Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: The OCEAN study

Authors


  • Part of the results reported in this article was published as an abstract presentation by the European Calcified Tissue Society (abstract number OC49, 2010, Glasgow, UK) and by the American Society for Bone and Mineral Research (abstract number 1067, 2010, Toronto, Canada).

Abstract

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. © 2011 American Society for Bone and Mineral Research.

Introduction

The fractures that result from osteoporosis are a major public health problem. There are now effective treatments for reducing fracture risk in osteoporosis. The most commonly used agents are the bisphosphonates. While bisphosphonates have been shown to reduce the risk for vertebral fractures by between 40% and 70%, the reduction for nonvertebral fractures is significantly less compared with placebo.1 In a meta-analysis based on key regulatory trials, the estimated risk-reduction values for nonvertebral fractures were 0.86 [95% confidence interval (CI) 0.76–0.97] for alendronate and 0.81 (95% CI 0.71–0.92) for risedronate, respectively,2 indicating that the magnitude of nonvertebral fracture risk-reduction with bisphosphonates is close to 20%. Recent studies with intravenous zoledronic acid and subcutaneous denosumab yielded similar reductions. In the HORIZON-PFT and FREEDOM trials, zoledronic acid and denosumab reduced nonvertebral fracture risk by 25% and 20%, respectively.3, 4 Furthermore, there is concern that by decreasing bone turnover for many years, there may be complications such as atypical fractures of the femur.1 It has been proposed that there may be approaches to inhibiting osteoclast activity but not reducing osteoclast number that might allow bone formation to be unaffected by the treatment.5 There are a number of key enzymes that may be suitable targets for osteoporosis therapy, including cathepsin K.6

Cathepsin K is a member of the papain cysteine proteinase superfamily7 and has a critical role in the bone-resorption process. Cathepsin K is the most highly expressed cysteine protease in osteoclasts and is excreted into resorption lacunae beneath the ruffled border of the osteoclast, where it degrades the organic matrix of bone. Major organic components of bone and cartilage, including collagen types 1 and 2, are degraded by cathepsin K under acidic conditions. Peptides of cathepsin K–mediated type 1 collagen degradation, C-terminal telopeptide of type 1 collagen (CTX-1), and N-terminal telopeptide of type 1 collagen (NTX) have been used as biochemical markers in order to assess bone-resorption status and efficacy of medications in bone metabolic diseases.8 Humans lacking cathepsin K owing to an inherited mutation of the gene exhibit pycnodysostosis, which is characterized by abnormally dense bones (osteosclerosis).9 Cathepsin K–deficient mice show osteopetrosis and display features characteristic of pycnodysostosis.10, 11 Specific inhibition of cathepsin K therefore has been a new drug target for diseases that have elevated bone resorption, such as osteoporosis.

Although no cathepsin K inhibitor is currently marketed, some cathepsin K inhibitors, including balicatib, relacatib, and odanacatib, have been developed for the indication of osteoporosis or bone metastasis. Efficacy on bone mineral density (BMD) in postmenopausal women with low bone density has been demonstrated with balicatib12 and odanacatib.13 Balicatib is no longer in clinical development.

ONO-5334 (Ono Pharmaceutical Company, Ltd.; N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-[(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide]) is a low-molecular-weight synthetic inhibitor of cathepsin K and is being developed as a therapeutic agent for bone metabolic diseases including osteoporosis. ONO-5334 has shown potent and selective inhibition of cathepsin K in vitro14–16 and has shown improvement in both BMD and bone strength in the ovariectomized monkey osteoporosis model.17, 18 Potent suppression with ONO-5334 on biochemical markers of bone resorption has been observed in a healthy postmenopausal female phase I study.19 Here we report the first proof-of-concept study for ONO-5334 to investigate efficacy and safety of ONO-5334 in postmenopausal women with osteoporosis (OCEAN study: ONO-5334 cathepsin K inhibitor European study). The primary objective of the study was to compare the percentage change in BMD of the lumbar spine between baseline and month 12 following treatment with ONO-5334 and placebo. A key feature of the study design was to include an active reference, the bisphosphonate alendronate, currently the most commonly used agent for the management of osteoporosis. Although the study was not powered to compare differences between ONO-5334 and alendronate (only versus placebo), it does provide the first opportunity to see how a cathepsin K inhibitor may compare with current standard drug therapy.

