Osteoporos Int (2016) 27:309–318 DOI 10.1007/s00198-015-3342-4 ORIGINAL ARTICLE Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial R. Eastell1,5 & D.-J. Dijk2 & M. Small3 & A. Greenwood2 & J. Sharpe3 & H. Yamada3 & M. Yuba4 & M. Tanimoto4 & S. Deacon3 Received: 19 May 2015 /Accepted: 24 September 2015 /Published online: 7 October 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract period and morning doses in the second or vice versa. Serum and Summary The cathepsin K inhibitor, ONO-5334, improves urinary levels of CTX-I were measured throughout the study. bone mineral density in postmenopausal women with osteopo- Results Both regimens showed similar patterns of reduction in rosis. The effects of morning versus evening administration of serum and urinary CTX-I; however, CTX-I suppression was more ONO-5334 were investigated by measuring bone turnover consistently >60% over 24 h following morning administration. marker levels in healthy postmenopausal women. Morning Morning administration led to 6% greater suppression of 24-h administration of ONO-5334 showed a more consistent sup- serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < pressive effect on bone resorption than evening administration. .05) and 7% greater suppression of urinary CTX-I/creatinine AUE Introduction Bone turnover is thought to be subject to circa- (93 vs 86%; P < .01) than evening administration. Higher plasma dian variation, and the efficacy of osteoporosis treatments may ONO-5334 concentrations were observed between 12 and 24 h be optimized by regulating the time of dosing. This study postdose following morning administration, with mean trough assessed whether evening administration of the cathepsin K concentrations for the morning and evening regimens at 9.4 and inhibitor, ONO-5334, had a differential effect on the bone 4.0 ng/mL, respectively. There were no safety findings of concern. turnover marker, C-terminal telopeptide of type I collagen Conclusion Morning dosing of ONO-5334 is more effica- (CTX-I), compared with morning administration. cious at reducing markers of bone turnover in healthy post- Methods This was a single-center, single blind crossover study. menopausal women than evening dosing. Fourteen healthy postmenopausal women were assigned to re- Trial registration ClinicalTrials.gov: NCT01384188, ceive ONO-5334 150 mg once daily for 5 days in each period; registered on June 27, 2011 they were randomized to receive either evening doses in the first EudraCT: 2008-006284-37 Electronic supplementary material The online version of this article (doi:10.1007/s00198-015-3342-4) contains supplementary material, Keywords Anti-resorptive . Bone resorption . Menopause . which is available to authorized users. Osteoporosis * R. Eastell [email protected] Abbreviations AUC24h Area under the concentration–time curve during 1 Academic Unit of Bone Metabolism, University of Sheffield, the dosing interval Sheffield, UK AUE Area under the effect curve 2 Surrey Clinical Research Centre, University of Surrey, BMD Bone mineral density Guildford, UK Cmax Maximum observed concentration 3 Ono Pharma UK Ltd, London, UK CTX-I C-terminal telopeptide of type I collagen 4 OnoPharmaceuticalCo.,Ltd,Osaka,Japan IRT Immediate-release tablet 5 Metabolic Bone Centre, Northern General Hospital, Herries Road, SRT Sustained-release tablet Sheffield, South Yorkshire S5 7AU, UK Tmax Time to maximum plasma concentration 310 Osteoporos Int (2016) 27:309–318 Introduction be of little value; however, ONO-5334 is intended as a once- daily medication Osteoporosis mainly arises in postmenopausal women and This study investigated healthy postmenopausal women as a affects >10 million people in the USA; the incidence is set representative potential patient population with similar predom- to increase as the population ages [1]. Osteoporosis is charac- inant features of gender, age and hormonal milieu of patients terized by low bone mass disordered bone architecture, lead- with osteoporosis, without the attendant concomitant treatments ing to an increased risk of vertebral and other fractures. that might confound the results. The aim of this randomized, Osteoporosis is associated with significant morbidity, and single blind, two-part crossover study was to investigate the hip fractures as sequelae confer a 1-year mortality risk of effects of morning versus evening administration on the phar- 8.4–36% primarily due to thromboembolic events [1]. macokinetics and pharmacodynamics of multiple doses of An important contributory factor to low bone mass in oste- ONO-5334 150-mg SRT in healthy postmenopausal women. oporosis is increased bone resorption. Antiresorptive drugs such as the bisphosphonates