Abstract 4366197: Selnoflast reduces markers of systemic inflammation in participants with coronary artery disease and elevated C-reactive protein

Introduction: While low-density lipoprotein (LDL) cholesterol lowering is central to coronary artery disease (CAD) management, elevated interleukin-6 (IL-6) and high-sensitivity CRP (hsCRP) in statin-treated patients signals residual NLRP3-driven inflammation and ongoing risk. Research Questions: We hypothesized that selnoflast, an oral NLRP3 inflammasome inhibitor, is safe and would significantly reduce IL-6 and hsCRP levels in participants with CAD and elevated hsCRP. Methods: This randomized, double-blinded, placebo-controlled trial (ISRCTN10520571) assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of selnoflast (200 mg po BID) in 22 participants, with history of myocardial infarction and elevated hsCRP (≥2 mg/L), randomized 1:1 to receive selnoflast or placebo (PBO). The primary endpoint was safety; secondary and exploratory endpoints included PK and PD assessment of IL-6 and hsCRP change from baseline (BL). Results: Among the 22 participants, mean (standard deviation [SD]) age was 64.5 (7.6) years, 11 (50%) were female, and BL mean (SD) IL-6 and hsCRP were 1.79 (28.24) pg/mL and 6.36 (4.52) mg/L, respectively. Selnoflast demonstrated a favorable safety profile, consistent with prior studies. Seventeen adverse events (AEs) were reported: 11 AEs in 3 of 11 (27.3%) participants on selnoflast and 6 AEs in 5 of 11 (45.5%) participants on PBO. On Day 15, mean (SD) plasma concentrations of selnoflast were 5.31 (3.68) μg/mL pre-dose and 10.5 (4.62) μg/mL at 2 hours post-dose (Cmax). Steady-state PK was approached by Day 2, with <2-fold accumulation of mean Cmax from Day 1 6.31 (3.68) μg/mL to Day 15 10.5 (4.62) μg/mL. IL-6 levels were comparable at BL, with greater mean reductions by Day 8 in the selnoflast group (–36% change, 13.27±31.22 pg/mL) vs PBO (–9.03% change, 6.57±5.85 pg/mL). Absolute reductions remained ≥36% through Day 29, with individual PBO-corrected IL-6 decreases ranging from 27-79% ( Fig 1A ). hsCRP levels were also comparable at BL, with greater mean reductions by Day 8 in the selnoflast group (–70.95% change, 1.35±1.01 mg/L) vs PBO (–29.45% change, 4.99±5.59 mg/L). Absolute reductions remained ≥55% through Day 29, with individual PBO-corrected decreases ranging from 25-66% ( Fig 1B ). Conclusion: Selnoflast was well tolerated without notable safety signals relative to PBO, approached steady-state PK by Day 2, and demonstrated consistent reductions in inflammatory biomarkers IL-6 and hsCRP in patients with CAD and residual inflammation.