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

Abstract

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.

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

“…Nitrile group containing inhibitors have been widely recognized as covalent and reversible inhibitors of a certain class of enzymes that depend on cysteine-mediated nucleophilic attack for catalysis; the nitrile residue traps the sulfur and forms a thioimidate bond ( Figure 15) that hydrolyzes over the time rendering free enzyme. Odanacatib is one of the prime examples of this class of compounds that has been evaluated as a clinical agent, although with limited success [143,144]. Because of nitrile's tunable target engagement nature, this scaffold has been adapted to target other relevant enzymes, including cathepsin.…”

Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism

“…In contrast to traditional anti-resorptive therapies, odanacatib, a small-molecule inhibitor of cathepsin K (CTSK), blocks bone resorption without reducing osteoclast numbers. Similar to osteopetrosis patients with impaired osteoclast resorptive activity, clinical trials of odanacatib showed promise to reduce resorption with minimal decreases in bone formation rate [11][12][13][14][15] . However, further development of this therapy was impeded by an off-target increase in cerebrovascular accident incidence in odanacatibtreated patients 16 .…”

Structure-activity relationships of cysteine protease inhibitors

“…5, n. 6, p. 506-519, nov. 2015. Five CPs were studied in this work that present functional structural similarities in which three are mammalian cathepsins: Cathepsin L (hCatL), Cathepsin S (hCatS) and Cathepsin K (hCatK), and two protozoa CPs: cruzain (Cz) from Trypanosoma cruzi and Leishmania mexicana CPB (LmCPB). The human cathepsins are widely studied for being essential targets for cancer and immune system-related diseases (DENNEMÄRKER et al, 2010;STONE et al, 2019). As a result of that, a lot is known of their structures and substrate specificity, having a large number of inhibitors deposited in the ChEMBL data bank (GAULTON et al, 2017).…”

“…The human cathepsins play chief roles in tumor progression, cardiovascular diseases, osteoporosis and arthritis, neurodegenerative diseases and obesity, making them attractive as drug targets (DENNEMÄRKER et al, 2010;OLSON;JOYCE, 2015;STONE et al, 2019).…”

“…It is known to be involved in tumor invasion and metastasis for many types of cancers like ovarian, breast, prostate, lung, gastric and pancreatic (DENNEMÄRKER et al, 2010;QUILLES JR et al, 2019;TABISH et al, 2019), hCatK is predominantly expressed in osteoclasts. It is a therapeutic target for bone diseases, such as osteoporosis (STONE et al, 2019;ZAIDI et al, 2001). The hCatK are also involved in atherosclerosis and cancer (MULDER et al, 2014).…”