Methods: MTX naïve patients (N=201) with moderate to severe RA were enrolled in this 16 week, multi-center, randomized and double-blind study. Patients received either CH-1504 (0.25mg, 0.5mg or 1.0mg once daily oral doses) or MTX (titrated to 20.0mg once weekly). All patients received a once weekly 10mg folate supplement. Observations were made at 2, 4, 8 and 12 weeks with a treatment free follow-up at 16 weeks. The primary efficacy endpoint of the study was the ACR20 response at week 12. Secondary endpoints included DAS28 scores and the individual components of the ACR20 composite index as well as the safety and tolerability of treatment.
Results: Demographic parameters were similar in the 4 treatment groups with a mean age at enrollment for the entire study population of 54.3 ± 11.4 years, a majority being female (87%) and a mean DAS28 was 6.6 ± 0.9. At week 12 all CH-1504 treatment groups showed comparable efficacy to MTX as measured by ACR20 and DAS28 response rates. This was also seen in the key indicator sub components of the composite index including tender and swollen joints. A dose-response relationship over the dose range tested was not observed in the timeframe of this trial.
20mg 0.25mg 0.5mg 1.0mg
weekly daily daily daily
Patient Number 52 48 48 53
ACR 20 38.5 % 43.8% 39.6% 34.0%
Patients with > 20%
Reduction in SJC 73.1% 70.8% 83.3% 79.2%
Patients with > 20%
Reduction in TJC 65.4% 58.3% 62.5% 71.7%
Mean change in
DAS28 - 1.4 - 1. 0 -1.2 -1.1
% Patients with ALT (>1 X ULN) 13.5 4.2 6.3 7.5
% Patients with GI related AEs 5.8 2.1 4.2 3.8
% Patents withdrawn for GI AEs 3.8 0 0 0
CH-1504 appeared safe and well tolerated at all dose levels. Adverse events (AEs) were generally mild in all arms of the study. The % of patients with serum ALT elevations above 1X upper limit of normal was lower at all doses of CH-1504 compared to MTX. The % of patients with, and dropouts because of, GI related AEs were lower at all doses of CH-1504 compared to MTX.
Conclusions: This 16 week proof-of-concept study in MTX-naïve RA patients demonstrated that CH-1504 has comparable efficacy to MTX and may be safer and better tolerated. Metabolically inert antifolates are a promising therapeutic option and warrant further study.
Disclosure: E. C. Keystone, Independant, 5 ; L. A. Hewitt, Chelsea Therapeutics, 3 ; L. S. Simon, Independant, 5 ; V. Shirinsky, Institute of Clinical Immunology RAMS, 5 ; S. Pedder, chelsea therapeutics, 3 .