The Selective Oral Immunomodulator Vidofludimus in Patients with Active Rheumatoid Arthritis: Safety Results from the COMPONENT Study

Abstract

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.

Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU-838) After Single and Multiple Ascending Oral Doses in Healthy Male Subjects

“…Although there is no strict dose correlation, very high doses of vidofludimus in the phase 1 trials seemed to also result in lowering of serum uric acid levels. Urinary crystallization of uric acid in acidic urine may be speculated to be the event mechanism for these events of hematuria at multiple doses of 70 mg or higher [12]. For this reason, the doses in this trial were selected to not exceed the AUC found in the previous phase 1 trial (SC12267-2-2004) of 70 mg daily repeated SC12267 (AUC 0-24,ss of 259.5 h μg/ml), which led to the findings of hematuria (data on file).…”

“…Vidofludimus in its form as free acid (lab code: SC12267) using capsules or tablets containing amorphous vidofludimus (previous formulation name: 4SC-101) previously underwent a phase 1 and 2 clinical development program. The clinical efficacy and safety profile of vidofludimus (free acid) were analyzed in clinical studies in healthy volunteers [ 4 ] and patients suffering from rheumatoid arthritis [ 11 , 12 ] and Crohn’s disease and ulcerative colitis [ 4 ]. Single doses up to 350 mg and multiple doses up to 70 mg for 14 days have been tested in healthy volunteers.…”

“…Single doses up to 350 mg and multiple doses up to 70 mg for 14 days have been tested in healthy volunteers. Patients with rheumatoid arthritis, Crohn’s disease and ulcerative colitis have been exposed to daily doses of 20 or 35 mg vidofludimus with individual treatment durations of 12–13 weeks [ 4 , 11 , 12 ]. An in-depth analysis of the whole clinical database has demonstrated that vidofludimus free acid at daily doses < 70 mg is not associated with an increased rate of clinically relevant adverse reactions.…”

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

“…The oral drug formulation is currently in phase 2 clinical development for autoimmune diseases including multiple sclerosis, ulcerative colitis and primary sclerosing cholangitis. More than 650 individuals have already been treated with IMU-838 or its active moiety, and the safety profile is comparable to the placebo cohort [1][2][3]. Data from the EMPhASIS trial have shown activity of IMU-838 in multiple sclerosis patients who have met the primary and secondary endpoints with high statistical significance [3].…”

Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro

“…Cmp 4 is IM90838 (IMU-838), the Ca 2+ salt of vidofludimus ( Figure 8A), which is currently under testing in phase 2b clinical trials against multiple sclerosis, ulcerative colitis, and primary sclerosing cholangitis. Both vidofludimus and Cmp 4 depend on the same active ingredient in blood (vidofludimus) for their mechanism of action, toxicology, and pharmacology [31].…”