182: Pharmacokinetics of RBN-3143 in Healthy Adults, A Novel Mono (ADP-Ribose) Polymerase-14 (PARP14) Inhibitor

Statement of Purpose: RBN-3143 is a potent inhibitor of PARP14 in early development for the treatment of atopic dermatitis. PARP14 is expressed downstream of interferon and is a key mediator of Th2 and Th17 cytokine signaling. PARP14 is upregulated in tissues of inflammatory diseases, such as atopic dermatitis and inhibition suppresses disease phenotypes in rodent models of lung and skin inflammation. This first-in-human study of RBN-3143 evaluated the clinical pharmacology properties of RBN-3143, including single dose and steady state pharmacokinetics (PK), food effect and potential drug-drug interactions.

Description of Methods & Materials: A Phase 1 study was conducted in healthy male and female subjects aged 18 to 65 years. The study consisted of a randomized, double-blind, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) part, followed by an open label cohort to determine the effect of food (FE) and a proton pump inhibitor (PPI) on the PK of RBN-3143. The SAD cohorts tested RBN-3143 doses of 25, 50, 100, 150, 300, 600 and 1,000 mg administered orally as tablets. The MAD cohort tested RBN-3143 oral doses of 150, 300, and 500 mg dosed twice a day (BID) for 14 days. A dose of 500 mg RBN-3143 was tested in the cohort assessing the effect of food and PPI (pantoprazole 40 mg once daily) on RBN-3143 PK. Blood was collected at specific time points and harvested plasma was analyzed using a validated LC-MS method. PK parameters were estimated using non-compartmental analysis.

Data & Results: Seventy-seven subjects were enrolled in the SAD and MAD cohorts, of which 79% were males with a mean age of 30 years (range: 18 to 65 years). In the SAD cohorts, RBN-3143 plasma C_max and AUC_inf increased with a single dose from 25 to 1,000 mg. Peak plasma concentrations were achieved at approximately 2 hours after oral administration. RBN-3143 was cleared from plasma with a half-life of 2.9 to 10.9 hours. RBN-3143 free plasma concentrations exceeded the in vitro PARP14 enzyme IC90 for at least 12 hours following a dose of 100 mg and higher. In the MAD cohorts, Day 1 PK was consistent with the data observed in SAD at the same dose level. Plasma AUC and C_max increased approximately 1.6- and 1.5-fold, respectively, following 14 days of 150, 300 and 500 mg BID dosing. Pre-dose sampling between Days 1 and 14 indicates that steady state is reached on Day 3. Dosing of RBN-3143 with food resulted in higher C_max and AUC_inf with ratios (90% confidence interval) of 1.74 (1.48-2.04) and 1.42 (1.28-1.58), respectively. Co-administration with PPI did not impact RBN-3143 plasma exposures.

Interpretation, Conclusion or Significance: The PK of RBN-3143 in healthy subjects supports further development of RBN-3143 for the treatment of atopic dermatitis.

Disclosures: Nothing to disclose