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.
Highlights
MIV-711 is a highly potent and selective cathepsin K inhibitor
Urinary helical peptide (HP-1) levels in rabbits subjected to anterior cruciate ligament transection (ACLT) increased app. 2.3- to 2.4-fold vs. baseline (p < 0.001) during the 7-day period after surgery
HP-1 levels in ACLT rabbits treated with vehicle increased more than in sham-operated rabbits treated with vehicle after 10 days of dosing (2.6-fold vs. 1.6-fold, p < 0.05)
Summary
MIV-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). While the disease is characterized by cartilage degradation, the role of subchondral bone in the development and progression of OA has received increasing recognition in recent years [2,3,4]. Progress has been made in understanding the molecular signaling mechanisms between these two compartments, but they are not yet completely understood. It has been shown in clinical trials that agents that inhibit bone resorption such as strontium ranelate [12], risedronate [13] and calcitonin [14] show positive effects on OA-related endpoints such as joint space narrowing and on patient reported outcomes such as WOMAC scores in Phase II studies. Either inconsistent efficacy or safety concerns have precluded approval of these agents for OA
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