A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis

Ann Clin Transl Neurol. 2022 Jul;9(7):977-987. doi: 10.1002/acn3.51574. Epub 2022 Jun 14.


Objective: Inhibition of dihydroorotate dehydrogenase suppresses magnetic resonance imaging brain lesions and disease activity in multiple sclerosis but has limiting tolerability. We assessed the safety and efficacy of vidofludimus calcium, a novel, selective dihydroorotate dehydrogenase inhibitor, in patients with relapsing-remitting multiple sclerosis.

Methods: This double-blind, 24 weeks, placebo-controlled, phase 2 trial (EMPhASIS) enrolled patients 18-55 years with relapsing-remitting multiple sclerosis. Eligible patients were randomly assigned (1:1:1) to once-daily vidofludimus calcium (30 mg or 45 mg) or placebo. The primary endpoint was the cumulative number of combined unique active lesions to week 24 between vidofludimus calcium 45 mg and placebo (clinicalTrials.gov number NCT03846219; EudraCT 2018-001896-19).

Results: After 24 weeks, the mean cumulative number of combined unique active lesions was 6.4 (95% CI: 2.8-13.9) with placebo compared to 2.4 (95% CI: 1.1-4.9) with vidofludimus calcium 45 mg (rate ratio 0.38, 95% CI: 0.22-0.64; p = 0.0002); the rate ratio between vidofludimus calcium 30 mg and placebo was 0.30 (95% CI: 0.17-0.53; p < 0.0001). Treatment-emergent adverse events occurred in 30 (44%) of patients assigned placebo and 60 (43%) of patients assigned vidofludimus calcium. Serious adverse events occurred in one (1%) assigned placebo and two (1%) assigned vidofludimus calcium. No increased incidence of infectious, hepatic, or renal treatment-emergent adverse events or serious adverse events was observed.

Interpretation: Treatment with vidofludimus calcium led to a reduction in new magnetic resonance imaging lesions in patients with relapsing-remitting multiple sclerosis and was well tolerated with a favorable safety profile. Assessment in longer, larger trials is justified.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biphenyl Compounds
  • Calcium / therapeutic use
  • Dicarboxylic Acids
  • Dihydroorotate Dehydrogenase
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Multiple Sclerosis* / drug therapy
  • Multiple Sclerosis, Relapsing-Remitting* / drug therapy
  • Multiple Sclerosis, Relapsing-Remitting* / pathology


  • Biphenyl Compounds
  • Dicarboxylic Acids
  • Dihydroorotate Dehydrogenase
  • Immunosuppressive Agents
  • vidofludimus
  • Calcium

Associated data

  • ClinicalTrials.gov/NCT03846219
  • EudraCT/EudraCT 2018–001896-19

Grant support

This work was funded by Immunic AG.