The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human dihydroorotate dehydrogenase (DHODH) with a recently proven antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics.

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Background and Objective Vidofludimus is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The clinical efficacy and safety profile of vidofludimus has been analyzed in patients suffering from rheumatoid arthritis and Crohn's disease and ulcerative colitis. In previous sudies, hematuria at higher doses occurred in close temporal relationship to vidofludimus administration and appeared to be dose related. The present report describes the results from two phase 1 studies conducted in healthy male subjects to investigate the safety, tolerability and pharmacokinetics after single and multiple ascending (SAD and MAD) oral doses of IMU-838 (vidofludimus calcium, tablets containing a specific polymorph). The effect of food on the pharmacokinetics of IMU-838 was also assessed in the SAD study. Methods In the SAD study, 12 subjects received single doses of IMU-838 under fasting (10-40 mg) or fed (10 mg) condition in an open-label, partial parallel group design. In the MAD study, 52 subjects received multiple doses of IMU-838 (30-50 mg) in a double-blind, placebo-controlled, parallel group design. Results IMU-838 showed dose-proportional pharmacokinetics after single and multiple oral dosing in both SAD and MAD studies. IMU-838 was well absorbed after single daily doses. Food did not impact the pharmacokinetics of IMU-838. The accumulation factor for multiple daily dosing was approximately 2. Steady-state concentrations were reached within about 6-8 days for 30-50 mg groups. The geometric mean plasma half-life of IMU-838 at steady state was approximately 30 h, which supports its use for once-daily dosing regimen. Single and multiple oral doses of IMU-838 were safe and well tolerated. Conclusion Overall, oral IMU-838 was generally well tolerated in SAD and MAD studies in healthy subjects over a wide dose range of 10-50 mg. IMU-838 was well absorbed after single daily doses. IMU-838 showed dose proportional pharmacokinetics after single and multiple oral dosing.

Introduction The dihydroorotate dehydrogenase (DHODH) inhibitors leflunomide and teriflunomide are immunomodulatory agents approved to treat rheumatoid arthritis (RA) and multiple sclerosis, respectively, and are actively being investigated as therapeutic agents for other immune-related diseases; however, both structurally related compounds have a number of potentially serious adverse effects. Vidofludimus, a new selective second-generation DHODH inhibitor, is chemically distinct from leflunomide/teriflunomide and appears to exhibit a distinct safety profile. Objective The aim of the COMPONENT study was to assess the efficacy, safety, and pharmacokinetics of vidofludimus in the treatment of patients with active RA on a background therapy of methotrexate. This report focuses solely on the safety results of the COMPONENT trial. Methods Patients received once-daily oral vidofludimus (N = 122) or placebo (N = 119) along with their standard of care methotrexate treatment for 13 weeks. Efficacy endpoints were assessed. Safety parameters were monitored throughout treatment and at follow-up. Plasma concentrations of vidofludimus were measured. Results The primary efficacy endpoint, American College of Rheumatology 20 (ACR 20) responder rate at 13 weeks, demonstrated numerical superiority in the treatment group compared with placebo; however, it did not reach statistical significance. Nonetheless, the COMPONENT study yielded important safety and pharmacokinetic data that could provide important information regarding the use of vidofludimus in other clinical trials, not only for RA but also for other autoimmune diseases. A safety profile for vidofludimus similar to placebo was obtained in this RA patient population. This includes similar rates of the adverse events of diarrhea, alopecia, neutropenia, and elevated liver enzymes, all of which are known drug-related adverse events reported for leflunomide and teriflunomide. A potential pharmacokinetic interaction between vidofludimus and methotrexate was observed. Conclusions Vidofludimus demonstrated a positive safety profile, making it a promising candidate for the treatment of a variety of immune-related diseases. Trial Registrations ClinicalTrials.gov identifier: NCT01010581.

Summary Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC 0-inf ) and maximum concentrations (C max ) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC 0-inf and C max in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC 0-inf and C max in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC 0-inf and C max in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.