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

The thalamus is a key gray matter structure, and a sensitive marker of neurodegeneration in multiple sclerosis (MS). Previous reports have indicated that thalamic volumetry on clinical-quality T2-FLAIR images alone is fast and reliable, using artificial intelligence (AI).

Objectives

To investigate the feasibility of thalamic atrophy measurement using AI in patients with MS, in a large multi-center, clinical routine study.

Methods

DeepGRAI (Deep Gray Rating via Artificial Intelligence) is a multi-center (31 USA sites), longitudinal, observational, real-word, registry study that will enroll 1,000 relapsing-remitting MS patients. Brain MRI exams previously acquired at baseline and at follow-up on 1.5T or 3T scanners with no prior standardization are used, in order to resemble real-world situation. Thalamic volume measurement is performed at baseline and follow-up on T2-FLAIR by DeepGRAI tool and on 3D T1-weighted image (WI) and 2D T1-WI by using FIRST software.

Results

In this pre-planned interim analysis, 515 RRMS patients were followed for an average of 2.7 years. There were 487 (94.6%) T2-FLAIR, 342 (66.4%) 2D T1-WI and 176 (34.2%) 3D T1-WI longitudinal pair of MRI exams available for analyses. Estimation of thalamic volume by DeepGRAI on T2-FLAIR correlated significantly with FIRST on 3D-T1-WI (r=0.733 and r=0.816, p<0.001) and with FIRST on 2D-T1-WI (r=0.555 and r=0.704, p<0.001) at baseline and at follow-up. The correlation between thalamic volume estimated by FIRST on 3D T1-WI and 2D T1-WI was r=0.642 and r=0.679, p<0.001, respectively. The thalamic volume % change over the follow-up was similar between DeepGRAI (-0.75) and 3D T1-WI (-0.82), but somewhat higher for 2D T1-WI (-0.92). Similar relationship was found between the Expanded Disability Status Scale (EDSS) and thalamic volume by DeepGRAI on T2-FLAIR and by FIRST on 3D T1-WI at baseline (r=-0.214, p=0.01 and r=-0.287, p=0.001) and at follow-up (r=-0.298, p=0.001 and r=-0.291, p=0.001).

Conclusions

DeepGRAI provides feasible thalamic volume measurement on multi-center clinical-quality T2-FLAIR images. The relationship between thalamic atrophy and physical disability is similar using DeepGRAI T2-FLAIR and standard high-resolution research approaches. This indicates potential for real-world thalamic volume monitoring, as well as quantification on legacy datasets without research-quality MRI.