Novel drug STRIDES in the right direction for knee OA

In the phase III STRIDES X-Ray Extension study, additional doses of the investigational CLK/DYRK inhibitor lorecivivint delivered favourable outcomes for individuals with advanced knee osteoarthritis (OA).

“Regarding the potential benefit of lorecivivint in terms of structure and joint space width (JSW), this emerged after the second injection at 24 months, and there appeared to be additional benefit with the third injection,” said study investigator Dr Timothy McAlindon from Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts, US, during his presentation at EULAR 2023.

In the parent study, 501 individuals with moderately severe knee OA were randomized 1:1 to receive an intra-articular injection of lorecivivint 0.07 mg or placebo. A year after, a single-blind extension phase ensued wherein 277 participants (mean age 61 years, 63 percent female) from the parent cohort received another dose of their allocated regimen. [EULAR 2023, abstract OP0074]

After another year, participants rolled over to another extension phase wherein everyone received the active drug. Of note was the fairly low numbers in this phase, as the assessment was confined to participants who proceeded the entire way throughout the study to data cutoff at month 36.

In the ANCOVA analysis, the curves did not diverge during the first year. But after the second injection, there was some divergence in medial JSW between arms. “At this point, participants in the placebo group were exhibiting more loss of joint space,” said McAlindon. When comparing the lorecivivint arm at month 36 against the placebo arm at month 24, a statistically significant difference was observed (p=0.019).

Regarding Pain NRS*, an improvement was seen in terms of the change from extension baseline to month 24 favouring lorecivivint over placebo (–0.25 vs 0.09; change –0.34; p=0.207). Albeit lacking statistical significance, the curves began to split from the beginning of the single-blind phase. It tracked similarly from month 18 towards the open-label phase, McAlindon noted.

The results were more differentiated in terms of WOMAC** Pain. A divergence began from month 12, and by month 24, the between-arm difference was statistically significant (–5.18; p=0.047). When all participants were on active treatment however, the arms appeared to have converged.

A similar trajectory was observed in terms of WOMAC Function between months 12 and 24, yielding a between-arm difference of –4.9 at the end of the single-blind phase. This however does not reach statistical significance (p=0.056). After which, the study arms reconverged, meeting at around month 30 and sustaining this effect through month 36.

Why no effect at year 1?

The lack of treatment effect during the first year may have been driven by the COVID-19 pandemic, McAlindon noted. “This is conjectural, but this has been seen in other trials … Individuals could have been inactive during the pandemic, so perhaps disease progression and pain was less manifest.”

“When participants rolled over to the extension phase, the pandemic restrictions were already lifting. That is when we start to see differences. [Around this time,] people could have become more active,” he explained.

In the current study looking at a cohort of patients with structurally advanced knee OA, the changes in joint space and patient-reported outcomes underscore the potential structural and quality-of-life benefits that lorecivivint can deliver as opposed to placebo.

The study is ongoing, and another trial looking at pain and symptoms within a shorter timeframe (12 weeks) is in progress.