First‐in‐Human Phase 1 Study to Evaluate the Clinical Pharmacology Properties of RBN‐3143, a Novel Inhibitor of Mono‐Adenosine Diphosphate Ribosyltransferase‐PARP14

RBN-3143 is an inhibitor of PARP14 in development for inflammatory diseases. Multiple assessments were conducted to evaluate the clinical pharmacology properties of RBN-3134. A randomized, double-blind, placebo-controlled study assigned healthy volunteers (HVs) to single ascending doses (SADs) (25-1000 mg) or multiple ascending doses (MADs) (150, 300, and 500 mg twice daily [BID] for 14 days) of RBN-3143 or placebo. An open-label, randomized, 3-period, cross-over study evaluated the effects of food and pantoprazole (40 mg once daily [QD]) on the pharmacokinetics of RBN-3143 (500 mg), and a pharmacokinetic drug-drug interaction study with oral midazolam (2 mg) determined whether RBN-3143 (300 mg BID for 14 days) is an inducer of cytochrome P4503A4 (CYP3A4). The most common treatment-related treatment-emergent adverse events in subjects taking RBN-3143 were headache, nausea, vomiting, and elevated serum creatinine. In the SAD, RBN-3143 C_max and AUC_inf increased with dose, and T_max was 2 hours. RBN-3143 was cleared from plasma with an apparent terminal half-life ranging from 3 to 11 hours. In the MAD, C_max and AUC_inf increased 1.5- and 1.6-fold, respectively, following 14 days of 150, 300, and 500 mg BID dosing. Dosing of RBN-3143 with food resulted in higher C_max and AUC_inf ratios of 1.74 and 1.42, respectively. Coadministration with pantoprazole did not impact RBN-3143 exposure. RBN-3143 was an inducer of CYP3A4 in most but not all subjects, with mean midazolam C_max and AUC_inf ratios of 0.92 and 0.88, respectively. The clinical pharmacology properties of RBN-3143 in HVs support further development for inflammatory diseases.