Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711

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

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

Chondroprotective Factors in Osteoarthritis: a Joint Affair

“… Anti-protease Alpha-2-macroglobulin Phase I trial to look at the reduction of pro-inflammatory synovial fluid biomarkers in OA due for completion in 2019 (NCT03656575). Cathepsin K inhibitor MIV-711 MIV-711 was well tolerated in a phase I study in healthy subjects [ 26 ]. Phase IIa trial showed significant reductions in bone and cartilage disease progression in the femur [ 27 ].…”

“…ADAMTS-inhibitorsAnti-ADAMTS-5 nanobodyCurrently awaiting results from phase I clinical trial (NCT03224702) after in vitro studies showed protection against cartilage breakdown [25]. Phase I clinical trial of multiple ascending doses of anti-ADAMTS-5 nanobody in knee OA, due for completion in May 2019 (NCT03583346).Anti-proteaseAlpha-2-macroglobulinPhase I trial to look at the reduction of pro-inflammatory synovial fluid biomarkers in OA due for completion in 2019 (NCT03656575).Cathepsin K inhibitorMIV-711MIV-711 was well tolerated in a phase I study in healthy subjects [26]. Phase IIa trial showed significant reductions in bone and cartilage disease progression in the femur [27].…”

New Trends in Pharmacological Treatments for Osteoarthritis

“…Cathepsin-K may be an attractive therapeutic target for diseases with excessive bone resorption such as osteoporosis and OA. Cathepsin K inhibitors have shown structural protection and analgesic effects in animal models of joint degeneration (Lindström et al, 2018a;Nwosu et al, 2018).…”