AMSTERDAM (FRONTLINE MEDICAL NEWS) A single intra-articular injection of a novel corticosteroid formulation provided substantial and persistent pain relief for at least 12 weeks in patients with knee osteoarthritis in a phase III trial that was presented at the World Congress on Osteoarthritis.

FX006 (Zilretta), given at a dose of 40 mg, significantly (P less than .05) reduced the mean daily pain intensity score from around 2 weeks onwards in the region of 3.0 to 3.5 points on a 0-10 scale compared with a reduction of around 1.5 to 2.0 points for placebo. There were also significant reductions in additional efficacy outcomes such as Western Ontario and McMaster Universities Index ( WOMAC ) pain and function versus placebo and a standard formulation of triamcinolone acetate (TCA).

Data from a phase IIb trial had originally been scheduled to be presented at the meeting – which is sponsored by the Osteoarthritis Research Society International – but the phase III findings had just become available, said Dr. Philip Conaghan of the University of Leeds (England). The phase II findings showed that there was a substantial and persistent pain relieving effect of FX006 versus placebo and that there was evidence of a dose response.

These data provide “proof of concept that we can develop long-acting steroids that have real potential for changing how we might manage knee OA,” said Dr. Conaghan, professor of musculoskeletal medicine and deputy director of the Leeds Musculoskeletal Biomedical Research Unit.

Intra-articular steroids have long been used to treat OA and they can be effective, albeit for a short period of time. FX006 is an investigational formulation of TCA in polylactic-co-glycolic acid microspheres that has been designed to try to extend the analgesic effects of the steroid and to reduce overall systemic exposure and thus side effects. Each microsphere is around 45 microns in diameter.

The aim of the phase IIb study was to examine the efficacy of two doses of FX006 (20 mg and 40 mg) versus placebo in patients with moderate to severe OA knee pain. The double-blind, randomized trial involved 310 patients who were followed for 24 weeks. The primary outcome was the change from baseline to week 12 in the weekly mean of the average daily pain intensity scores, compared with placebo.

There was evidence of a dose response, with the 40-mg dose of FX006 producing statistically significantly greater changes in pain scores versus placebo. Although the primary endpoint of a statistical difference at 12 weeks was not met, there were significant differences at all other time points from week 1 to 13. WOMAC pain and function scores were also significantly reduced with the 40-mg dose versus placebo.

The phase III trial involved 484 patients who were randomized to intra-articular injections of FX006 40 mg, standard TCA 40 mg, or placebo. As in the phase IIb trial patients were well matched at baseline, with a mean overall age of 62 years, a body mass index of 30 kg/m2 and around two-thirds having OA in both knees.

Dr. Conaghan reported that there were “no unexpected safety signals” during the trials. A combined safety summary showed that treatment-emergent adverse events occurred in 42.2% and 50.9% of patients treated with FX006 20 mg and 40 mg, respectively, in 49.2% of placebo-treated patients, and in 56.5% of TCA-treated patients. Serious adverse event rates were 1%, 3%, 1.1%, and 2.5%, respectively, and were assessed as being unrelated to treatment. Adverse events related to the knee occurred in 14.7%, 16.6%, 14.1%, and 9.9%, and injection-related adverse events in 2%, 1.9%, 4.2%, and 1.9%, respectively.

The studies were funded by Flexion Therapeutics. Dr. Conaghan did not report his financial disclosures.

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