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SAN DIEGO -- Two intra-articular injections of a liposomal formulation of dexamethasone given 6 months apart provided a year of pain relief for patients with osteoarthritis (OA) of the knee, a researcher said here.

In a , average daily pain (ADP) levels in patients receiving the investigational product called TLC599 declined by half after the first dose, according to David Hunter, MBBS, MSc, of the University of Sydney in Australia, and this was significantly greater than with placebo.

The second injection boosted the pain relief even more, such that ADP scores declined an additional full point on the index's 10-point scale, Hunter told attendees at the American College of Rheumatology (ACR) annual meeting.

Pain did rebound slightly over the final months of the year-long study, but at week 52 the average ADP score was still lower than just before the second injection was given.

Steroid injections are commonly used to treat knee OA, but the effects don't last long and many clinicians are reluctant to give repeat doses. One approach that industry is now taking is to develop long-acting formulations. Another trial reported at the ACR meeting examined a polymer-coated version of fluticasone, previously best known in its inhalable formulation for asthma. TLC599 represents a similar approach, using lipid bubbles to encapsulate the steroid for extended release.

For the current study, Hunter and colleagues enrolled 504 patients with moderate knee OA (Kellgren-Lawrence grade 2/3), randomizing them 2:1:1 to the following treatment regimens:

• TLC599 (n=252)
• Placebo (n=126)
• Regular dexamethasone sodium phosphate

Each was delivered in a single injection to one knee at week 0 and then, at participants' option, again at week 24. Roughly three-quarters of each group requested the repeat injection.

Participants' mean age was about 60. Body mass index values averaged 31, and a little more than half of patients were women.

Besides ADP, the 4-point Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) score for pain was a secondary endpoint. All three treatment arms saw substantial drops in this pain score 1 week after the first dose, by a full point in the regular dexamethasone and TLC599 groups, and 0.8 points with placebo, all from baseline means of 2.2-2.3. Some pain returned over the following 6 months but remained well below baseline. (Hunter did not report WOMAC pain scores for the second treatment phase, nor WOMAC function scores.)

In response to an audience question, Hunter said the absolute decline in WOMAC pain score met a standard threshold for clinical significance. But the difference between the TLC599 and placebo groups was well short of that because of the strong placebo response. Hunter also said it wasn't clear why the regular dexamethasone largely matched the liposomal formulation throughout the study period. He noted, however, that the same phenomenon was seen in a trial of extended-release triamcinolone: it provided substantial pain relief lasting several months, but injections of regular triamcinolone did just as well.

The only adverse event of note was increased reports of pain in the injected joint immediately following the TLC599 shots relative to the other treatments. Other adverse events appeared unconnected to treatment or were typical of any intra-articular injection. TLC599 was "generally well tolerated," Hunter said.

What's next for TLC599 is unclear. The developer, Taiwan Liposome Co., hasn't said whether it plans to take these phase III data to regulatory authorities for marketing approval. No additional phase III testing is ongoing either, although the company does have a that again tests TLC599 against intravenous regular dexamethasone, with pharmacokinetics as the principal outcome and without placebo control -- presumably to better understand what happened in the phase III study.

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