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SAN DIEGO -- Boosting levels of interleukin-10 (IL-10) via intra-articular gene therapy is a viable approach for treating osteoarthritis (OA) of the knee, results of a phase II study indicated.

Although the missed its primary endpoint, enough advantages were seen in secondary outcomes -- arguably better measures of the technology's potential -- to warrant additional clinical studies, according to Howard Rutman, MD, MBA, chief medical officer of Xalud Therapeutics in Berkeley, California, who presented the findings here at the American College of Rheumatology's annual meeting.

Rutman explained that, unlike more familiar interleukin species that promote inflammation, IL-10 is a regulatory protein that keeps other cytokines in check. Lab studies and animal models have suggested that increasing IL-10 levels within arthritic joints diminishes inflammation and improves function.

IL-10 is quickly degraded after release, however, so simply injecting it is not likely to work clinically. Instead, Xalud has developed a "naked" gene therapy approach in which plasmids containing IL-10 nucleic acid sequences are delivered into the joint. It does not involve a viral vector and the gene isn't integrated into the patient's genome, Rutman said. Nevertheless, as the plasmids are absorbed into synovial cells, IL-10 expression continues for weeks, giving hope for durable benefit from infrequent dosing.

The current study was conducted in two stages, with six different dosing regimens tested. In stage A, 286 patients were randomized in equal numbers to single injections of placebo or either 0.15 or 0.45 mg of the company's IL-10 gene therapy, called XT-150. The trial's primary endpoint, achievement of at least 30% reduction in Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain score, was assessed 6 months after this initial dosing.

In stage B, the placebo group was re-randomized to receive 0.15 or 0.45 mg of XT-150, while each of the two active-drug groups from stage A were given a second injection of either their same original dose or the other one. No placebo was given in stage B. Thirty-five participants in stage A withdrew without participating in stage B (Rutman said the COVID-19 pandemic was a factor here). WOMAC pain and function scores were determined again 6 months after the second dose.

At the end of stage A, WOMAC pain responses of 30% or more were seen in 40% of the placebo group versus 27%-30% of the two active drug groups; the differences were not statistically significant.

Although this was disappointing, as the researchers hoped to see an advantage for XT-150 at this point, results from the second dose were clearly encouraging. The 36 participants who received 0.45 mg of the product in both injections had an average 4.93-point decrease from baseline in WOMAC pain score, versus mean declines of roughly 2.5-3 points in the participants whose stage A assignment was placebo and who then had 0.15 or 0.45 mg of XT-150 in stage B. Improvements in WOMAC function score followed a similar pattern.

Rutman said that, for future studies in knee OA, XT-150 will be dosed at 0.45 mg and the repeat injection delivered at day 90, in hopes of seeing benefit faster than in the current trial. Data on the time course of change in WOMAC scores indicated that the second dose did more than simply extend benefit from the first injection but actually expanded it. Maximal effects seemed to appear about 60-90 days after dosing.

Besides the approximately 12% dropout rate between stages A and B, another limitation was that 49 patients had only minimal pain when they began stage A, and thus could not have shown significant improvement with treatment. This arose because some weeks elapsed between screening -- at which point a WOMAC pain score of at least 8 was needed for eligibility -- and initial dosing. Scores in those 49 declined during that interval to the point that they should not have been included. The stage B analyses excluded those patients as well as 27 others whose baseline WOMAC score was exactly 8.

Besides knee OA, Xalud also is pursuing an indication for OA in the facet joint; the company just completed a , with results not yet released.

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