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

Piotr Krzeski, Chris Buckland-Wright, G. Bálint, Gary A. Cline, Karen Stoner, Robert Lyon, John Beary, William S. Aronstein, Tim D. Spector

Research output: Contribution to journalArticle

95 Citations (Scopus)

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 onerange-of-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.

Original languageEnglish
Article numberR109
JournalArthritis Research and Therapy
Volume9
Issue number5
DOIs
Publication statusPublished - Oct 24 2007

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Musculoskeletal Development
Matrix Metalloproteinase Inhibitors
Knee Osteoarthritis
Placebos
Arthralgia
Osteoarthritis
Knee
Joints
Dupuytren Contracture
Myalgia
Ontario
Articular Range of Motion
Radiography
Tendons
Oral Administration
PG-116800
Edema
Fibrosis
Hand
Safety

ASJC Scopus subject areas

  • Rheumatology
  • Medicine(all)

Cite this

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. / Krzeski, Piotr; Buckland-Wright, Chris; Bálint, G.; Cline, Gary A.; Stoner, Karen; Lyon, Robert; Beary, John; Aronstein, William S.; Spector, Tim D.

In: Arthritis Research and Therapy, Vol. 9, No. 5, R109, 24.10.2007.

Research output: Contribution to journalArticle

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