Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711
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...
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doaj-382cff9db65d44afb7a828169477e0872020-11-24T21:51:14ZengBMCJournal of Translational Medicine1479-58762018-05-0116111410.1186/s12967-018-1497-4Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711Erik Lindström0Biljana Rizoska1Ian Henderson2Ylva Terelius3Markus Jerling4Charlotte Edenius5Urszula Grabowska6Medivir ABMedivir ABMedivir ABMedivir ABMedivir ABMedivir ABMedivir ABAbstract 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. 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. Results MIV-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. 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 2011http://link.springer.com/article/10.1186/s12967-018-1497-4Cathepsin KOsteoarthritisCTX-INTX-ICTX-IISubchondral bone |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Erik Lindström Biljana Rizoska Ian Henderson Ylva Terelius Markus Jerling Charlotte Edenius Urszula Grabowska |
spellingShingle |
Erik Lindström Biljana Rizoska Ian Henderson Ylva Terelius Markus Jerling Charlotte Edenius Urszula Grabowska Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711 Journal of Translational Medicine Cathepsin K Osteoarthritis CTX-I NTX-I CTX-II Subchondral bone |
author_facet |
Erik Lindström Biljana Rizoska Ian Henderson Ylva Terelius Markus Jerling Charlotte Edenius Urszula Grabowska |
author_sort |
Erik Lindström |
title |
Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711 |
title_short |
Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711 |
title_full |
Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711 |
title_fullStr |
Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711 |
title_full_unstemmed |
Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711 |
title_sort |
nonclinical and clinical pharmacological characterization of the potent and selective cathepsin k inhibitor miv-711 |
publisher |
BMC |
series |
Journal of Translational Medicine |
issn |
1479-5876 |
publishDate |
2018-05-01 |
description |
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. 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. Results MIV-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. 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 |
topic |
Cathepsin K Osteoarthritis CTX-I NTX-I CTX-II Subchondral bone |
url |
http://link.springer.com/article/10.1186/s12967-018-1497-4 |
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