The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis

Abstract

BackgroundMIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA).MethodsStarting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.ResultsIn ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55–57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25–37% lower macroscopic scores in the femur condyles and 13–33% lower macroscopic scores in the tibial plateaus.ConclusionsMIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1425-7) contains supplementary material, which is available to authorized users.

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

“…The CTX-II data suggests that MIV-711 may be useful in reducing subchondral bone turnover and attenuating cartilage disease progression in OA patients. Indeed, MIV-711 has demonstrated protective effects on subchondral bone and articular cartilage in nonclinical disease models [ 40 ] at exposures that are in the same range as reported in this study. Additionally, recent clinical data from a Phase II study with MIV-711 in knee OA patients, given once daily for 6 months, demonstrated benefit on joint structure, with significantly lower increases in bone area and cartilage thinning in the diseased knee, as assessed by magnetic resonance imaging (MRI), compared to patients who received placebo [ 24 ].…”

Cathepsin K: The Action in and Beyond Bone

“…Consequently, CatK is currently among the promising therapeutic target candidates for the development of disease-modifying osteoarthritic drugs. It is encouraging to learn that CatK inhibition could exert obvious chondroprotective effect in preclinical OA models (Connor et al, 2009;McDougall et al, 2010;Hayami et al, 2012;Lindstrom et al, 2018). Furthermore, a novel selective CatK inhibitor MIV-711 by Medivir was recently reflected to reduce bone remodeling and cartilage volume loss but have no impact on pain in OA patients in a Phase-IIa trial (Conaghan et al, 2019).…”

Future of Chondroprotectors in the Treatment of Degenerative Processes of Connective Tissue

“…OA is the most common joint disease characterized by progressive cartilage degeneration, changes in the subchondral bone, and chronic synovitis [ 1 , 2 , 3 ]. Modern treatment of OA is limited to the use of drugs that affect the symptoms of the disease: analgesics, anti-inflammatory drugs, and devices for treatment [ 4 , 5 , 6 , 7 ].…”