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.