Safety, Tolerability, and Pharmacokinetics of Same-Knee Intra-Articular Injection of Corticosteroid and Lorecivivint Within 7 Days: An Open-Label, Randomized, Parallel-Arm Study.

ABSTRACT

INTRODUCTION: Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart. METHODS: Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by "epoch", with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction. RESULTS: A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences. CONCLUSION: No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT04598542.

Knee osteoarthritis (OA) is a common disorder characterized by pain and loss of function. This clinical trial tested if two different treatments for OA injected into the same knee 1 week apart would impact the safety or exposure of either treatment. The treatments evaluated were an injection of a corticosteroid, triamcinolone acetonide, and a potential OA treatment in development, lorecivivint, a novel small molecule thought to inhibit inflammation and a biological pathway called the Wnt pathway. The amount of either treatment found in circulation was not different when injected before or after the other treatment. The order of injection did not change the safety profile for either agent, suggesting injection of the two agents 1 week apart is unlikely to pose a safety concern.