Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial

Abstract

Background: Gout flares are driven by interleukin (IL)-1β. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1β. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare.

Methods: In this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18-80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed.

Findings: Between May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving <80% of study drug and two had major protocol deviations): eight patients received 100 mg/day, seven received 300 mg/day, six received 1000 mg/day, and eight received 2000 mg/day. Between baseline and day 3, there was a mean reduction in patient-reported target joint pain of 52·4% (SD 32·94; p=0∙016) for the 100 mg/day group, 68·4% (34·29; p=0∙016) for the 300 mg/day group, 55·8% (44·90; p=0∙063) for the 1000 mg/day group, and 57·6% (38·72; p=0∙016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82·1% (22·68; p=0∙031) for the 100 mg/day group, 84·2% (16·33; p=0∙016) for the 300 mg/day group, 68·9% (34·89; p=0∙031) for the 1000 mg/day group, and 83·9% (15·44; p=0∙008) for the 2000 mg/day group, compared to baseline. 25 (73·5%) of 34 patients reported a total of 45 treatment-emergent adverse events, most of which were metabolism and nutrition disorders (17 [37·8%]) and gastrointestinal disorders (ten [22·2%]). Two serious adverse events occurred during the study, admission to hospital because of worsening of gout flare at day 3, and admission to hospital because of coronary stenosis 18 days after the patient received their last dose; these were considered moderate in severity and unrelated to the study drug.

Interpretation: Dapansutrile is a specific NLRP3 inflammasome inhibitor with a satisfactory safety profile and efficacy in the reduction of target joint pain in this study. Future studies are needed to confirm the clinical potential of dapansutrile.

Figure 1:

Trial profile

Figure 2:. Target joint pain and joint inflammation

A) Target joint pain for all timepoints. Patients scored target joint pain on a 0–100 mm VAS scale twice daily. Data are presented as mean target joint pain in comparison with the pain score at baseline, which was set at 100%. (B) Investigator-assessed signs of inflammation. At day 3 a score graded from no change to slight improvement, major improvement, or fully normalised was given for the target joint for all five components of inflammation. Each column represents one individual (one patient in the 1000 mg/day group missed the day 3 visit). (C) Investigator-scored tenderness at day 3 (mean ± SEM; 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain), and investigator-scored swelling in target joint at day 3 (mean ± SEM; 0=no swelling, 1=mild swelling, 2=moderate swelling, 3=severe swelling). VAS=visual analogue scale.

Figure 3:. Plasma cytokine levels and release

At all timepoints (baseline, day 3, day 7, and day 14) edetic acid plasma was collected and plasma IL-1β (A) and IL-6 (B) determined by Ella (Protein Simple). Data are shown as scatterplots with median for each group. Differences within each group between baseline and day 3 or day 7 were tested by Wilcoxon matched-pairs signed rank test. Plasma concentrations of dapansutrile at day 3 and day 7 for all individuals in the study were correlated to IL-1β (C) and IL-6 (D) release from stimulated peripheral blood mononuclear cells at the same timepoints. Spearman’s correlation was performed to analyse the correlation between the variables. Unstimulated peripheral blood mononuclear cellsfrom individuals taking 2000 mg/day and 100 mg/day were lysed and intracellular mature IL-1β and pro-IL-1β were measured by specific ELISA (E). Data are shown as mean ± SEM of relative change from baseline (value set at 1). One extreme outlier in each group was removed based on Grubb’s test. p values were calculated using Wilcoxon matched-pairs signed rank test for differences between day 0 and day 3. IL=interleukin.