Key Points:
- Inflammation is mechanistically linked to atherosclerosis and recurrent cardiovascular events but approved anti-inflammatory treatment options remain limited. Ruvonoflast is an oral NLRP3 inflammasome inhibitor designed to act upstream of IL-1β, IL-18, and IL-6 pathways.
- The phase 2 RESOLVE-1 trial randomized 176 adults, approximately half with type 2 diabetes, 1:1:1 to ruvonoflast 150 mg, ruvonoflast 300 mg, or placebo for 24 weeks.
- Ruvonoflast 300 mg significantly reduced hsCRP compared with placebo in participants with and without type 2 diabetes, with concurrent reductions in fibrinogen and IL-6, no statistically significant effect on body weight or HbA1c, and no observed increase in infections.
Inflammation is mechanistically linked to atherogenesis, plaque progression, and recurrent cardiovascular events, yet anti-inflammatory treatment options remain limited. Targeting downstream cytokines within the NLRP3-to-IL-1β-to-IL-6 pathway have yielded mixed results, with some signal towards increased infection risk. NLRP3 inhibition offers an upstream approach to inflammation mediation while potentially preserving host immunity. Oral ruvonoflast (Rezera), a NLRP3 inhibitor, was previously shown to reduce high-sensitivity C-reactive protein (hs-CRP) by 82% from baseline without apparent increase in infections at a dose of 450mg daily.
RESOLVE-1 was a phase 2, randomized, placebo-controlled, dose-ranging trial. The study enrolled adults aged 21 to 75 years, approximately half of whom had type 2 diabetes mellitus (DM), with no GLP-1 receptor agonist use within 6 months. Participants were randomized 1:1:1, stratified by DM status, to ruvonoflast 150 mg, ruvonoflast 300 mg, or placebo for 24 weeks, followed by a 4-week washout. Of note, participants were originally consented into a weight loss trial, but the ruvonoflast program subsequently shifted its focus to inflammation. The hierarchical primary endpoint, independently powered in participants with and without DM, included change in hs-CRP up to week 24, change in body weight at week 24, and change in HbA1c at week 24 in the DM cohort. The prespecified primary hs-CRP analysis used a modified intention-to-treat population with censoring for intercurrent events; some participants with infection or substantial missing data were excluded. A prespecified sensitivity analysis used the full intention-to-treat population without censoring for intercurrent events
The results were presented at the American Heart Association (AHA) Scientific Sessions on November 7, 2026. Of the 176 participants, 89 had DM; mean body mass index was approximately 34 to 35 kg/m2 and median baseline hs-CRP ranged from 2.5 to 3.95 mg/L across groups. In the primary modified intention-to-treat analysis, assessing hs-CRP change up to week 24 among participants with DM, hs-CRP decreased by 23.6% with ruvonoflast 300 mg (P = 0.011) and 30.3% with 150 mg (P < 0.001) compared with a 7.8% increase with placebo. Among participants without DM, hs-CRP decreased by 34.2% with the 300-mg dose (P < 0.001) compared with a 7.0% increase with placebo, while the 11.4% reduction with the 150-mg dose was not significant (P = 0.154). In the intention-to-treat sensitivity analysis, hs-CRP reductions were significant at both doses in those with and without DM. Fibrinogen decreased by 10.2% and 8.9% with the 150-mg and 300-mg doses compared with a 1.1% increase with placebo (both P < 0.0001), and IL-6 decreased by 16.1% and 19.1%, respectively, compared with a 6.5% increase with placebo in an exploratory analysis. In a post hoc analysis at week 4, biomarker reductions were largest in participants with baseline hsCRP >3 mg/L and consistent drug exposure. There were no significant differences in body weight or HbA1c compared with placebo. Ruvonoflast was generally well tolerated, with no treatment-related serious adverse events, and no increase in infections. Thirty participants (17%) discontinued early, most often by choice or loss to follow-up, frequently attributed to logistical barriers or perceived lack of weight loss efficacy. A phase 3 trial of ruvonoflast in peripheral artery disease is planned for the first half of 2027.
Limitations of the trial reflect its phase 2 design, including a small sample size and short treatment duration. Enrollment was also based on metabolic risk rather than established atherosclerotic cardiovascular disease, and there were no clinical or functional outcomes assessed. Finally, there was notable participant attrition and variable treatment exposure.
Presenting the results, Dr. Javed Butler concluded that “RESOLVE-1 met its primary hs-CRP endpoint, with concurrent reductions in IL-6 and fibrinogen” and that “these data support further evaluation of upstream NLRP3 inhibition with ruvonoflast, especially in inflammation-enriched populations.”