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

Abstract

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 (http://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.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

“…5A and B ). Notably, the peak plasma concentration (C max ) of vidofludimus calcium used in relapsing-remitting multiple sclerosis is 8.738–14.571 ​μmol/L ( Muehler et al., 2020a ; Fox et al., 2022 ). And the C max of vidofludimus calcium used to combat SARS-CoV-2 infection in patients hospitalized with COVID-19 is 14.323–14.57 ​μmol/L ( Vehreschild et al., 2022 ).…”

“…They are structurally distinct from leflunomide and teriflunomide and exhibit favorable safety profiles ( Jones et al., 2021 ). Vidofludimus calcium has been well-studied in over 1400 healthy volunteers or patients with immune-related conditions with a safety and tolerability profile similar to placebo ( Muehler et al., 2020a ; Fox et al., 2022 ). Vidofludimus calcium has advanced in phase 3 clinical development for patients with multiple sclerosis ( Therapeutics ) or hospitalized with COVID-19 ( ClinicalTrials.gov NCT04379271).…”

Safety and Efficacy of Vidofludimus Calcium in Patients Hospitalized with COVID-19: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial

“…Hypertriglyceridemia occurred more frequently in the patients treated with vidofludimus calcium compared to placebo although the reason for this observation is not clear. Hypertriglyceridemia has not been associated with DHODH inhibitors, including vidofludimus calcium, so the apparent higher incidence of hypertriglyceridemia in patients treated with vidofludimus calcium is unlikely to be related to inhibition of DHODH [ 27 , 29 – 32 ]. All non-published clinical studies investigating vidofludimus calcium also have no reported adverse events of hypertriglyceridemia.…”

Nanocluster-antibody-drug conjugates (NADC) as an intravesical precision theranostic agent for interstitial cystitis

“…Meanwhile, non-invasive intravesical therapy can preserve high local concentrations of drugs by direct exposure. Recent studies revealed the anti-inflammatory and immunomodulatory effects of selective dihydroorotate dehydrogenase inhibitors (DHODHi) via suppressing mitochondrial pyrimidine synthesis, exemplified by clinically investigational vidofludimus (IMU-838) 7 . While elevated levels of interleukin (IL)-17A are found in the bladder tissues and urine of IC patients, IL-17A triggers the release of other pro-inflammatory cytokines 8 .…”