Alan J. Kivitz
CHICAGO — An intra-articular injection of extended-release triamcinolone acetonide administered to both knees of patients with bilateral knee osteoarthritis was associated with a 10-fold reduction in drug plasma concentrations compared with traditional immediate-release triamcinolone acetonide, according to results of a phase 2 trial.
The findings are consistent with previous research demonstrating a prolonged benefit of triamcinolone acetonide extended-release (TA-ER; Zilretta, Flexion Therapeutics) — approved by the FDA last year for knee OA pain —among patients with unilateral knee OA.
“Typically, physicians do not treat OA with corticosteroid injections in both knees at the same time due to concerns about potential systemic overexposure, which may require patients to return at a separate office visit to receive treatment in the second knee,” Scott Kelley, MD, chief medical officer at Flexion Therapeutics, said in a press release. “These findings suggest that the extended-release formulation of Zilretta may result in substantially lower systemic concentrations of triamcinolone acetonide following bilateral injections compared to traditional immediate-release steroids.”
At the ACR/ARHP 2018 Annual Meeting, Alan J. Kivitz, MD, CPI, founder and medical director of the Altoona Center for Clinical Research and Altoona Arthritis and Osteoporosis Center in Duncansville, Pennsylvania, told Healio that limited treatment options for knee OA is a “major problem for rheumatologists.” Although patients respond well to traditional corticosteroid intra-articular injections, most experience knee pain 6 weeks after receiving the injection.
“We know that we cannot reinject patients that frequently,” he said. “That led to the need for a product that would be longer lasting, which is what this product is.”
Phase 3 data previously showed that TA-ER maintains efficacy up to 12 weeks after injection.
“Its long-lasting benefit separates it out from the traditional corticosteroid injection,” Kivitz said.
However, because the FDA approval is based on a single injection, additional trials are needed to examine the safety and efficacy of repeated injections.
For the current phase 2 trial, Kivitz and colleagues compared the pharmacokinetics (PK) of a bilateral TA-ER injection with a traditional intra-articular corticosteroid injection, which has a shorter duration of benefit that is “likely due to rapid efflux of corticosteroid from the joint,” Kivitz and colleagues wrote in the abstract.
Twenty-four patients with bilateral knee OA were randomized in a 1:1 ratio to receive 32 mg of TA-ER or 40 mg of Kenalog (immediate-release triamcinolone acetonide in crystalline suspension; TAcs; U.S. Pharmacopeia) in both knees. The researchers collected blood samples for plasma PK analyses 1 hour before injection; at several timepoints during the 12 hours after injection; and on days 2, 8, 15, 29 and 43 after injection.
Overall, triamcinolone acetonide exposure was significantly lower among patients who received TA-ER than TAcs (2,577.8 pg/mL vs. 24,289.4 pg.mL). The safety profiles of TA-ER and TAcs were similar. The most common treatment-emergent adverse events related to the study drug were injection site pain (8.3%) among patients who received TA-ER and arthralgia (8.3%) and joint swelling (8.3%) among patients who received TAcs. No serious treatment-emergent serious adverse events were reported, and there were no prolonged reductions in systemic cortisol production in either treatment group.
“The findings add to the robust and growing body of data that has been generated to provide clinicians with a deeper understanding of Zilretta’s clinical profile,” Kelley said in the release.
Additional research is currently underway to the determine the amount of time it takes for patients who received an initial injection of TA-ER to request a second injection.
“After receiving a single injection, patients are permitted to receive another injection after 12 weeks, if they need it,” Kivitz said. “Thus far, it is a median of 16.6 weeks for patients to ask for another injection. Those patients will be followed up to week 52 for both safety and efficacy.” – by Stephanie Viguers
Kivitz A, et al. Abstract 1371. Presented at: ACR/ARHP Annual Meeting, Oct. 20-24, 2018; Chicago.
Disclosure: Kivitz reports being a speaker and advisor for Flexion Therapeutics.