Materials and Methods

Study subjects

This study was conducted in postmenopausal women aged 55 to 75 years old with osteoporosis. Postmenopausal was defined as more than 5 years after menopause and with estradiol less than 92 pmol/L and follicle-stimulating hormone (FSH) greater than 30 IU/L. Subjects were diagnosed using BMD T-score. Osteoporosis was defined as a T-score of −2.5 or less, and osteopenia was defined as a T-score of less than −1 and greater than −2.5 at the lumbar spine (LS) or total hip.

Subjects with a T-score of less than −3.5 were excluded from the study for safety reasons because it was not considered acceptable to include such individuals in a placebo-controlled early-phase trial. Osteoporosis patients who had any vertebral fragility fractures between T4 and L4 of the spine, osteopenia patients with two or more vertebral fragility fractures between T4 and L4, and any subjects who had experienced nonvertebral fragility fractures after age 50 also were excluded. Osteopenia subjects who had no vertebral fragility fractures between T4 and L4 and subjects with low bone turnover defined as urinary CTX-1 below 200 µg/mmol of creatinine (Cr) also were excluded. Thus we defined postmenopausal women with osteoporosis as an osteopenic BMD plus a fragility fracture or an osteoporotic BMD without a fragility fracture. We excluded subjects with low bone resorption because in previous studies with antiresorptive drugs, such as alendronate and denosumab, low bone resorption was associated with a smaller BMD response.20 The effect of such an exclusion would be greater increases in BMD for both alendronate and ONO-5334, but the relative change should not differ.

This study was conducted at 13 study sites in 6 European countries and was conducted in accordance with applicable regulations and International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and local legal requirements. All subjects gave written informed consent, and the study was approved by the appropriate ethics committees and regulatory authorities.

Study design

This study was designed as a multicenter, randomized, double-blind, placebo- and active-controlled parallel-group study. The study consisted of two phases including a 2- to 6-week screening phase and a 12-month treatment phase. Subjects were invited to the study unit every 3 months during the 12 months of the treatment phase, although an additional visit was arranged at month 1.5 to ensure adequate initial safety monitoring. Subjects were randomized into one of five treatment arms, including placebo, ONO-5334 50 mg twice daily, 100 mg once daily, 300 mg once daily, and alendronate 70 mg once weekly. ONO-5334 300 mg once daily was chosen because phase I data suggested that 300 mg or higher of ONO-5334 showed maximum suppressive effect in both serum and urinary CTX-1, and 300 mg of ONO-5334 maintained its suppressive effect on serum CTX-1 for 24 hours after administration.19 The ONO-5334 dose 100 mg once daily was added to allow evaluation of dose response. Fifty milligrams twice daily was chosen to compare the efficacy and safety profile of two different dose regimens (with 100 mg total daily dose) because the outcome may have suggested possible development of a sustained-release formulation.

Randomization was stratified by the following study-balancing factors: study site, diagnosis (osteopenia plus a fragility fracture or osteoporosis), and urinary CTX-1 (below/above 300 µg/mmol Cr). ONO-5334 can be classified as an anti-bone-resorption medication and, therefore, there was the possibility of a difference in the magnitude of efficacy on BMD based on pretreatment bone turnover level. Therefore, subjects with low bone turnover, defined as a urinary CTX-1 below 200 µg/mmol Cr, were excluded, as well as having urinary CTX-1 (below/above 300 µg/mmol Cr) as one of the stratifying factors. Urinary CTX-1 levels of 200 and 300 µg/mmol Cr were considered to be the mean of healthy premenopausal and postmenopausal female population, respectively.21, 22

Daily medication, ONO-5334 or matching placebo, was given in the morning and the evening owing to one of the treatment arms being a twice daily regimen. The subjects were instructed to take the morning dose after breakfast and the evening dose at anytime before bed. Active treatment of ONO-5334 once daily was given as an evening dose. Alendronate 70 mg and its matching placebo was given once weekly.

All subjects received daily supplemental calcium (at least 500 mg a day) and vitamin D (at least 400 IU a day) throughout the study, including the screening period.

BMD was measured using GE Lunar Prodigy dual-energy X-ray absorptiometry (DXA) equipment (GE Lunar, Madison, WI, USA). DXA images obtained at study sites were sent to a central analysis unit for image analysis (Synarc A/S, Zweigniederlassung, Hamburg, Germany). LS (L1–L4), total hip, and femoral neck BMD values were obtained at baseline and at months 3, 6, and 12.

