Morning administration of the new cathepsin k inhibitor, ONO-5334, causes greater suppression of bone resorption markers compared with evening administration

Bone resorption is highest at night, thus it would seem preferable to administer anti-resorptive drugs in the evening. Evening administration of the cathepsin K inhibitor, ONO-5334, has been shown to increase BMD at least comparably to alendronate in patients with osteoporosis in the Phase II OCEAN study.This study was designed to investigate the effects of morning (M) (8am) versus evening (E) (8pm) dosing of multiple doses of 150 mg ONO-5334 on bone resorption markers in healthy post-menopausal women. The study had a randomized, single-blind, 2 period crossover design. Subjects were randomised to 1 of 2 different dosing sequences, either to E active dose in the first period and M active dose in the second period, or to M active dose in the first period and E active dose in the second period. Subjects received 2 doses per day (one active, one placebo). There was at least 10 days washout between periods. All subjects were dosed in the fed condition 30 minutes after a standard meal. 14 subjects were enrolled and 11 subjects completed and were eligible for the per protocol set. There was a marked difference in effect between M and E administration on the serum CTX profile across 24h (time-matched against individual's own D-1 24h baseline), Figure 1. Although E administration showed a larger suppressive effect this appeared less sustained. M dosing showed a more consistent suppressive effect across 24h. Summarising over the whole 24h using area under the curve (AUC) analysis, the effect appeared to be of a lesser magnitude although significant differences were still observed. M dosing achieved a 5.9 % greater suppression of serum CTX (24h AUC) compared with E dosing (p<0.05) (LS means % change from baseline (CFB), M=68.8% and E=62.9%). With urine CTX/Cr (24h AUC), M dosing showed 6.8% greater suppression compared with E dosing (p<0.01) (LS means %CFB, M=92.6% and E=85.8%). Whether suppressing CTX levels consistently for longer across 24h is clinically meaningful compared to a shorter but equally or more potent suppression with a once daily regimen remains to be proven with ONO-5334. The study highlights that time of administration may be important when administering ONO-5334 (at least at 150mg) and this may be PK related. E administration of ONO-5334 has been shown to significantly improve BMD. It remains to be seen whether M administration would show increased efficacy (on BMD) and whether the M vs E effect is observed with higher doses of ONO-5334.