DHODH Inhibitor Reduces Lesions Significantly in Relapsing-Remitting MS

A phase 2 clinical trial (NCT03846219) of a selective oral Dihydroorotate dehydrogenase (DHODH) inhibitor (IMU-838; Immunic, New York, NY) provided a significant reduction in lesions in participants with relapsing-remitting multiple sclerosis (RRMS). Individuals treated with the DHODH inhibitor 30 mg (n=69) or 45 mg (n=71) had a 70% or 62% reduction in the cumulative number of combined unique active (CUA) lesions on MRI up to week 24 compared with placebo (n=69) (P<0.0001 and P=.0002, respectively).

Consistent with prior data sets in other populations, administration of the DHODH inhibitor in this trial was safe and well-tolerated, providing evidence of an attractive target product profile for the DHODH inhibitor for individuals with RRMS. The rate of treatment-emergent adverse events was 42.9% in participants treated with DHODH inhibitor compared with 43.5% of participants treated with placebo. The phase 2 EMPhASIS trial was an international multicenter double-blind placebo-controlled parallel-group study, designed to assess the efficacy and safety of DHODH inhibitor in participants with RRMS. Of the 210 participants randomized across 36 centers in 4 European countries, 209 received at least 1 dose of DHODH inhibitor or placebo, and 197 participants completed the blinded 24-week treatment period. All enrolled participants were required to have shown disease activity based on clinical evidence of relapse and additional MRI criteria. The primary and key secondary endpoints were the cumulative number of CUA MRI lesions, up to week 24, for 30 mg or 45 mg of DHODH inhibitor, respectively. MRI was performed at baseline and at weeks 6, 12, 18 and 24, and was evaluated centrally by an independent blinded MRI reader. The study includes an optional extended treatment period for up to 9.5 years to evaluate long-term safety and tolerability of DHODH inhibitor.

Serious treatment-emergent adverse events were rare, occurring in 3 out of 140 DHODH participants treated with DHODH inhibitor, and in 1 out of 69 participants treated with placebo. The rate of treatment withdrawals in the 24-week blinded treatment period was only 5.0% in the pooled DHODH inhibitor treatment arms vs 7.2% in the placebo group. In addition, the rate of discontinuations due to adverse events or protocol-specified discontinuation criteria were equivalent between the pooled DHODH inhibitor treatment arms and placebo. There was no increase in liver or renal events for the DHODH inhibitor treatment arms vs placebo.