We examined whether the
cathepsin K inhibitor,
ONO-5334, administered alone or in combination with
methotrexate (MTX), could ameliorate joint destruction evoked by
collagen-induced arthritis (CIA) in female cynomolgus monkeys. CIA was induced by immunizing with bovine
type II collagen.
ONO-5334 (30 mg/kg/day) was orally administered once daily and MTX (10 mg/body/day) twice weekly for 9 weeks. X-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MP) joints were evaluated. Urinary concentrations of
C-terminal telopeptide of type I collagen (CTX-I) and
type II collagen (CTX-II) were measured.
Arthritis, accompanied by bone and cartilage destruction, was successfully induced in this
collagen-induced arthritis monkey model.
ONO-5334 showed no suppressive effect on joint swelling, while the joint swelling scores in the MTX and combination (ONO-5334 + MTX) groups were less than 50% compared with the control group.
ONO-5334 decreased X-ray score by a mean of 64% (p<0.05 vs the control group), and MTX also decreased in X-ray score by a mean of 46% but with no statistical significance. Combination of
ONO-5334 and MTX further decreased the X-ray score by 28% over MTX group (74% reduction vs the control group, p<0.01). Maximum increase in CTX-I (10-fold) and CTX-II (7-fold) compared to baseline was observed at 7 and 3 weeks after the first sensitization, respectively.
After treatment with
ONO-5334 alone or in combination with MTX, concentrations were maintained near baseline for both markers. In conclusion,
ONO-5334 prevented joint destruction but not joint
inflammation in this monkey CIA model. Concomitant use of
ONO-5334 with MTX reduced architectural joint destruction compared to MTX alone; therefore,
ONO-5334 may help to prevent joint destruction in combination with MTX for the treatment of
rheumatoid arthritis.