Bone-resorption markers urinary NTX (Osteomark NTX Diagnostic Kit; Osteometrics, Decatur, GA, USA), serum and urinary CTX-1 (Serum and Urine CrossLaps ELISA, Immunodiagnostic Systems Ltd, Boldon, UK), and urinary free deoxypyridinoline (fDPD; ELISA) were assessed during the study. Serum bone-specific alkaline phosphatase (B-ALP; Metra BAP Immunoassay Kit, Quidel, San Diego, CA, USA), serum osteocalcin (OC; Metra Osteocalcin EIA Kit), and procollagen type 1 intact N-terminal propeptide (P1NP; Orion Diagnostica UniQ P1NP RIA, Espoo, Finland) were assessed as bone-formation markers. Serum C-terminal cross-linked telopeptide of type 1 collagen (1-CTP; Orion Diagnostica UniQ ICTP EIA), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b; METRA TRACP-5b Enzyme Immunoassay, Quidel), C-terminal telopeptide of type 2 collagen (CTX-2; Urine CartiLaps ELISA, Immunodiagnostic Systems Ltd) also were assessed. Bone turnover markers were assessed at screening, baseline, and months 1.5, 3, 6, 9, and 12. Assays were performed centrally (Charles River Laboratories, Edinburgh, UK).

Standard safety assessments, including adverse event (AE) monitoring, physical examination, 12-lead electrocardiogram (Clearstone Central Laboratories, Baillet en France, France), vital signs, hematology, biochemistry, and urinalysis, were performed throughout the study.

Statistical analysis

The primary efficacy variable for the study was the mean lumbar spine BMD. The primary analysis was based on the percentage change from baseline at month 12 and was performed on the full-analysis-set (FAS) population using a final on-therapy [last observation carried forward (LOCF)] approach to account for patients who withdrew prematurely from the study. Seven patients were excluded from the FAS population because they had no posttreatment BMD data owing to premature withdrawal. Each dose of ONO-5334 and alendronate was compared with placebo using an analysis of covariance (ANCOVA) with treatment group and country as factors in the model. Baseline values for age, body mass index (BMI), LS BMD, and urinary CTX-1 were used as covariates. Total hip and femoral neck BMD were key secondary endpoints and were analyzed using a similar ANCOVA model. BMD data are shown as mean ± standard error in this article.

ANCOVA was performed on the change from baseline in log-tranformed values for each of the bone turnover markers on the FAS population using LOCF data. Changes in bone turnover markers were expressed as a ratio of geometric means compared with placebo. Urinary markers are presented relative to creatinine. The baseline value of each marker was fitted as a covariate in addition to those factors fitted in the model used for the primary analysis.

With a sample size of 42 patients in each group, the study had 95% power to detect a difference of 4.0% between ONO-5334 and placebo in BMD at month 12, assuming that the standard deviation was 5.0% using a two-group t test with a 5% two-sided significance level. Because this is an exploratory study, no adjustment has been made to control the type 1 error for multiple treatment groups of ONO-5334.

The steering committee (SC), consisting of investigators (RE, SB, and TS) who were not employees of the study sponsor, oversaw the execution of the protocol and planned the analyses for the study before unblinding of the study-drug assignments. The committee members approved the manuscript for publication and vouch for the completeness and accuracy of the data. The data were transferred to the first author (RE) and the analyses checked. The sponsor was involved in the design, conduct, analysis, and reporting of the study. The authors employed by the sponsor and the medical advisor (JS) were specifically involved in the design, data review, analysis, and interpretation of the study and in the writing of the article. There was an independent data monitoring committee (DMC) that oversaw the safety of the subjects by reviewing the safety data on a regular basis throughout the study. The DMC reported to the SC.

Results

Patient disposition

A total of 928 patients were screened, and 285 patients were randomized (Fig. 1). The most frequent reasons for screening failure were osteopenia with no vertebral fracture (191 subjects), low urinary CTX-1 (149 subjects), and osteoporosis with one or more vertebral fractures (103 subjects).

Figure 1.

Patient allocation. bid = twice daily; qd = once daily; qw = once weekly.

Premature discontinuation occurred for no more than 11 patients (19.3%) in each group, with the greatest number of discontinued patients in the ONO-5334 50-mg twice daily group and the fewest in the alendronate group (5 patients, 8.8%). The most frequent reason for premature discontinuation was due to an AE/serious AE, affecting the greatest number of patients in the ONO-5334 50 mg twice daily group [2 (3.5%), 8 (14.0%), 2 (3.5%), 5 (8.8%), and 3 (5.3%) patients in the placebo, 50 mg twice daily, 100 mg once daily, and 300 mg once daily of ONO-5334 and of alendronate groups, respectively].

