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

Statement of Purpose: The small molecule, orally bioavailable PROTAC AR degrader bavdegalutamide (ARV-110) is being investigated as a potential prostate cancer treatment. Bavdegalutamide demonstrated an acceptable safety profile in a multiple-dose study in men with prostate cancer. In preclinical studies, food increased bavdegalutamide exposure whereas H2 blockers decreased exposure. Esomeprazole (commonly taken for gastroesophageal reflux disease) is used to evaluate gastric pH-dependent drug interactions, as it is expected to provide a near-maximum effect on pH elevation. We evaluated the effect of food and esomeprazole on the single-dose PK of bavdegalutamide in healthy male participants, and safety.

Description of Methods & Materials: This was a Phase 1, open-label, 3-treatment, crossover study. Healthy male volunteers received a single oral dose of bavdegalutamide 280 mg in a fasted state during treatment A and in a fed state (high-fat meal) during treatment B; during treatment C, participants received esomeprazole 40 mg for 5 days and a single oral dose of bavdegalutamide 280 mg on Day 5 in a fed state. Participants were randomized 1:1 to fixed-dosing sequences of treatments ABC or BAC. There was a 28-day washout period between each bavdegalutamide treatment. A single dose of bavdegalutamide 280 mg was selected to provide an adequate safety margin in healthy participants to mitigate: the risk of first administration in this population and the risk of increased bavdegalutamide exposure expected with food. PK blood samples were collected predose and at selected times up to 648 hours post-bavdegalutamide 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 bavdegalutamide. Secondary endpoints included additional PK parameters and treatment-emergent adverse events (TEAEs).

Data & Results: A total of 18 participants were enrolled. Analysis sets were PK food effects (n=16), PK PPI effects (n=15), and safety (n=18). Some participants were excluded from PK analyses due to emesis or discontinuation. In fed vs fasted states, median time to C_max was delayed by 4 hours (10 vs 6 hours) and C_max and AUC_inf increased 9.7-fold and 6.5-fold, respectively (Table). Interindividual variability in PK was generally lower under fed vs fasting conditions. In combination with esomeprazole, C_max and AUC_inf were reduced 4.8-fold and 4.1-fold, respectively, vs bavdegalutamide alone (Table), and median time to C_max was reduced by 2 hours (8 vs 10 hours). Overall, 16 (88.9%) participants experienced a TEAE (all grade 1/2). Bavdegalutamide-related TEAEs were reported in 6 (33.3%), 8 (47.1%) and 3 (18.8%) participants with treatments A, B and C, respectively.

Interpretation, Conclusion or Significance: Food improved absorption, significantly increased peak concentration and extent of systemic exposure, and reduced PK variability of bavdegalutamide. Co-administration with esomeprazole notably decreased the peak concentration and extent of systemic exposure of bavdegalutamide. Based on these findings, in clinical studies bavdegalutamide should be administered with food, and concomitant use of stomach acid–modifying agents is not recommended. A single oral dose of bavdegalutamide 280 mg was generally well tolerated by healthy male participants.

Disclosures: All authors are employees of Arvinas Operations Inc. Diane Healey holds stock in Bristol-Myers Squibb, Pfizer and BioXcel Therapeutics. Haolan Lu holds stock in Arvinas Operations Inc and Bristol-Myers Squibb.