ONO PHARMA UK LTD

London, United Kingdom

ONO PHARMA UK LTD

London, United Kingdom

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Eastell R.,University of Sheffield | Eastell R.,Northern General Hospital | Nagase S.,Ono Pharma UK Ltd. | Ohyama M.,Ono Pharmaceutical Co. | And 6 more authors.
Journal of Bone and Mineral Research | Year: 2011

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. Copyright © 2011 American Society for Bone and Mineral Research.


Engelke K.,Synarc Inc | Engelke K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Nagase S.,Ono Pharma UK Ltd | Fuerst T.,Synarc Inc | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2014

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. © 2014 American Society for Bone and Mineral Research.


Eastell R.,University of Sheffield | Nagase S.,Ono Pharma UK Ltd. | Small M.,Ono Pharma UK Ltd. | Boonen S.,Catholic University of Leuven | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2014

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. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


PubMed | Plymouth Hospitals NHS Trust, CHRU, Cardiff CLL Research Group, ONO Pharma UK Ltd and 4 more.
Type: Clinical Trial, Phase I | Journal: Blood | Year: 2016

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.


PubMed | Ono Pharma United States, University of Toronto, Ono Pharma UK Ltd and University of California at Los Angeles
Type: Journal Article | Journal: The British journal of ophthalmology | Year: 2016

The novel prostaglandin E (EP) 3 and prostaglandin F (FP) receptor agonist ONO-9054 is effective in lowering intraocular pressure (IOP) in patients with ocular hypertension and open-angle glaucoma when administered once daily. This study compares the effects of morning (AM) versus evening (PM) dosing of ONO-9054 on tolerability and IOP lowering.This was a single-centre, randomised, double-masked, two-sequence, placebo-controlled crossover study in 12 subjects with bilateral primary open-angle glaucoma or ocular hypertension. Two 14-day crossover regimens were separated by a 2-week washout: ONO-9054 (1 drop to each eye) in the morning (07:00) and vehicle in the evening (19:00) and vice versa. IOP was measured multiple times during select days. Ocular examinations also evaluated safety and tolerability.Mild ocular hyperaemia, reported by six subjects with PM dosing, was the most frequent adverse event. Mild to moderate dryness was also slightly more frequent after PM dosing. Maximum IOP reduction from baseline occurred on day 2 with decreases from baseline of -7.4mmHg (-30.8%) for AM dosing and -9.1mmHg, (-38.0%) for PM dosing; after 14days, mean reduction in IOP was -6.8mmHg (-28.6%) for AM dosing and -7.5mmHg (-31.0%) for PM dosing.PM dosing of ONO-0954 was associated with a slightly increased frequency of mild hyperaemia and mild to moderate dryness. Both dosing schedules provided sustained reduction in IOP.NCT01670266.


Nagase S.,ONO PHARMA UK Ltd. | Ohyama M.,Ono Pharmaceutical Co. | Hashimoto Y.,Ono Pharmaceutical Co. | Small M.,ONO PHARMA UK Ltd. | And 2 more authors.
Journal of Clinical Pharmacology | Year: 2012

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). © 2012 American College of Clinical Pharmacology, Inc.


Nagase S.,ONO PHARMA UK LTD | Hashimoto Y.,Pharmacokinetic Research Group | Small M.,ONO PHARMA UK LTD | Ohyama M.,Ono Pharmaceutical Co. | And 2 more authors.
British Journal of Clinical Pharmacology | Year: 2012

AIMS: To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO-5334. METHODS: A double-blind, placebo-controlled, randomized studywas carried out in 52 healthy post menopausal females. Single ascending doses of ONO-5334 (3-600mg) were evaluated in six cohorts. The effect of food was studied at ONO-5334 100mg. RESULTS: Across the doses tested, mean ONO-5334 Cmax occurred 0.5-1.0h after dosing and the the t1/2 ranged from 9.1 to 22h. Linear increases in Cmax and AUC(0,∞) were observed in the 3-300mg and 3-600mg dose range, respectively. After food, the geometric mean ratio (95% CI) Cmax 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 4h vs. placebo. Statistical significance was achieved for ONO-5334 doses ≥30mg for C-terminal telopeptide of type 1 collagen (CTX) and ≥300mg for N-terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24h for ONO-5334 100mg with serum CTX and 600mg with serum NTX. The maximum suppression in serum CTX occurred at 4h post dose with difference compared with placebo of -32%, -59%, -60% and -66% for 30, 100, 300 and 600mg ONO-5334, respectively. Second morning urine void 24h post dose showed statistically significant suppression of urinary CTX and NTX at 100mg and above vs. placebo. ONO-5334 600mg showed statistically significant suppression up to 72h for serum CTX, urinary CTX and urinary NTX and 48h for serum NTX vs. placebo. Adverse events were transient with no evidence of dose relationship. CONCLUSIONS: ONO-5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3-300mg, with clear suppression of urinary bone resorption markers at doses ≥100mg for serum markers at 24h. ONO-5334 was well tolerated up to 600mgday-1 when administered to healthy post menopausal women. © 2012 Ono Pharmaceutical Co., Ltd. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.


Tanaka M.,Ono Pharmaceutical Co. | Hashimoto Y.,Ono Pharmaceutical Co. | Sekiya N.,Ono Pharmaceutical Co. | Honda N.,Ono Pharmaceutical Co. | And 2 more authors.
Journal of Bone and Mineral Metabolism | Year: 2014

The purpose of the study was clarify the effect of the cathepsin K inhibitor ONO-5334 on bone resortion markers using sustained release (SR) formulations with different pharmacokinetic (PK) patterns, and identify the optimal SR formulation. The PK profiles and pharmacodynamic effect on bone resorption markers of 4 SR candidates formulations were evaluated in healthy postmenopausal women within a randomized, 2-part, open-label crossover study. In Part A, subject received a single dose of each formulation orally in the fed state. In Part B, two selected formulations were evaluated in the fasted state. From the results from Part A, C max was reduced and plasma concentrations of ONO-5334 were sustained with all SR formulations compared with an immediate release tablet. In pharmacodynamics, the level of C-terminal telopeptide of type I collagen (CTX) in serum and urine were inhibited with SR tablets rather than with granules. C max and area under the concentration-time curve from time 0 to the last measurable time point (AUC 0-t ) of SR tablets were higher than those of granules. From Part B, C max in the fasted condition was lower than that in the fed condition with two SR tablets. In contrast, C 24 h in the fasted condition was slightly higher than that in the fed condition, but AUC 0-t was similar. The inhibitory effect on CTX in serum and urine may depend on the PK pattern of ONO-5334. The SR tablets was well tolerated in postmenopausal women and has the optimal SR profiles on pharmacodynamics effect on bone resortion markers and PK profile. These results suggest that SR tablets of ONO-5334 are an excellent drug candidate for osteoporosis. © 2013 The Japanese Society for Bone and Mineral Research and Springer.


PubMed | Ono Pharma UK Ltd and Ono Pharmaceutical Co.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016

The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.

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