Demographics and baseline characteristics

Demographic and baseline characteristics of the FAS population are summarized in Table 1. Patients randomized were all white. There was no clinically relevant difference across the five treatment arms in any demographic or baseline characteristics.

Table 1. Demographics and Baseline Characteristics of the Study Population
 PlaceboONO-5334ONO-5334ONO-5334Alendronate
50 mg twice daily100 mg once daily300 mg once daily70 mg once weekly
n5753565557
Age (years)     
 Mean65.065.365.764.665.7
 SD4.295.125.035.204.39
Investigator's diagnosis (n, %)     
 Osteopenia10 (17.5)10 (18.9)10 (17.9)8 (14.5)10 (17.5)
 Osteoporosis47 (82.5)43 (81.1)46 (82.1)47 (85.5)47 (82.5)
BMI (kg/m2)     
 Mean25.225.525.626.125.4
 SD3.512.714.204.173.58
LS BMD (g/cm2)     
 Mean0.860.860.870.870.86
 SD0.0680.0560.0980.0820.060
Total hip BMD (g/cm2)     
 Mean0.800.820.790.820.82
 SD0.0940.0760.0790.0880.090
Urinary CTX-1 (µg/mmol creatinine)     
 Mean316285277301301
 SD150.4124.090.5131.0139.4

Efficacy Results

Treatment compliance (by pill counting) for ONO-5334 or its placebo was 94%, 92%, 94%, 94%, and 94% for the placebo, 50 mg twice daily, 100 mg once daily, and 300 mg once daily of ONO-5334 and of alendronate groups, respectively. Treatment compliance for alendronate or its placebo also was calculated as 97%, 96%, 97%, 97%, and 96% for the placebo, 50 mg twice daily, 100 mg once daily, and 300 mg once daily of ONO-5334 and of alendronate groups, respectively.

Bone mineral density

The primary analysis, percentage change from baseline at month 12 in LS BMD with ONO-5334 compared with placebo, showed a significant increase in LS BMD with all ONO-5334 doses (Fig. 2). LS BMD increased by 3.7% ± 0.50%, 3.1% ± 0.48%, and 5.1% ± 0.49% with ONO-5334 50 mg twice daily, 100 mg once daily, and 300 mg once daily, respectively, versus 0.6% ± 0.48% for placebo. Alendronate also significantly increased LS BMD (5.2% ± 0.48%) compared with placebo. The increase in LS BMD with ONO-5334 300 mg was observed to be greater than with ONO-5334 50 mg twice daily or 100 mg once daily.

Figure 2.

Mean percentage changes (±SE) from baseline in (A) lumbar spine, (B) total hip, and (C) femoral neck BMD during 12 months of treatment are shown. Closed circles (●), open circles (○), open triangles (equation image), open squares (□), and crosses (×) indicate placebo, ONO-5334 50 mg twice daily, 100 mg once daily, 300 mg once daily, and alendronate 70 mg once weekly, respectively. *p < .05; **p < .01; ***p < .001 versus placebo (FAS, LOCF).

ONO-5334 300 mg once daily showed a 3.0% ± 0.36% and a 2.6% ± 0.44% increase in total hip and femoral neck, respectively (both p < .001 versus placebo; Fig. 2). Among the three dosing arms of ONO-5334, 50 mg twice daily and 300 mg once daily appeared to show a similar increase at these sites.

In all regions assessed, a progressive increase with time was observed for all doses of ONO-5334 (and alendronate) compared with placebo.

Biochemical markers of bone turnover

Since the primary time point for the study was month 12, changes from baseline in all bone turnover markers at month 12 are summarized in Table 2. For key bone-resorption and bone-formation markers, the complete time profiles across 12 months are shown for urinary NTX, serum and urinary CTX-1, serum B-ALP, and serum P1NP in Figs. 3 and 4.

Table 2. Change from Baseline in Log-Transformed Bone Turnover Markers After 12 Months of Treatment: Geometric Means and Ratio of Geometric Means (Versus Placebo)
  PlaceboONO-5334ONO-5334ONO-5334Alendronate
50 mg twice daily100 mg once daily300 mg once daily70 mg once weekly
  • Note: 95% confidence intervals are shown in parentheses. Analysis population: Full analysis set using last observation carried forward.

