsing-remitting MS. Patients entered the study either as newly enrolled in the DRF clinical development program or after completing EVOLVE-MS-2 (NCT03093324), a randomized, blinded, phase 3 study in which patients received DRF or DMF over 5 weeks.

Results

As of 2 July 2019, 1051 patients were enrolled, 458 of whom had completed EVOLVE-MS-2. Median DRF exposure was 1.5 (range 0.0-1.9) years. Overall, 44.2% of patients completed the study and 17.3% discontinued treatment; 6.3% discontinued due to AEs and 0.7% due to GI AEs. AEs occurred in 82.1% (863/1051) of patients; 90% (779/863) were mild or moderate in severity. Incidence of GI AEs was 28.4% (299/1051) in the overall population, 21.7% (51/235) in patients with prior DRF treatment, and 21.5% (48/223) in patients with prior DMF treatment. Patients who had experienced GI AEs in EVOLVE-MS-2 (DRF to DRF, 33.6% [79/235]; DMF to DRF, 44.8% [100/223]) had low rates of recurrence (3.4% [8/235] and 3.6% [8/223] for those previously treated with DRF and DMF, respectively) and/or onset of new GI AEs (19.6% [46/235] and 20.6% [46/223], respectively) in EVOLVE-MS-1, regardless of prior treatment group. In the overall population (n=1051), annualized relapse rate was 0.14, and 86.1% of patients were relapse-free. Outcomes in patients who were newly diagnosed or most recently switched from interferon or glatiramer acetate will be presented.

Conclusions

Safety and efficacy results from the ongoing EVOLVE-MS-1 study were consistent with previous findings of DRF and the known benefit-risk profile for DMF. In patients who switched from DMF to DRF, no worsening of tolerability was observed.

Supported by: Biogen

Background

In clinical studies, delayed-release dimethyl fumarate (DMF) demonstrated a favorable benefit–risk profile in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies enable characterization of risks that may only emerge with long-term exposure in clinical practice. ESTEEM (NCT02047097) is an ongoing 5-year study characterizing long-term safety and effectiveness of routinely prescribed DMF in MS patients.

Objectives

To report 5-year safety and effectiveness in patients with multiple sclerosis (MS) treated with DMF under routine care.

Methods

Patients treated with DMF were recruited from ~380 sites. The primary objective was to determine incidence, type, and pattern of serious adverse events (SAEs), and AEs leading to discontinuation. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs).

Results

On April 3, 2019, 5084 patients had ≥1 dose of DMF and qualified for analysis. Mean (SD) age was 40.0 (11.2) years at enrollment, and 74% were female. In total, 1506 patients were treated for >24–48 months, and 441 were treated for >48 months. Two hundred and forty-five patients (4.8%) experienced SAEs; infections (n=64; 1.3%) and nervous system disorders (n=35; <1%) were most common. There were 1676 (33.0%) permanent treatment discontinuations: 965 (19.0%) due to AEs (most commonly: gastrointestinal AEs [395, 7.8%] and occurrence of lymphopenia [125, 2.5%]) and 260 (5.1%) due to insufficient efficacy. Overall ARR over the period of up to 5 years (0.09; 95% CI: 0.09–0.10) was significantly lower than in the year prior to baseline (0.82, 95% CI: 0.80–0.84), representing an 88.6% risk reduction [95% CI: 87.7–89.4 P<0.0001]). At 54 months, the Kaplan-Meier estimated probability of patients without relapse was 71.1% (n=4286). PROs were generally stable from baseline to Year 5.

Conclusions

Results from the ongoing study with up to 5 years follow-up reveal no new safety concerns emerging from real-world use of DMF. DMF demonstrated beneficial therapeutic effects for those patients that remained on treatment up to 5 years.