Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotrexate on Collagen-Induced Arthritis in Cynomolgus Monkeys

Abstract

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.

Cathepsin K: The Action in and Beyond Bone

“…Inhibition of CatK could suppress the cartilage degradation as well as the systemic and local bone loss to prevent joint destruction in preclinical RA models. Skoumal et al, 2005;Asagiri et al, 2008;Svelander et al, 2009;Hao et al, 2015;Yamashita et al, 2018;Yamada et al, 2019…”

“…By genetic approach, it was found that CatK deficiency largely prevented the cartilage erosion and bone destruction and reduced the joint inflammation in mice with TNF-α-mediated arthritis (Hao et al, 2015). By pharmacological approach, several preclinical studies concordantly showed that inhibition of CatK could suppress the cartilage degradation as well as the systemic and local bone loss to prevent joint destruction in preclinical RA models (Asagiri et al, 2008;Svelander et al, 2009;Yamashita et al, 2018;Yamada et al, 2019). Interestingly, the efficacy of CatK inhibition on joint inflammation are contradictory among these studies.…”

Recent advances in developing small-molecule inhibitors against SARS-CoV-2

“…9 ( 78 ‒ 81 )], were effective against SARS-CoV-2 infection with IC 50 s of 0.023, 0.22, 0.19, 0.3 and 0.41 μmol/L, respectively, in Vero E6 cells ( Table 3 ). As reported, MDL-28170, a cathepsin B inhibitor, could impairs infection by SARS-CoV and Ebola virus 192 , 193 , ONO 5334 is a cathepsin K inhibitor 194 , and VBY-825 acts as a reversible cathepsin protease inhibitor 195 . Apilimod, a specific PIKfyve kinase inhibitor, was shown to be effective in inhibiting virus entry, which is in agreement with the report that PIKfyve is predominately presented in early endosomes and plays an important role in maintaining endomembrane homeostasis 196 .…”

Therapeutic Treatments for Osteoporosis—Which Combination of Pills Is the Best among the Bad?

“…So far, several cathepsin K inhibitors were tested in clinical trials, but there is still no approved drug. Balicatib terminated in phase II clinical studies [204,205], ONO-5334 passed clinical studies phase I and II and is still under further investigation [206,207], and Odanacatib, the most promising cathepsin K inhibitor which showed a high therapeutic efficacy, was terminated after a clinical trial phase III study showed adverse side effects in non-bone tissue of the osteoporotic patients [208]. As cathepsins are a family of proteases with functions in a variety of tissues, these findings must be expected when the inhibitors are not specific enough for bone tissue.…”