  • a

    Geometric mean expressed as a ratio of the baseline value.

  • b

    Geometric mean expressed as a ratio of the placebo value.

  • c

    p Value for difference from placebo, respectively.

Urinary NTXa0.920.470.490.370.33
 b0.51 (0.39, 0.65)0.54 (0.42, 0.69)0.40 (0.31, 0.51)0.35 (0.28, 0.46)
 c<0.001<0.001<0.001<0.001
Serum CTX-1a0.800.650.670.470.29
 b0.80 (0.66, 0.98)0.83 (0.68, 1.01)0.58 (0.48, 0.71)0.37 (0.30, 0.44)
 c0.0290.059<0.001<0.001
Urinary CTX-1a0.940.240.270.130.23
 b0.25 (0.18, 0.36)0.28 (0.20, 0.40)0.13 (0.09, 0.19)0.25 (0.18, 0.35)
 c<0.001<0.001<0.001<0.001
fDPDa1.041.211.391.140.73
 b1.17 (1.04, 1.32)1.34 (1.19, 1.51)1.09 (0.97, 1.23)0.70 (0.63, 0.79)
 c0.011<0.0010.142<0.001
B-ALPa0.840.860.900.720.55
 b1.02 (0.92, 1.13)1.07 (0.96, 1.19)0.85 (0.77, 0.95)0.66 (0.59, 0.73)
 c0.7430.2170.003<0.001
OCa1.621.621.631.281.07
 b1.00 (0.86, 1.17)1.01 (0.86, 1.18)0.79 (0.68, 0.93)0.66 (0.57, 0.77)
 c0.9520.9350.004<0.001
P1NPa0.961.011.070.700.35
 b1.05 (0.88, 1.26)1.11 (0.93, 1.33)0.73 (0.61, 0.87)0.36 (0.30, 0.43)
 c0.5840.259<0.001<0.001
TRACP-5ba1.191.251.331.130.99
 b1.05 (0.97, 1.14)1.12 (1.04, 1.22)0.95 (0.87, 1.03)0.83 (0.77, 0.90)
 c0.2010.0050.191<0.001
1-CTPa0.992.372.402.320.86
 b2.39 (1.98, 2.89)2.42 (2.01, 2.92)2.34 (1.94, 2.82)0.86 (0.72, 1.04)
 c<0.001<0.001<0.0010.120
Urinary CTX-2a1.090.740.600.530.70
 b0.67 (0.53, 0.86)0.54 (0.43, 0.69)0.48 (0.38, 0.61)0.64 (0.51, 0.81)
 c0.001<0.001<0.001<0.001
Figure 3.

Changes from baseline in serum and urinary biochemical markers of bone turnover: (A) urinary NTX, (B) serum CTX-1, and (C) urinary CTX-1 are shown as geometric means ± 95% confidence intervals. Closed circles (●), open circles (○), open triangles (equation image), open squares (□), and crosses (×) indicate placebo, ONO-5334 50 mg twice daily, 100 mg once daily, 300 mg once daily, and alendronate 70 mg once weekly, respectively. *p < .05; **p < .01; ***p < .001 versus placebo (FAS, LOCF).

Figure 4.

Changes from baseline in bone formation markers, (A) serum PINP and (B) serum B-ALP are shown as geometric means ± 95% CI. Closed circles (●), open circles (○), open triangles (equation image), open squares (□) and crosses (×) indicate placebo, ONO-5334 50 mg twice daily, 100 mg once daily, 300 mg once daily, and alendronate 70 mg once weekly, respectively. *p < 0.05, **p < 0.01, ***p < 0.001 versus placebo (FAS, LOCF).

All three ONO-5334 doses and alendronate significantly suppressed urinary NTX and serum and urinary CTX-1 throughout the 12 months, with the majority of suppression observed at the first time point assessed (1.5 months). Urinary NTX levels decreased from baseline by approximately 61%, 56%, 70%, and 49% with 50 mg twice daily, 100 mg once daily, and 300 mg once daily of ONO-5334 and of alendronate at month 1.5 compared with placebo, respectively. The onset of effect with alendronate appeared slightly slower but, at month 3, urinary NTX levels were comparable with those of ONO-5334. For serum CTX-1, all ONO-5334 doses caused significant suppression, although the highest dose appeared to show greatest effect throughout 12 months. Alendronate showed the greatest consistent suppression of all treatments across 12 months. The magnitude of suppression with ONO-5334 on urinary CTX-1 appeared greater compared with serum CTX-1, although alendronate showed a similar pattern of response on both markers. Also, 300 mg once daily ONO-5334 showed the greatest suppression on these resorption markers of all ONO-5334 treatments throughout 12 months.

