First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor.
Ewa GatlikBeata MehesEmilie VoltzUlrike SommerElaine TrittoGiulia LestiniXiaoxi LiuParasar PalMaria VelinovaWilliam S DenneyYunlin FuAnthony OpipariDennis DeanGuido JungePublished in: Clinical and translational science (2024)
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 IC 50 and IC 90 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.
Keyphrases
- open label
- double blind
- endothelial cells
- placebo controlled
- phase iii
- room temperature
- clinical trial
- drug delivery
- insulin resistance
- randomized controlled trial
- machine learning
- blood glucose
- type diabetes
- toll like receptor
- metabolic syndrome
- coronary artery
- pulmonary artery
- pulmonary hypertension
- artificial intelligence
- big data
- glycemic control