Phase i single and multiple ascending dose studies to investigate the safety, tolerance and pharmacokinetics of CH-4051 in healthy male subjects

Purpose: Methotrexate (MTX) is the gold standard treatment for rheumatoid arthritis. However its use is frequently limited by common side effects including hepatotoxicity, nephrotoxicity, and gastrointestinal distress (nausea and diarrhea). It is hypothesized that a significant proportion of the toxicity profile of MTX is attributed to its hydroxylated and polyglutamylated metabolites. Therefore, an antifolate that is metabolically stable, that does not convert to toxic metabolites, yet maintains the efficacy of MTX should prove to be a superior therapy. CH-4051 is a metabolically stable antifolate and is the more potent “L” isomer of the racemic mixture CH-1504. In a recent double-blind, randomized phase II study in MTX naive RA patients, CH-1504 in the dose range of 0.25 to 1.0 mg QD showed comparable efficacy to MTX and a better safety profile. It is our proposition that CH-4051 will demonstrate superior efficacy and safety to MTX. As such we conducted a phase I study of the safety, tolerance and pharmacokinetics (PK) of single and multiple doses of CH-4051 in a single-center, double-blind, randomized, clinical trial. Method: This study was conducted in accordance with ICH/GCP guidelines by Kendle International Utrecht, The Netherlands following favorable opinions from an Independent Ethics Committee and national Competent Authority. This study consisted of a Single Ascending Dose (SAD) trial followed by a 14 day Multiple Ascending Dose (MAD) trial. In both SAD and MAD portions of the study 4 groups of healthy male volunteers were studied. Six subjects per group in the SAD and 8 subjects per group in the MAD were randomized 5:1 and 6:2 respectively to CH-4051 or placebo p.o. Doses tested were 5, 10, 20 and 40.0 mg in the SAD and 5, 7.5, 10, and 20 mg in the MAD. Subjects remained under clinical supervision for the duration of the dosing and PK collection periods. Dose escalation occurred following a review of the previous group's safety and tolerance data. Safety assessments included: AEs, hematology, serum biochemistry, urinalysis, vital signs, physical examination and ECG. Results: There were no serious AEs in either study; no AE was definitively attributed to CH-4051and all possibly related AEs resolved with cessation of dosing. In the SAD study no AEs led to study discontinuation or major intervention. In the MAD study, 7 AEs in 5 subjects led to study discontinuation at higher doses. These AEs included blepharitis, upper abdominal pain and vomiting, increased ALT and AST, and an unconfirmed case of melena. With respect to PK parameters; Tmax occurred ∼1-2h post dose and T1/2 was approximately 4 h. Cmax increased in a greater than dose proportional manner from 5 to 10 mg and a less than dose proportional manner from 10 to 40 mg. Conclusion: CH-4051 was safe and well tolerated in a single dose up to 40.0 mg and multiple doses up to 7.5 mg daily for 14 days. PK parameters indicate CH-4051 is suitable for daily dosing.