Alendronate significantly suppressed fDPD. ONO-5334 increased fDPD, although no dose-response was observed, with a greater increase observed with the lower doses (Table 2). There were no changes in 1-CTP level during 12 months of treatment with alendronate or placebo. However, all doses of ONO-5334 showed a comparable and significant increase in 1-CTP.

At month 12, only alendronate and 300 mg once daily ONO-5334 significantly suppressed B-ALP. A similar pattern of response was observed for P1NP with alendronate and 300 mg once daily ONO-5334. OC was increased from baseline with all treatments but only significantly suppressed with 300 mg once daily and alendronate compared with placebo. There were no appreciable changes in the placebo group in the levels of B-ALP and P1NP throughout the study period, although a 62% increase was observed at month 12 for OC.

Alendronate significantly reduced TRACP-5b at month 12. There were no consistent dose-response effects of ONO-5334 on TRACP-5b, with only 100 mg once daily ONO-5334 showing a significant increase in TRACP-5b.

Safety Results

One patient died during the study owing to multiple myeloma, considered unrelated to ONO-5334 treatment (50 mg twice daily). Overall, serious treatment-emergent adverse events (TEAEs) were reported by 19 (11.1%) ONO-5334-treated patients and by 4 (7%) patients in each of the comparator groups. Table 3 summarizes the overall AE profile during the study according to system organ classes (SOC) for which TEAEs were reported by more than 10% of subjects. For the ONO-5334 groups, the most frequent TEAEs were dyspepsia (50 mg twice daily: 10.5%; 100 mg once daily: 3.5%; 300 mg once daily: 8.8%; alendronate and placebo: 5.3%) and hypertension (50 mg twice daily: 5.3%; 100 mg once daily: 12.3%; 300 mg once daily: 8.8%; alendronate: 8.8%; and placebo: 3.5%). No dose relationship was evident for any individual AE. The most frequent TEAE for the alendronate group was upper abdominal pain, affecting 6 patients (versus none for placebo).

Table 3. Frequent TEAEs and Other AEs of Interest by System Organ Class After 12 Months of Treatment
 PlaceboONO-5334ONO-5334ONO-5334Alendronate
50 mg twice daily100 mg once daily300 mg once daily70 mg once weekly
(N = 57)(N = 57)(N = 57)(N = 57)(N = 57)
n (%)n (%)n (%)n (%)n (%)
  • a

    One subject in this group died owing to multiple myeloma, considered unrelated to treatment.

Overall TEAEs41 (71.9)47 (82.5)51 (89.5)44 (77.2)41 (71.9)
Overall serious TEAEs4 (7.0)7 (12.3)a7 (12.3)5 (8.8)4 (7.0)
Most frequent TEAEs (>10% subjects in any SOC)
 Gastrointestinal disorders22 (38.6)20 (35.1)18 (31.6)12 (21.1)21 (36.8)
 Infections and infestations13 (22.8)18 (31.6)17 (29.8)13 (22.8)10 (17.5)
 Musculoskeltal and connective tissue disorders17 (29.8)11 (19.3)11 (19.3)12 (21.1)11 (19.3)
 Nervous system disorders12 (21.1)9 (15.8)9 (15.8)11 (19.3)6 (10.5)
 Respiratory thoracic and mediastinal disorders01 (1.8)5 (8.8)3 (5.3)6 (10.5)
 Vascular disorders5 (8.8)5 (8.8)8 (14.0)5 (8.8)7 (12.3)
Other AEs of interest
 Skin and subcutaneous tissue disorders3 (5.3)2 (3.5)5 (8.8)2 (3.5)1 (1.8)

Overall the profile of gastrointestinal (GI) AEs observed in ONO-5334-treated patients was similar to placebo. All events were mild or moderate in severity and resolved by the end of study. GI AEs reported by more than 2 patients in an ONO-5334 dose group were abdominal discomfort, upper abdominal pain, constipation, diarrhea, dyspepsia, and nausea. AEs affecting the skin (Table 3) were either mild or moderate in severity. There was no evidence of either a temporal relationship of AE to study drug initiation/duration or of a dose-response relationship.

