Anti-Inflammatory Effects of Oral NLRP3 Inhibition With Ruvonoflast Among Individuals at Elevated Cardiovascular Risk
13 affiliations
- 1Department of Primary Care and Public Health, Imperial College London, London, United Kingdom; Imperial Clinical Trials Unit-Global, Imperial College London, London, United Kingdom. Electronic address: [email protected]
- 2NodThera, Boston, Massachusetts, USA
- 3Diabetes Research Centre, University of Leicester, Leicester, United Kingdom; NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom
- 4Natick, Massachusetts, USA
- 5HJ Clinical Trial Consultancy, George, South Africa
- 6Imperial Clinical Trials Unit-Global, Imperial College London, London, United Kingdom
- 7University of Glasgow, Glasgow, United Kingdom
- 8University Hospital Aachen, Aachen, Germany
- 9University of Texas Southwestern Medical School, Dallas, Texas, USA
- 10Duke University School of Medicine, Durham, North Carolina, USA
- 11NodThera, Boston, Massachusetts, USA. Electronic address: [email protected]
- 12Baylor Scott and White Research Institute, Dallas, Texas, USA; University of Mississippi, Jackson, Mississippi, USA
- 13Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, Massachusetts, USA
Abstract
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: , 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).
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BibTeX
@article{ray2026antiinflammatory,
title = {{Anti-Inflammatory Effects of Oral NLRP3 Inhibition With Ruvonoflast Among Individuals at Elevated Cardiovascular Risk}},
author = {Kausik Kumar Ray and Nicholas P. Clarke and Peter Thornton and Amy E. Miles and Zsofia Digby and Melanie Jane Davies and Michelle Gorman and Bianca Mullen and Valérie Reader and Missy Magill and Hilary Johnstone and Cono Ariti and Naveed A. Sattar and Nikolaus Marx and Ann Marie Navar and Adrian F. Hernandez and Jyothis T. George and Alan P. Watt and Javed Butler and Paul M. Ridker},
journal = {Journal of the American College of Cardiology},
year = {2026},
month = may,
doi = {10.1016/j.jacc.2026.05.014},
url = {https://doi.org/10.1016/j.jacc.2026.05.014},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Anti-Inflammatory Effects of Oral NLRP3 Inhibition With Ruvonoflast Among Individuals at Elevated Cardiovascular Risk
AU - Kausik Kumar Ray
AU - Nicholas P. Clarke
AU - Peter Thornton
AU - Amy E. Miles
AU - Zsofia Digby
AU - Melanie Jane Davies
AU - Michelle Gorman
AU - Bianca Mullen
AU - Valérie Reader
AU - Missy Magill
AU - Hilary Johnstone
AU - Cono Ariti
AU - Naveed A. Sattar
AU - Nikolaus Marx
AU - Ann Marie Navar
AU - Adrian F. Hernandez
AU - Jyothis T. George
AU - Alan P. Watt
AU - Javed Butler
AU - Paul M. Ridker
PY - 2026
DA - 2026/05/26
JO - Journal of the American College of Cardiology
DO - 10.1016/j.jacc.2026.05.014
UR - https://doi.org/10.1016/j.jacc.2026.05.014
AB - 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: , 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).
SN - 0735-1097
SN - 1558-3597
ER -