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Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711.
- Source :
-
Journal of translational medicine [J Transl Med] 2018 May 09; Vol. 16 (1), pp. 125. Date of Electronic Publication: 2018 May 09. - Publication Year :
- 2018
-
Abstract
- Background: Cathepsin 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.<br />Methods: The 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.<br />Results: MIV-711 was a potent inhibitor of human cathepsin K (K <subscript>i</subscript> : 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC <subscript>50</subscript> 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.<br />Conclusions: MIV-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.
- Subjects :
- Administration, Oral
Adult
Animals
Biomarkers urine
Bone Resorption metabolism
Bone Resorption pathology
Cysteine Proteinase Inhibitors administration & dosage
Cysteine Proteinase Inhibitors blood
Cysteine Proteinase Inhibitors pharmacokinetics
Female
Humans
Macaca fascicularis
Male
Middle Aged
Organic Chemicals administration & dosage
Organic Chemicals blood
Organic Chemicals pharmacokinetics
Osteoclasts drug effects
Osteoclasts metabolism
Osteoclasts pathology
Young Adult
Cathepsin K antagonists & inhibitors
Cysteine Proteinase Inhibitors pharmacology
Organic Chemicals pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 29743078
- Full Text :
- https://doi.org/10.1186/s12967-018-1497-4