title: 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 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.
authors.affiliation: Procter & Gamble Pharmaceuticals, Whitehall Lane, Egham TW20 9NW, Surrey, UK. krzeski.p@pg.com
authors.forename: Piotr
authors.initials: P
authors.lastname: Krzeski
authors.forename: Chris
authors.initials: C
authors.lastname: Buckland-Wright
authors.forename: Géza
authors.initials: G
authors.lastname: Bálint
authors.forename: Gary A
authors.initials: GA
authors.lastname: Cline
authors.forename: Karen
authors.initials: K
authors.lastname: Stoner
authors.forename: Robert
authors.initials: R
authors.lastname: Lyon
authors.forename: John
authors.initials: J
authors.lastname: Beary
authors.forename: William S
authors.initials: WS
authors.lastname: Aronstein
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D009140:Musculoskeletal Diseases / Q000139:chemically induced* / Q000201:enzymology; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000201:enzymology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C512048:PG-116800; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases