Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis

Tanaka, Makoto; Hashimoto, Yoshitaka; Hasegawa, Chihiro; Deacon, Steve; Eastell, Richard

doi:10.1186/s12891-017-1625-y

Cited by 14 publications

(9 citation statements)

References 38 publications

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“…Balicatib (AAE581) developed by Novartis terminated in its Phase II trial due to cutaneous lesions such as pruritus, skin rashes and rare morphea-like skin changes (Peroni et al, 2008;Runger et al, 2012). ONO-5334, a novel synthetic inhibitor of CatK, developed by Ono Pharmaceutical Co has passed its phase I and II clinical trials (Tanaka et al, 2017). But this project was recently terminated due to some market reasons.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

125

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Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.

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Section: Introductionmentioning

confidence: 99%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

125

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“…This could allow for other cathepsin levels to be above normal and proteolyze more of the cathespin's targets than it would have under homeostatic, nonperturbed conditions. Balicatib, odanacatib, and ONO-5334 are three catK inhibitors that showed beneficial effects for treating bone resorption, but off-target effects precluded their movement through the pipeline (41)(42)(43)(44). Odanacatib was the most promising catK inhibitor, and was even fast-tracked through phase II and phase III clinical trials, as it reduced vertebral hip and nonvertebral fractures compared to placebo and increased lumbar spine and total hip bone density (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Reassessing enzyme kinetics: Considering protease-as-substrate interactions in proteolytic networks

Ferrall‐Fairbanks

Kieslich

Platt

2020

Proc. Natl. Acad. Sci. U.S.A.

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Enzymes are catalysts in biochemical reactions that, by definition, increase rates of reactions without being altered or destroyed. However, when that enzyme is a protease, a subclass of enzymes that hydrolyze other proteins, and that protease is in a multiprotease system, protease-as-substrate dynamics must be included, challenging assumptions of enzyme inertness, shifting kinetic predictions of that system. Protease-on-protease inactivating hydrolysis can alter predicted protease concentrations used to determine pharmaceutical dosing strategies. Cysteine cathepsins are proteases capable of cathepsin cannibalism, where one cathepsin hydrolyzes another with substrate present, and misunderstanding of these dynamics may cause miscalculations of multiple proteases working in one proteolytic network of interactions occurring in a defined compartment. Once rates for individual protease-on-protease binding and catalysis are determined, proteolytic network dynamics can be explored using computational models of cooperative/competitive degradation by multiple proteases in one system, while simultaneously incorporating substrate cleavage. During parameter optimization, it was revealed that additional distraction reactions, where inactivated proteases become competitive inhibitors to remaining, active proteases, occurred, introducing another network reaction node. Taken together, improved predictions of substrate degradation in a multiple protease network were achieved after including reaction terms of autodigestion, inactivation, cannibalism, and distraction, altering kinetic considerations from other enzymatic systems, since enzyme can be lost to proteolytic degradation. We compiled and encoded these dynamics into an online platform (https://plattlab.shinyapps.io/catKLS/) for individual users to test hypotheses of specific perturbations to multiple cathepsins, substrates, and inhibitors, and predict shifts in proteolytic network reactions and system dynamics.

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“…Two other CatK inhibitors progressed to date to clinical studies: balicatib (Phase 1 and 2 studies) and ONO‐5334 (Phase 1 and 2 studies). PD results from these programmes are generally consistent with the key findings from odanacatib, including: robust reversible inhibition of bone resorption demonstrated by biomarkers and associated with BMD increases; modest reductions of formation biomarkers (small relative to other osteoporosis therapies) at doses with near maximal resorption inhibition, and increased formation biomarkers over baseline at subtherapeutic (very low) dose; transient acceleration of bone resorption on discontinuation of treatment of ≥3 months duration, and osteoclast effects enhancing size, number and/or CatK enzyme levels . Of note, both balicatib and ONO‐5334 were dosed daily in Phase 2, which contrasts with the weekly dosing regimens studied in Phase 2 and 3 for odanacatib.…”

Section: Discussionmentioning

confidence: 99%

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Stone

McCrea

Witter

et al. 2019

Brit J Clinical Pharma

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Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formationsparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.

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Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis

Cited by 14 publications

References 38 publications

Cathepsin K: The Action in and Beyond Bone

Cathepsin K: The Action in and Beyond Bone

Reassessing enzyme kinetics: Considering protease-as-substrate interactions in proteolytic networks

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

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