Other safety parameters generally were unremarkable, with no clinically relevant differences occurring across the treatments.

Discussion

Treatment with the three doses of ONO-5334 resulted in significant increases in LS BMD at month 12 compared with placebo in women at moderate risk of fracture. In fact, 50 mg twice daily and 300 mg once daily ONO-5334 showed significant increases in BMD in all regions measured, that is, LS, total hip, and femoral neck. Increases in BMD with 300 mg once daily were consistently larger than with 100 mg once daily, which suggested a dose-response increase in BMD with once daily treatment with ONO-5334. ONO-5334 50 mg twice daily consistently showed greater increases in BMD than 100 mg once daily and was comparable with 300 mg once daily on total hip and femoral neck. Since the plasma concentration of ONO-5334 is considered to be a good surrogate for its pharmacodynamic effects,19 this finding may suggest that a higher trough level rather than a higher maximum plasma concentration (Cmax) may be more important for a more potent increase in BMD. In other words, a sustained-release formulation that can achieve higher trough levels may be useful to reduce the daily amount of ONO-5334 administered.

Alendronate was used as an active reference to confirm the sensitivity of the study design and reduce the risk of showing a false-negative result for ONO-5334 in this first proof-of-concept study. The study was not powered to look at differences or noninferiority to alendronate. However, this study does provide the first opportunity to see how a cathepsin K inhibitor may compare with current standard drug therapy.

The effects of alendronate on BMD generally were consistent compared with other reported studies.20, 23–25 With the clear dose-response relationship observed with ONO-5334, it would be of interest to see whether higher doses of the once daily or a higher twice daily regimen than 50 mg or a sustained-release formulation could achieve greater effects on BMD in comparison with alendronate. The magnitudes of increases in LS and total hip BMD seen with the highest dose of ONO-5334 (300 mg) of 5.1% and 3.0% at 1 year are similar to the increases at the same two sites with odanacatib at the highest dose (50 mg) of 5.4% and 3.2% at 2 years, although comparisons between studies should be made with caution.13

Since it was considered possible that baseline bone turnover may have affected the efficacy of ONO-5334, baseline urinary CTX-1 was used as a randomization stratification factor and as a covariate in the ANCOVA model. It was not found to be significant; therefore, there is no evidence to suggest that baseline CTX-1 levels are useful in predicting treatment outcome or in characterizing patients who may benefit more from treatment.

ONO-5334 and alendronate significantly suppressed the bone-resorption markers urinary NTX and serum and urinary CTX-1 throughout 12 months of treatment, with the majority of the effect occurring by 1.5 months. There appeared to be some differences in the degree of suppression with ONO-5334 between the markers, whereby urinary CTX-1 was more sensitive to ONO-5334 than serum CTX-1 and urinary NTX. In addition, ONO-5334 did not suppress fDPD and 1-CTP, unlike alendronate. In fact, an increase in fDPD and 1-CTP was observed with ONO-5334. 1-CTP is released from type 1 collagen by matrix metalloproteinase and usually is further degraded by cathepsin K to fragments, such as CTX-1. In the presence of a cathepsin K inhibitor, we might have predicted an increase here.26 Altered degradation pathways also may explain the increase in fDPD with cathepsin K inhibitor. The effect of odanacatib, another cathepsin K inhibitor that is administered orally on a weekly basis, has been evaluated on these bone-resorption markers, and the 1-year changes in urinary NTX and serum CTX are similar, as are the changes in 1-CTP.27 The biggest difference is in the lowest dose of odanacatib, which showed a paradoxical increase in bone-resorption markers for no clear reason.13 We cannot exclude such an effect with low-dose ONO-5334 because we only explored two daily doses (100 and 300 mg daily).

With regard to bone formation, alendronate showed clear and characteristic suppression of B-ALP and P1NP. However, there seemed to be a dose-dependent effect of ONO-5334. The highest dose showed significant suppression of B-ALP and P1NP but apparently less potently than alendronate. Moreover, the two lower doses did not show any significant suppression in bone-formation markers over 12 months. OC showed a similar pattern of effect to B-ALP and P1NP (versus placebo). Again, this pattern is similar to the changes in B-ALP and P1NP for odanacatib (OC was not included in that study).

At month 12, ONO-5334 had no consistent effect on TRACP-5b, with a tendency to increase it with lower doses and with no effect at 300 mg once daily. In comparison, there was clear suppression with alendronate. This pattern was reported for odanacatib.27 It may indicate that the number of osteoclasts actually increases, but the work of each cell decreases (and hence the decrease in CTX).

