Abstract

BackgroundCathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man.MethodsThe potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3–30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg.ResultsMIV-711 was a potent inhibitor of human cathepsin K (Ki: 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data.ConclusionsMIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA.Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011

Highlights

  • Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA)

  • Cartilage degradation can be assessed by measuring the C-terminal telopeptide of type II collagen (CTXII)

  • Cathepsin K is expressed in other tissues, its main physiological role seems to be in bone resorption

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Summary

Introduction

Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). While bone mineral calcium hydroxyapatite dissolves in the acidic environment, cathepsin K, which is proteolytically active at the acidic pH present in hemivacuoles [3], degrades key organic bone matrix proteins, such as type I collagen. Cathepsin K is expressed in chondrocytes in cartilage, and is able to cleave type II collagen and aggrecan, the main organic components of the cartilage matrix. Cathepsin K is expressed in other tissues, its main physiological role seems to be in bone resorption. This is reflected by the lack of bone resorption and the high bone mass phenotype in cathepsin K-deficient mice [4] and in pycnodysostosis patients, who lack functional cathepsin K due to various inactivating mutations in the cathepsin K gene [5]

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