ono-5334 and Osteoporosis--Postmenopausal

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

Topics: Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Bone Resorption; Cathepsin K; Clinical Trials as Topic; Drug Evaluation, Preclinical; Female; Humans; Osteoclasts; Osteoporosis, Postmenopausal; Thiazolidines

Cathepsin K is the protease that is primarily responsible for the degradation of bone matrix by osteoclasts. Inhibitors of cathepsin K are in development for treatment of osteoporosis. Currently available antiresorptive drugs interfere with osteoclast function. They inhibit both bone resorption and formation, due to the coupling between these processes. Cathepsin K inhibitors, conversely, target the resorption process itself and may not interfere with osteoclast stimulation of bone formation. In fact, when cathepsin K is absent or inhibited in mice, rabbits, or monkeys, bone formation is maintained or increased. In humans, inhibition of cathepsin K is associated with sustained reductions in bone resorption markers but with smaller and transient reductions in bone formation markers. The usefulness of cathepsin K inhibitors in osteoporosis is now being examined in phase 2 and phase 3 clinical trials of postmenopausal osteoporotic women.

Topics: Alkaline Phosphatase; Animals; Biphenyl Compounds; Bone Density; Bone Remodeling; Bone Resorption; Cathepsin K; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Thiazolidines

ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain.. Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study.. The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study.. The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334.. The registration number in The European Union Clinical Trials Register is 2007-002417-39 . The date of registration was August 31, 2007.

Topics: Aged; Bone Density; Bone Density Conservation Agents; Cathepsin K; Double-Blind Method; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Thiazolidines; Treatment Outcome

The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration.. Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration.. This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study.. Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern.. Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.. ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Topics: Aged; Biomarkers; Bone Density Conservation Agents; Bone Resorption; Cathepsin K; Circadian Clocks; Collagen Type I; Cross-Over Studies; Drug Administration Schedule; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Peptides; Postmenopause; Single-Blind Method; Thiazolidines

Cathepsin K inhibitors, such as ONO-5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24-month treatment with ONO-5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001). ONO-5334 300 mg significantly suppressed the bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO-5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO-5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation.

Topics: Aged; Alendronate; Biomarkers; Bone Density; Bone Density Conservation Agents; Bone Resorption; Cathepsin K; Double-Blind Method; Female; Humans; Male; Middle Aged; Osteogenesis; Osteoporosis, Postmenopausal; Thiazolidines; Time Factors

ONO-5334 (Ono Pharmaceutical Co., Ltd., Osaka, Japan) inhibits cathepsin K and has been shown to increase areal bone mineral density (BMD) at the hip and spine in postmenopausal osteoporosis. Quantitative computed tomography (QCT) allows the study of the cortical and trabecular bone separately and provides structural information such as cortical thickness. We investigated the impact of 2 years of cathepsin K inhibition on these different bone compartments with ONO-5334. The clinical study was a randomized, double-blind, placebo, and active controlled parallel group study conducted in 13 centers in six European countries. The original study period of 12 months was extended by another 12 months. A total of 147 subjects (age 55-75 years) of the QCT substudy who participated in the extension period were included. Subjects had been randomized into one of five treatment arms: placebo; ONO-5334 50 mg twice per day (BID); ONO-5334 100 mg once daily (QD); ONO-5334 300 mg QD; or alendronate 70 mg once weekly (QW). QCT was obtained to evaluate bone structure at the lumbar spine and proximal femur. After 24 months ONO-5334 showed statistically significant increases versus placebo for integral, trabecular, and cortical BMD at the spine and the hip (for ONO-5334 300 mg QD, BMD increases were 10.5%, 7.1%, and 13.4% for integral, cortical, and trabecular BMD at the spine, respectively, and 6.2%, 3.4%, and 14.6% for integral, cortical, and trabecular total femur BMD, respectively). Changes in cortical and trabecular BMD in the spine and hip were similar for alendronate as for ONO-5334. Integral volume did not demonstrate statistically significant changes under ONO-5334 treatment, thus there was no evidence of periosteal apposition, neither at the spine nor at the femur. Cortical thickness changes were not statistically significant for ONO-5334 in the spine and hip, with exception of a 2.1% increase after month 24 in the intertrochanter for ONO-5334 300 mg QD. Over 2 years ONO-5334 showed a statistically significant and persistent increase of trabecular and integral BMD at the spine and the hip. Cortical BMD also progressively increased but at a lower rate. Changes in bone size and of periosteal apposition were not observed.

Topics: Absorptiometry, Photon; Aged; Bone Density; Cathepsin K; Double-Blind Method; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Placebos; Thiazolidines; Tomography, X-Ray Computed

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers).