These bone turnover marker results highlight the difference in mechanism of action between the standard biphosphonate therapy and ONO-5334. In general, for ONO-5334, there was effective suppression of the major bone-resorption markers and either no suppression (at lower doses) or a slight suppression (with 300 mg once daily) of the bone-formation markers. Alendronate showed potent and significant suppressive effects on all bone turnover markers (although not significantly with 1-CTP), and this is consistent with that reported for antiresorptive agents in the literature.28 The balance between resorption and formation favors formation, and this might indicate why odanacatib appears to show a year-on-year increase in BMD over 3 years27 rather than the plateau of effect seen with antiresorptives such as alendronate after 18 months.

Since ONO-5334 inhibits the enzyme activity of cathepsin K and does not suppress osteoclast cell activity significantly, bone turnover regulation between osteoclasts and osteoblasts may not be affected or certainly may be less affected with (higher doses of) ONO-5334. It is interesting to speculate whether such a difference in the mechanism of action will contribute to differences in BMD with time (greater than 12 months). Clearly, there was no discernible difference over 12 months, as seen in this study. However, maintaining osteoblast function during treatment may be beneficial in terms of bone quality during long-term treatment. It has been suggested that the long-term use of bisphosphonates potentially may affect the quality and structural integrity of bone. Whether this relates to an increase in atypical fractures seen in certain vulnerable patients treated with bisphosphonates remains unknown.29, 30 If bone quality is a potential concern with long-term suppression of bone turnover, antiresorptive agents that have little or no suppression of bone formation may be of interest. However, only long-term observational studies or prospective intervention studies can help to address the clinical significance of osteoporosis treatment on bone quality over time.

Most TEAEs were either mild or moderate in severity, with no evidence of a dose-response relationship. Another cathepsin K inhibitor, balicatib, has been reported to have an increased risk of skin-related AEs,12, 31 mainly pruritus. Although ONO-5334 has a similar mode of action, there were no trends to indicate any safety concerns in skin AEs in this study. The results of this study indicate that ONO-5334 generally was well tolerated at doses up to 300 mg once daily for a year.

In summary, ONO-5334 showed a significant and progressive increase in LS, total hip, and femoral neck BMD compared with placebo. The effect of ONO-5334 on the bone turnover marker profile suggests a new mechanism of action versus standard antiresorptive agents such as alendronate, with little or no suppression of bone-formation markers and TRACP-5b. Whether this may translate into a different long-term effect of BMD change needs to be investigated with longer-term studies. Treatment with ONO-5334 generally was well tolerated up to daily doses of 300 mg and for up to 12 months. Further clinical studies are warranted to investigate the long-term efficacy and safety of ONO-5334 as a potential treatment for osteoporosis.

Disclosures

SN, MO, MS, TK, and SD are employees of the study sponsor, Ono Pharmaceutical Company, Ltd. (Osaka, Japan) or its European office, Ono Pharma UK, Ltd. SN, MO, and TK have stock options of Ono Pharmaceutical Company, Ltd. RE, SB, and TS have provided the study sponsor with scientific advice, receiving consultancy fees as members of the study steering committee. JS received fees as a medical consultant for the study.

Acknowledgements

This study was sponsored by Ono Pharmaceutical Company, Ltd. (Osaka, Japan). RE is a National Institute for Health Research (NIHR) Senior Investigator. SB is senior clinical investigator of the Fund for Scientific Research, Flanders, Belgium (F.W.O.-Vlaanderen). TS is director of the Department of Twin Research and consultant rheumatologist at St Thomas' Hospital, Kings College, London, and is an NHS NIHR Senior Investigator and an European Research Council Senior Investigator.

We wish to thank the 13 principal investigators: Dr Peter Kasalicky (Czech Republic), Dr Mojmir Sugarek (Czech Republic), Dr Vaclav Vyskocil (Czech Republic), Dr Hans Christian Hoeck (Denmark), Dr Christence Stubbe Teglbjærg (Denmark), Dr Peter Alexandersen (Denmark), Dr Katre Maasalu (Estonia), Dr Ivo Valter (Estonia), Dr Tibor Hídvégi (Hungary), Dr Miklós Szendrői (Hungary), Dr Vidmantas Alekna (Lithuania), Dr Agne Abraitiene (Lithuania), and Dr Lenie de Schipper (The Netherlands).

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