166: The Effect of Food & the Proton Pump Inhibitor (PPI) Esomeprazole on the Single-Dose Pharmacokinetics (PK) & Safety of ARV-766, a PROteolysis Targeting Chimera (PROTAC) Androgen Receptor (AR) Degrader, in Healthy Volunteers

Statement of Purpose: ARV-766 is a small molecule, orally bioavailable PROTAC AR degrader that is being evaluated as a potential treatment for men with prostate cancer. Esomeprazole, a common gastroesophageal reflux disease treatment, raises gastric pH and is used for evaluating pH-dependent drug interactions. In preclinical studies, food increased and an acid reducing agent decreased ARV-766 exposure. We evaluated food and esomeprazole effects on single-dose ARV-766 PK, and safety.

Description of Methods & Materials: This Phase 1, open-label study included a crossover, fed/fasted cohort and a fixed-sequence PPI cohort. For the fed/fasted cohort, healthy male volunteers received a single oral dose of ARV-766 200 mg in a fasted state during treatment A and in a fed state, following a high-calorie/high-fat meal, during treatment B. Participants were randomized to a dosing sequence of treatments AB or BA. For the PPI cohort, a single oral dose of ARV-766 300 mg was administered alone in a fed state during treatment C, and during treatment D, participants received esomeprazole 40 mg for 5 days prior to a single oral dose of ARV-766 300 mg on day 5 in a fed state. Participants were assigned to a fixed-dosing sequence of treatments CD. There was a 24-day washout period between ARV-766 treatments. PK blood samples were collected predose and at selected times up to 312 hours post-ARV-766 dose. Primary endpoints were area under the plasma concentration-time curve from the time of dosing extrapolated to infinity (AUC_inf) and maximum plasma concentration (C_max) of ARV-766. Secondary endpoints included additional PK parameters and safety and tolerability.

Data & Results: A total of 30 volunteers were enrolled. Analysis populations were food effects (n=14), PPI effects (n=16), and safety (n=30). The median time to C_max (T_max) was delayed by ≈4 hours in fed vs fasted states (12 vs 7.75 hours), and C_max and AUC_inf increased 3.9-fold and 3.1-fold, respectively (Table). Interindividual variability in PK was lower under fed vs fasted conditions. ARV-766 in combination with esomeprazole vs ARV-766 alone resulted in slight reductions in C_max and AUC_inf (≈20% and 11%, respectively; Table), and median T_max was delayed by 3 hours (10 vs 7 hours). Overall, 5 (35.7%) participants in the food effects cohort and 8 (50.0%) in the PPI effects cohort experienced a treatment-emergent adverse event (TEAE). All TEAEs were grade 1/2. Among all participants, 3 (21.4%) in the food effects fasted group and 2 (12.5%) in the PPI effects cohort experienced an ARV-766–related AE.

Interpretation, Conclusion or Significance: Food improved absorption, increased the peak concentration and extent of systemic exposure of ARV-766, as well as decreased PK variability compared with fasting. Coadministration with esomeprazole slightly decreased the peak concentration and extent of systemic exposure of ARV-766 when given with food, but the magnitude is not anticipated to be clinically significant. ARV-766 as a single oral dose administered in the fasting state, fed state, or in combination with esomeprazole was generally well tolerated by healthy male participants. Based on these findings, in clinical studies ARV-766 should be administered with food and use of PPIs is not strictly restricted but will be monitored closely.

Disclosures: All authors are employees of Arvinas Operations Inc. Edward Chan holds stock in Amgen. Haolan Lu holds stock in Arvinas Operations Inc and Bristol-Myers Squibb.