First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers

Abstract

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1β and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development.

FIGURE 1

Mean GDC‐2394 plasma concentration‐time profiles in the (a) single‐ascending dose (150 mg [n = 6], 450 mg [n = 6], 900 mg [n = 6], 1800 mg [n = 6]), (b) food‐effect (n = 8), and (c) multiple‐ascending dose stages (300 mg b.i.d. [n = 6], 900 mg b.i.d. [n = 6]), and (d) mean midazolam plasma concentration‐time profile in the drug‐drug interaction stage (n = 9). Dashed lines represent the lower limit of quantification. Error bars represent standard deviation.

FIGURE 2

Mean percent inhibition of IL‐1β and IL‐18 relative to baseline after LPS/ATP stimulation of whole blood samples collected from participants at the indicated timepoints in the SAD, FE, and MAD stages. Each measurement of secreted IL‐1β/IL‐18 consisted of the mean of two technical replicates. (a) IL‐1β: SAD stage (placebo [n = 8], 150 mg [n = 6], 450 mg [n = 6], 900 mg [n = 6], 1800 mg [n = 6]), (b) IL‐1β: FE stage (placebo [n = 2], 600 mg [n = 8]), (c) IL‐1β: dosing period of the MAD stage (placebo [n = 4], 300 mg b.i.d. [n = 6], 900 mg b.i.d. [n = 6]), (d) IL‐18: SAD stage (placebo [n = 8], 150 mg [n = 6], 450 mg [n = 6], 900 mg [n = 6], 1800 mg [n = 6]), and (e) IL‐18: dosing period of the MAD stage (placebo [n = 4], 300 mg b.i.d. [n = 6], 900 mg b.i.d. [n = 6]). Percent IL‐18 inhibition was adjusted for circulating levels of IL‐18. Error bars represent standard deviation. FE, food‐effect; MAD, multiple‐ascending dose; SAD, single‐ascending dose.

FIGURE 3

Pharmacokinetic/pharmacodynamic modeling of individual data for (a) percent IL‐1β inhibition relative to baseline from all GDC‐2394‐treated participants in SAD, food‐effect, and MAD stages (n = 44) and (b) percent IL‐18 inhibition relative to baseline (adjusted for circulating levels of IL‐18) from all GDC‐2394‐treated participants in SAD and MAD stages (n = 36). Blue line represents the sigmoidal E_max model fit, and red circles represent individual observations. Dashed lines represent 0% and 90% inhibition relative to baseline. E_max, maximum effect; MAD, multiple‐ascending dose; SAD, single‐ascending dose.