口服NLRP3抑制剂Ruvonoflast对心血管高风险人群的抗炎效应

原文

BACKGROUND: The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a key sensor of diverse exogenous stimuli linked to noncommunicable diseases including atherosclerotic cardiovascular disease. Early clinical data with the oral NLRP3 inhibitor ruvonoflast suggested lowering of biomarkers of systemic and central nervous system inflammation. OBJECTIVES: The purpose of this study was to assess anti-inflammatory efficacy and safety of ruvonoflast in participants with residual inflammatory risk and high atherosclerotic cardiovascular disease risk. METHODS: In a double-blind Phase 1b trial, we randomly allocated individuals with high-sensitivity C-reactive protein (hsCRP) ≥2.5 mg/L and body mass index ≥30 to ≤40 kg/m2, plus dyslipidemia, hypertension, or type 2 diabetes, to oral ruvonoflast (225 mg twice daily; n = 40) or matching placebo (n = 23). Both groups were maintained on a 2,000 kcal/d diet. The primary endpoint was change in hsCRP at Day 28 (ratio to baseline), analyzed using a Bayesian analysis of covariance. Additionally, change in hsCRP ratio to baseline over time was analyzed using a mixed-effects model with repeated measures. Change from baseline in inflammatory biomarkers and body weight were secondary endpoints analyzed with mixed-effects model with repeated measures and ANCOVA, respectively. Safety and tolerability were analyzed descriptively. RESULTS: Of 63 participants (mean age: 52.6 years; 71.4% female; 69.8% White) randomized, 59 completed the study. Median hsCRP at baseline was 5.7 mg/L (IQR: 3.9-9.8 mg/L). The primary endpoint of hsCRP reduction was met with a posterior probability of >99% for superiority of ruvonoflast over placebo at Day 28. Between-group differences favoring ruvonoflast were significant from Day 3 onward (P ≤ 0.001); at Day 28, geometric least-squares mean reduction in hsCRP was 82.2% (95% CI: 75.9%-86.8%) with ruvonoflast vs 37.2% (95% CI: 7.0%-57.6%) with placebo. hsCRP returned to baseline 7 days post-treatment discontinuation. Ruvonoflast significantly lowered key secondary biomarkers interleukin-6 and fibrinogen vs placebo at Day 28 (P < 0.001). Treatment groups had comparable mean percentage body weight reductions at Day 28. Serious treatment-emergent adverse advents were similar between groups, but 4 (10%) ruvonoflast-treated participants discontinued treatment due to transient, reversible treatment-emergent adverse advents, vs none in placebo. CONCLUSIONS: Oral NLRP3 inhibition with ruvonoflast significantly reduced hsCRP with concurrent reductions in inflammatory biomarkers in participants with elevated inflammatory risk. Ongoing Phase 2 trials of larger size and longer duration will further characterize the therapeutic potential of ruvonoflast. (Effects of NT-0796 in Obese Participants at Risk of Cardiovascular Disease; NCT06129409).