Treatment with ruvonoflast, an oral nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inhibitor, results in a significant reduction in high-sensitive C-reactive protein (hsCRP) among individuals with elevated inflammatory risk compared with placebo, as shown in a phase I study.
Other inflammatory biomarkers, such as interleukin (IL)-6 and fibrinogen, have also decreased independent of changes in body weight, lipids, and measures of glycaemia.
The researchers randomized 63 individuals (mean age 52.6 years, 71.4 percent female, 69.8 percent White individuals) with hsCRP ≥2.5 mg/L and BMI ≥30 to ≤40 kg/m2, plus dyslipidaemia, hypertension, or type 2 diabetes, to oral ruvonoflast (225 mg twice daily; n=40) or matching placebo (n=23). All participants in each group maintained a 2,000 kcal/day diet.
The primary endpoint was change in hsCRP at day 28, assessed using a Bayesian analysis of covariance. A mixed-effects model with repeated measures was used to analyse change in hsCRP ratio to baseline over time. Secondary endpoints included change from baseline in inflammatory biomarkers and body weight, analysed using mixed-effects model with repeated measures and ANCOVA, respectively.
Of the participants, 59 completed the trial. The median hsCRP at baseline was 5.7 mg/L. On day 28, hsCRP decreased, with a posterior probability of >99 percent for superiority of ruvonoflast over placebo. [J Am Coll Cardiol 2026;88:1981-1994]
Significant between-group differences in favour of ruvonoflast began on day 3 onward (p≤0.001). Geometric least-squares mean reduction in hsCRP on day 28 was 82.2 percent (95 percent confidence interval [CI], 75.9‒86.8) with ruvonoflast compared with 37.2 percent (95 percent CI, 7.0‒57.6) with placebo. Notably, hsCRP levels returned to baseline 7 days after treatment discontinuation.
Furthermore, ruvonoflast also reduced IL-6 and fibrinogen on day 28 compared with placebo. Mean percentage body weight reductions were similar between groups, as were serious treatment-emergent adverse events (TEAEs). However, four (10 percent) participants treated with ruvonoflast discontinued treatment due to transient, reversible TEAEs compared with none in placebo.
“[R]uvonoflast [vs] placebo significantly lowered hsCRP, IL-6, and fibrinogen in a manner that appeared independent of changes in body weight, lipids, and measures of glycaemia,” the researchers said.
“Ruvonoflast is being evaluated in two ongoing phase II trials, which will help to inform whether targeting inflammation through upstream inhibition of the NLRP3 inflammasome with ruvonoflast is a viable, safe option to mitigate residual inflammatory atherosclerotic cardiovascular disease (ASCVD) risk,” they added.
ASCVD pathways
The researchers conducted this study based on emerging clinical data supporting the potential of ruvonoflast to modify inflammatory and thrombotic pathways implicated in ASCVD.
A recent phase Ib study in Parkinson’s disease showed the anti-inflammatory effects of ruvonoflast, reducing systemic hsCRP, with parallel IL-1β and IL-6 decreases in cerebrospinal fluid consistent with central nervous system anti-inflammatory activity. Ruvonoflast use also substantially lowered fibrinogen. [Mov Disord 2025;40:2199-2208]
In preclinical studies, use of ruvonoflast resulted in reductions in inflammatory markers and body weight, as well as improvements in glucose homeostasis and insulin sensitivity. [J Pharmacol Exp Ther 2024;388:813-826; Obesity 2025;33:1309-1321]
“Ruvonoflast is an oral small-molecule inhibitor of NLRP3 that is a unique chemotype distinct from earlier generations of NLRP3 inhibitors and designed for high tissue penetration, brain penetration, intracellular activity, and immune cell targeting,” the researchers said. [J Med Chem 2023;66:14897-14911]
“Ruvonoflast is converted to an active carboxylic acid through the action of hepatocyte and immune-cell carboxylesterase-1,” they added. [Biochem Pharmacol 2024;227:116455]