Source: [europepmc](https://pubmed.ncbi.nlm.nih.gov/42187339/)
Authors: Ray KK, Clarke N, Thornton P, Miles AE, Digby Z, Davies MJ, Gorman M, Mullen B, Reader V, Magill M, Johnstone H, Ariti C, Sattar N, Marx N, Navar AM, Hernandez AF, George JT, Watt AP, Butler J, Ridker
Venue: Journal of the American College of Cardiology · 2026-05-26
Abstract
The NLRP3 inflammasome is a key sensor of diverse exogenous stimuli linked to non-communicable 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. To assess anti-inflammatory efficacy and safety of ruvonoflast in participants with residual inflammatory risk and high ASCVD risk. In a double-blind Phase 1b trial, we randomly allocated individuals with hsCRP ≥2.5 mg/L and BMI ≥30 to ≤40 kg/m2, plus dyslipidemia, hypertension or type 2 diabetes, to oral ruvonoflast (225mg twice daily; N=40) or matching placebo (N=23). Both groups were maintained on a 2000 kcal/day 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 (MMRM). Change from baseline in inflammatory biomarkers and body weight were secondary endpoints analyzed with MMRM and ANCOVA, respectively. Safety and tolerability were analyzed descriptively. 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). 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 onwards (p≤0.001); at Day 28, geometric least-squares mean reduction in hsCRP was 82.2% (95% CI=75.9-86.8) with ruvonoflast versus 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 IL-6 and fibrinogen versus placebo at Day 28 (p<0.001). Treatment groups had comparable mean percentage body weight reductions at Day 28. Serious treatment-emergent adverse advents (TEAEs) were similar between groups, but four (10%) ruvonoflast-treated participants discontinued treatment due to transient, reversible TEAEs, versus none in placebo. 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.
AI relevance (5/5): Phase 1b interventional trial directly targeting NLRP3 inflammasome with hsCRP biomarker endpoint in metabolic disease population.
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