First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor

Abstract

This first-in-human study evaluated the safety, tolerability, single- and multiple-dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three-part trial including single and 2-week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3-600 mg] and MAD [fasted: 10-200 mg, once-daily or fed: 25 and 50 mg, twice-daily]). DFV890 was generally well-tolerated. Neither deaths nor serious adverse events were reported. A less than dose-proportional increase in exposure was observed with the initially used crystalline suspension (3-300 mg); however, an adjusted suspension formulation using spray-dried dispersion (SDD; 100-600 mg) confirmed dose-proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, C_max of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05- and 1.49-fold increase in C_max and AUC_0-last compared with the fasting condition. The median IC₅₀ and IC₉₀ for ex-vivo lipopolysaccharide-stimulated interleukin IL-1β release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once-daily or 25 mg twice-daily were sufficient to maintain ~90% of the IL-1β release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology.

FIGURE 1

Chemical structure of DFV890.

FIGURE 2

Disposition of subjects and analysis sets. *Subject had discontinued as the study was put on hold due to coronavirus disease 2019 pandemic. Part B was skipped because the data collected in Part A provided an adequate comparison of crystalline and SDD formulations. N, number of subjects randomized to treatment; n, number of subjects in each category; PD, pharmacodynamics; PK, pharmacokinetics; SAF, safety analysis set.

FIGURE 3

Summary of TEAE (Tornedo plot). The tornado plot for adverse events gives a visual interpretation of the scarcity of the events. The left side is maintained for the pooled placebo group with descending percentage of AE. The right side is the percentage of AE for the total active treatment groups in respective part with stacks inside to indicate contribution from different dose groups. The overall bar of active treatment groups represents the AE incidence percentage, but the stacks inside represent the portion of overall AE percentage coming from the particular dose group. b.i.d., twice‐daily; CS, crystalline suspension; CT, crystalline tablet; q.d., once‐daily; sd, single dose; ECT, encapsulated crystalline tablet; SDD, spray‐dried dispersion suspension; TEAE, treatment emergent adverse event; % = (n/N) × 100%.

FIGURE 4

Leukocyte and neutrophil counts after multiple ascending dosing (Part C). Longitudinal trajectory of mean leukocytes (a) and absolute neutrophils counts (b) by treatment and visit days in MAD cohorts (Part C). Participants received once or twice‐daily DFV890 or placebo for 13 days and last treatment in the morning on Day 14. Blood samples were taken at predose (baseline) and 8 h post (morning) dose on Day 1; at predose on Days 2–14; at 24 h (Day 15) and 48 h (Day 16) post last (morning)dose; and at the follow‐up visit (7–10 days after last dose). Data from placebo treatment was pooled from all cohorts. Dashed lines represent lower and upper limit of normal range (LLN and ULN, respectively). b.i.d., twice‐daily; q.d., once‐daily; SDD, spray‐dried dispersion.

FIGURE 5

Plasma concentration‐time profiles of DFV890 (a) SAD, (b) MAD from Day 1 to Day 14, (c) Relative bioavailability and food effect. b.i.d., twice‐daily; MAD, multiple ascending dose; N, number of subjects randomized to treatment; n, number of subjects in each category; q.d., once‐daily; SAD, single ascending dose; SDD, spray‐dried dispersion.

FIGURE 6

Geometric mean IL‐1β concentrations plots (a) in SAD, (b) in MAD, (c) IL‐1β versus DFV890 concentrations. Panel (c): Model‐estimated 90% credible interval (dark blue region), 90% prediction interval (light blue region), median estimate (black line), and observed IL‐1β concentration (points) versus DFV890 concentration, log–log scale. b.i.d., twice‐daily; MAD, multiple ascending dose; q.d., once‐daily; SAD, single ascending dose; SDD, spray‐dried dispersion.