Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Efficacy, Safety and Pharmacokinetics of Vidofludimus, a Novel Oral Immunomodulator, in Patients with Active Rheumatoid Arthritis on Methotrexate Background Therapy: The COMPONENT Study.
Sierakowski1, Stanislaw, Dietrich2, Bruno, Hentsch2, Bernd, Ammendola2, Aldo
Vidofludimus is an oral immunomodulator inhibiting dihydroorotate dehydrogenase (DHODH) and the expression of pro-inflammatory cytokines including interleukin-17 (IL-17A and IL-17F) and INF-gamma. In the presented Phase II COMPONENT study efficacy, safety, and pharmacokinetics of vidofludimus in combination with methotrexate (MTX) has been evaluated in rheumatoid arthritis (RA) patients. Vidofludimus has previously successfully completed a Phase IIa study in inflammatory bowel disease (IBD).
Primary endpoint of this randomized, double-blind, placebo-controlled Phase II study was ACR20 response at week 13. Secondary endpoints included ACR50, ACR70, DAS28, safety and pharmacokinetics. 241 patients were enrolled in two study arms across 28 sites in Eastern Europe. The first arm received 35 mg vidofludimus QD plus MTX over 13 weeks, the second arm received placebo plus MTX. Eligible patients must have had active RA, have received weekly doses of MTX (1025 mg/week) for a minimum of 3 months prior to Day 1 dosing, and a stable MTX dose for at least 6 weeks prior to Day 1 dosing.
ACR20 response improvement of the vidofludimus group compared to placebo was statistically significant (p<0.05) at week 2 (16.7% vs. 6.9%) and week 8 (46.7% vs. 31.9%), but did not reach statistical significance at week 13 (50.0% vs. 44.8%). The vidofludimus group also reported higher ACR50 (25.8% vs. 17.2%) and ACR70 (12.5% vs. 6%) response rates compared to placebo at week 13. DAS28 (CRP) response rate of vidofludimus also was significantly higher compared to placebo at week 4 (55.8% vs. 42.3%). Mean change of CRP (ESR) at week 13 compared to baseline was -1.82 mg/l (-3.98 mm/h) for vidofludimus and 1.38 mg/l (3.18 mm/h) for placebo. Mean changes of RA-specific parameters (joint counts, disease activity, pain, HAQ) were similar in both groups at week 13. In contrast to preclinical interaction studies, a substantial decrease of vidofludimus plasma concentrations below levels detected in earlier clinical trials has been observed with increasing MTX doses.
Vidofludimus was safe and well tolerated. No obvious differences in the adverse event profile between the vidofludimus and placebo group were observed. In particular, there were no relevant increases of diarrhea, neutropenia, anemia, hypertension, cholesterol or liver enzyme levels. Only one serious adverse event was reported in the vidofludimus group which was judged as unlikely drug-related. No deaths occurred. These safety results were consistent with previous clinical trial results in RA and IBD.
Certain efficacy endpoints (ACR20/DAS28) have been statistically significant at specific time points during the treatment period, though vidofludimus missed the primary ACR20 efficacy endpoint of the COMPONENT study at week 13. Decreases in objective inflammatory parameters CRP and ESR strongly support a general anti-inflammatory effect of vidofludimus. These results and the very clean safety profile indicate that a vidofludimus dose of 35 mg QD might be not high enough to show statistically significant results in RA. In addition, the observed drug interaction of vidofludimus with MTX may have hampered the full anti-inflammatory activity of vidofludimus.
To cite this abstract, please use the following information:
Sierakowski, Stanislaw, Dietrich, Bruno, Hentsch, Bernd, Ammendola, Aldo; Efficacy, Safety and Pharmacokinetics of Vidofludimus, a Novel Oral Immunomodulator, in Patients with Active Rheumatoid Arthritis on Methotrexate Background Therapy: The COMPONENT Study. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :397