Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study

Abstract

We performed a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-response study of the efficacy and safety of the oral administration of PG-116800, a matrix metalloproteinase (MMP) inhibitor, in patients with mild to moderate knee osteoarthritis. The primary efficacy endpoints included the progression of joint space narrowing in the osteoarthritic knee, as measured by microfocal radiography with fluoroscopic positioning, and the reduction of symptoms (pain and stiffness) and/or the improvement of function, as measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Four hundred and one patients were randomly assigned to either placebo (n = 80) or one of fourdoses of PG-116800: 25 mg (n = 81), 50 mg (n = 80), 100 mg (n = 80), or 200 mg (n = 80) taken twice daily for 12 months. During the study, the 200-mg dose was discontinued based on an increased frequency of musculoskeletal adverse effects. After 1 year of treatment, no statistically significant difference was observed between placebo and PG-116800 with regard to mean changes in minimum joint space width of the knee or to WOMAC scores. The most frequent adverse effect was arthralgia (35%). Twenty-three percent of evaluable patients had at least a 30% decrease from baseline of at least onerangeof-motion measurement of either shoulder at a follow-up visit. The percentage of patients with reduction in range of motion was significantly greater in the twohighest dose groups relative to placebo. Thirteen percent of patients, half of whom were in the 200-mg group, reported hand adverse events (oedema, palmar fibrosis, Dupuytren contracture, or persistent tendon thickness or nodules). The threemost frequent shoulder adverse events were reversible arthralgia, stiffness, and myalgia, which mostly affected the twohighest dose groups. The unfavorable risk-benefit balance of the MMP inhibitor PG-116800 in patients with knee osteoarthritis precludes further development of the compound for this indication. This study adds to the weight of evidence suggesting that side effect profiles of MMP inhibitors in general make them unsuitable for use in osteoarthritis.Trial Registration ClinicalTrials.gov NCT00041756.

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

“…It is possible that inhibition of multiple MMPs may lead to relatively higher efficacy. However, utility of broadspectrum MMP inhibitors for treatment of OA is limited by MSS liability (37). Therefore, we included assessment of MSS liability as a critical component of our effort to develop MMP-13 inhibitors for OA.…”

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

“…In animal models of OA, MMP inhibitors can prevent cartilage degradation and joint damage [31]. However, in clinical trials, oral administration of PG-116800 (a broadspectrum MMP inhibitor with high affinity for MMP-2, MMP-3, MMP-8, MMP-9, MMP-13, and MMP-14) showed adverse musculoskeletal effects, such as arthralgia, fibrosis, or contracture [36]. However, local administration of MMP inhibitors for meniscal repair procedures should minimize any toxicities.…”

Assessment of Potential Cross-Reactivity of Human Endogenous Matrix Metalloproteinases with Collagenase Clostridium histolyticum Antibodies in Human Sera Obtained from Patients with Dupuytren's Contracture

“…Clinical adverse events were reviewed as an additional supporting approach to evaluate crossreactivity, by comparison of the adverse events noted in seropositive subjects with those described in the published literature following the use of broad-spectrum MMP inhibitors in clinical trials (1,14). These products have been studied in clinical trial settings for potential therapeutic indications, including oncology uses and osteoarthritis.…”