Topics: Aged; Bone Density; Bone Density Conservation Agents; Cathepsin K; Computer Simulation; Dose-Response Relationship, Drug; Female; Humans; Middle Aged; Models, Biological; Osteoporosis, Postmenopausal; Thiazolidines

Selective inhibitors of cathepsin K, which has a major role in the degradation of bone collagen, are potential new treatments for osteoporosis. The pharmacokinetics and the pharmacodynamic effects on biochemical markers of bone turnover of the new cathepsin K inhibitor, ONO-5334, were investigated in a multiple ascending dose, phase 1 study. A total of 120 healthy postmenopausal women were enrolled, and doses of 10 to 600 mg once daily and 50 and 300 mg twice daily were evaluated in 15- and 28-day multiple-dosing cohorts. Plasma ONO-5334 concentration reached steady state within 2 days. Twenty-four hours after the last dose in the 15-day multiple-dose cohort, 100, 300, and 600 mg once daily reduced urinary C-terminal telopeptide of type I collagen by a mean (± standard deviation) 44.9% ± 13.6%, 84.5% ± 4.4%, and 92.5% ± 1.3%, respectively. The 28-day cohort showed similar effects. There were far smaller effects on bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRAP5b), or osteocalcin (OC) (measured after 28 days). ONO-5334 was well tolerated up to 600 mg/d and for up to 28 days of multiple dosing. Multiple dosing with ONO-5334 100 mg resulted in considerable suppression of bone resorption markers with no appreciable effects on bone formation markers (B-ALP, OC) or osteoclast number (TRAP5b).

Topics: Area Under Curve; Biomarkers; Bone Density; Bone Density Conservation Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Humans; Middle Aged; Osteoporosis, Postmenopausal; Thiazolidines

To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO-5334.. A double-blind, placebo-controlled, randomized study was carried out in 52 healthy post menopausal females. Single ascending doses of ONO-5334 (3-600 mg) were evaluated in six cohorts. The effect of food was studied at ONO-5334 100 mg.. Across the doses tested, mean ONO-5334 C(max) occurred 0.5-1.0 h after dosing and the the t(1/2) ranged from 9.1 to 22 h. Linear increases in C(max) and AUC(0,∞) were observed in the 3-300 mg and 3-600 mg dose range, respectively. After food, the geometric mean ratio (95% CI) C(max) and AUC(0,∞) for ONO-5334 were 0.78 (0.31, 1.94) and 0.95 (0.67, 1.35)-fold greater than fasted, respectively. ONO-5334 significantly reduced serum bone resorption markers within 4 h vs. placebo. Statistical significance was achieved for ONO-5334 doses ≥30 mg for C-terminal telopeptide of type 1 collagen (CTX) and ≥300 mg for N-terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24 h for ONO-5334 100 mg with serum CTX and 600 mg with serum NTX. The maximum suppression in serum CTX occurred at 4 h post dose with difference compared with placebo of -32%, -59%, -60% and -66% for 30, 100, 300 and 600 mg ONO-5334, respectively. Second morning urine void 24 h post dose showed statistically significant suppression of urinary CTX and NTX at 100 mg and above vs. placebo. ONO-5334 600 mg showed statistically significant suppression up to 72 h for serum CTX, urinary CTX and urinary NTX and 48 h for serum NTX vs. placebo. Adverse events were transient with no evidence of dose relationship.. ONO-5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3-300 mg, with clear suppression of urinary bone resorption markers at doses ≥100 mg for serum markers at 24 h. ONO-5334 was well tolerated up to 600 mg day(-1) when administered to healthy post menopausal women.

Topics: Administration, Oral; Aged; Area Under Curve; Biomarkers; Bone Resorption; Cathepsin K; Collagen Type I; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Peptides; Postmenopause; Thiazolidines

Osteoporosis occurs when there is an imbalance between resorption and formation of bone, with resorption predominating. Inhibitors of cathepsin K may rebalance this condition. This is the first efficacy study of a new cathepsin K inhibitor, ONO-5334. The objective of the study was to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double-blind, placebo- and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Subjects included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment arms: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70 mg once weekly. Lumbar spine, total hip, and femoral neck BMD values were obtained along with biochemical markers of bone turnover and standard safety assessments. All ONO-5334 doses and alendronate showed a significant increase in BMD for lumbar spine, total hip (except 100 mg once daily), and femoral neck BMD. There was little or no suppression of ONO-5334 on bone-formation markers compared with alendronate, although the suppressive effects on bone-resorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. Further clinical studies are warranted to investigate long-term efficacy as well as safety of ONO-5334.

Topics: Biomarkers; Bone Density; Bone Remodeling; Cathepsin K; Demography; Enzyme Inhibitors; Female; Humans; Osteoporosis, Postmenopausal; Thiazolidines; Treatment Outcome