reduce bone resorption and are the current drug class of choice for the prevention of fractures Methods in patients with osteoporosis [2]. However, bisphosphonates are not well tolerated by many patients, may cause abdominal Study population discomfort or dyspepsia and are difficult to administer. Furthermore, chronic bisphosphonate therapy may enhance Healthy female subjects aged 55–75 years with a body mass the risk of atypical femur fractures, although the overall inci- index of 19–30 kg/m2 were enrolled. Subjects had been amen- dence of fractures is reduced [3]. Hence, there is a need to orrheic for ≥5 years and had follicle-stimulating hormone >30 develop novel, safe and efficacious treatments for osteoporosis. IU/L and estrogen <92 pmol/L. Subjects had a sleep history Cathepsin K inhibitors including odanacatib [4] and ONO- (for ≥1 month before screening) of regular bedtime and sleep 5334 are a new class of drugs against osteoporosis which are duration, did not awake more than twice nightly for micturi- undergoing clinical development. ONO-5334 improved bone tion, had no habit of daytime naps >1 h and experienced no strength by preferentially increasing cortical bone mass in sleep complaint as determined by a Pittsburgh Sleep Quality ovariectomized rats [5] and significantly improved cortical Index (PSQI) [17] score of >5. Subjects were in good health at and trabecular bone mineral density (BMD) in postmenopausal both screening visits between 41 and 10 days before the first women with osteoporosis following 24 months of therapy [6]. dose. In healthy postmenopausal women, ONO-5334 100 mg To minimize possible confounding factors of exercise and sustained-release tablet (SRT) administered in the morning ex- sleep/wake (circadian) on bone turnover, exercise was restrict- hibited a median time to maximum plasma concentration (Tmax) ed, and a regular sleep/wake cycle was scheduled. Subjects of 4 h and mean half-life of 15 h following repeat administra- maintained bedtime at 22:30 and wake-up time at 06:30 tion [7, 8], suggesting the feasibility of once-daily dosing. throughout the study period. This applied at home from the Serum and urinary bone turnover markers such as C- second screening visit until admission to the clinical unit and terminal telopeptide of type I collagen (CTX-I) peak in the during the entire 10-day residential period. A subjective sleep early morning hours and reach nadir in the afternoon, demon- diary incorporating the Karolinska Sleepiness Scale [18]and strating that bone resorption is highest at night in healthy and actigraphy (as monitored by Actiwatch AW4; Cambridge osteoporotic postmenopausal women [9–13]. Neurotechnology, Cambridge, UK) confirmed compliance to Thus, evening administration of antiresorptive drugs such the sleep/wake schedule and limited exercise regimen. as ONO-5334, in contrast to the more conventional morning Informed consent was obtained from all individual partic- administration, is of interest because plasma drug levels may ipants included in the study. The study was approved by a be higher at the time when bone resorption is greatest. local review board (London Westminster Research Ethics The influence of administration time of anti-osteoporosis Committee) and conducted in accordance with the drugs on efficacy varies. For instance, Blumsohn and co- Declaration of Helsinki and Good Clinical Practice guidelines. workers [14] administered elemental calcium 1000 mg at bed- time, which suppressed nighttime increases of bone resorption Study design and reduced 24 h of excretion of bone resorption markers in premenopausal women, whereas morning administration had This was a randomized, single blind, single center, two-period no effect. In addition, Karsdal and coworkers [15, 16]showed crossover study (protocol: ONO-5334POE010; that oral calcitonin given between 17:00 and 22:00 exerted ClinicalTrials.gov: NCT01384188) between June and greater reductions of bone turnover markers compared with December 2011 at the Surrey Clinical Research Centre, with administration at 08:00. Odanacatib is administered once recruitment and initial screening performed at another site. weekly, so the effects of administration time on efficacy would Subjects received a single dose of oral ONO-5334 150-mg Osteoporos Int (2016) 27:309–318 311 SRT (Ono Pharmaceutical Co, Ltd, Osaka, Japan) once-daily CrossLaps ELISA; Immunodiagnostic Systems, Boldon, for 5 days in each treatment period. UK). Baseline serum samples for CTX-I were taken via an Subjects were randomly assigned to receive evening ONO- intravenous cannula on day −1 for the morning dosing period 5334 administration in the first period and morning adminis- at 08:00,