To report efficacy, safety and tolerability of oral vidofludimus calcium (IMU-838) in EMPhASIS (NCT03846219), a phase 2 double-blind, placebo-controlled, randomized, parallel-group trial in relapsing multiple sclerosis (MS).

Dihydroorotate dehydrogenase (DHODH) inhibition is an established mode of action for the disease-modifying treatment of relapsing MS. IMU-838 is a potent, selective next-generation oral DHODH modulator with no off-target effects on kinases and for which general antiproliferative effects (e.g. neutropenia or diarrhea) have not been observed in previous clinical trials.

Patients with relapsing MS were enrolled at 36 centers in four European countries. A total of 210 patients were randomly assigned in a 1:1:1 ratio to receive once-daily oral doses of IMU-838 (30 or 45 mg, respectively) or placebo for 24 months. The primary endpoint was the cumulative number of combined unique active (CUA) MRI lesions. Secondary endpoints included clinical efficacy, safety and tolerability parameters.

In the intention-to-treat population, significantly fewer CUA lesions were observed with both IMU-838 30 mg (-70%, p=0.0002) and 45 mg (-62%, p<0.0001) as compared to placebo. The annualized relapse rate was 0.39 with IMU-838 30 mg, 0.48 with IMU-838 45 mg, and 0.53 with placebo. In contrast to placebo, treatment with IMU-838 showed a robust decrease of serum neurofilament light levels. The overall treatment discontinuation rate was 4.3% with IMU-838 and 7.2% for placebo. Three serious treatment-emergent adverse events (TEAE) were reported in subjects assigned to 30 mg IMU-838 (open fracture, ureterolithiasis) and placebo (squamous cell carcinoma of the cervix), none was observed at the 45 mg dose. The most common TEAE were headache and nasopharyngitis.

Both 30 mg and 45 mg IMU-838 once daily significantly reduced CUA MRI lesions over 24 weeks compared to placebo, with a favorable safety and tolerability profile. Further assessment of this next generation DHODH modulator in Phase 3 clinical trials is warranted.