044: Effect of Food on the Pharmacokinetics & Safety Profile of p53 Reactivator Rezatapopt in Healthy Subjects & Patients With Solid Tumors Harboring a TP53 Y220C Mutation

Statement of Purpose, Innovation or Hypothesis: Rezatapopt (PC14586), a p53 reactivator in clinical development for solid tumors, selectively binds to the Y220C-mutated p53 protein and restores wildtype conformation and transcriptional activity. Rezatapopt is administered orally (PO) and has pH-dependent solubility. Physiologically-based pharmacokinetic (PBPK) modeling was performed, and pharmacokinetic (PK) studies were conducted, in healthy volunteers and patients with solid tumors in fasted and fed states to assess potential food effects on rezatapopt PK and safety.

Description of Methods & Materials: A PBPK model was developed using in vitro and clinical PK data to predict the effect of a standard meal on rezatapopt PKs in healthy volunteers and patients with solid tumors. The model was verified using PK data obtained following single and repeat rezatapopt doses (150-2,500 mg) in PYNNACLE (PMV-586-101, NCT04585750), an ongoing Phase 1/2 study assessing rezatapopt in patients with solid tumors harboring a TP53 Y220C mutation; most predictions were within 1.5-fold of observed. A Phase 1 study (PMV-586-102, NCT05249348) was also conducted in healthy volunteers receiving a single rezatapopt 2,000 mg dose (n=22) PO with or without a high-fat meal, with PK samples collected over 96h post-dose. Patients in PYNNACLE receiving rezatapopt (2,000 mg, PO, once daily) starting in the fasted (n=13) or fed state (n=12; ≥100kcal, 3g fat) were also assessed, with PK samples collected over 24h post-dose on Day 1 and at steady state. Primary objectives: PKs, safety and tolerability.

Data & Results: Using the PBPK model, 10 virtual trials of 10 healthy volunteers (50%/50% male/female; aged 20-50 yrs) and 10 virtual trials of 10 patients with solid tumors (50%/50% male/female; aged 30-75 yrs), receiving one rezatapopt 2,000 mg dose PO under a fasted or fed state were generated. Food intake in healthy volunteers was predicted to increase area under the curve (AUC) from 0–infinity (AUC_0-inf) by 45% and maximum concentration (C_max) by 28%. For patients with solid tumors, food intake was predicted to increase AUC_0-inf by 47% and C_max by 35%. Exposure predictions for multiple oral doses showed similar results. In PMV-586-102, in healthy volunteers administered a single rezatapopt 2,000 mg dose PO with or without a high-fat meal, AUC_0-inf and C_max were 79% and 84% higher, respectively, in the fed vs fasted state. In PYNNACLE, AUC from 0–24h (AUC_0-24) and C_max were 40% and 42% higher (at steady state), respectively, in patients with solid tumors administered rezatapopt 2,000 mg PO with vs without food (Table 1). In PYNNACLE, rates of treatment-related adverse events (TRAEs) were similar for rezatapopt 2,000 mg administered with vs without food; gastrointestinal (GI) TRAEs were less frequent with food (Table 1).

Interpretation, Conclusion or Significance: PBPK modeling predicted that rezatapopt exposure would be greater with food based on physicochemical characteristics and solubility inputs; this was confirmed by clinical PK data from healthy volunteers and patients with solid tumors. Observed variability in PK parameters decreased with food. Rezatapopt 2,000 mg administered with food was well-tolerated and associated with fewer GI TRAEs in patients with solid tumors. The increase in exposure may be due to enhanced solubilization with bile salt following food intake; the decrease in GI toxicities may be attributed to the local effect of food.

Disclosures: HCDK/AW/MF/LS: PMV Pharmaceuticals employees (stock options). HG: None. EED: research funding/grant (Bayer/Immunocore/Amgen/Aileron Therapeutics/Compugen/TRACON Pharmaceuticals/Unum Therapeutics/Gilead Immunomedics/BOLT Therapeutics/Aprea Therapeutics/Bellicum Pharmaceuticals/PMV Pharmaceuticals/Triumvira Immunologics/Seagen/Mereo BioPharma/Sanofi/Rain Oncology/Astex Therapeutics/Sotio/Poseida/Mersana Therapeutics/Genentech/Boehringer Ingelheim/Dragonfly Therapeutics/A2A Pharmaceuticals/Volastra/AstraZeneca); advisory board (BOLT Therapeutics/Mersana Therapeutics/Orum Therapeutics/Summit Therapeutics/Fate Therapeutics/PMV Pharmaceuticals); speaker role (PMV Pharmaceuticals); reimbursements (ASCO/LFSA Association/Rain Oncology/Banner MD Anderson Cancer Center/Triumvira Immunologics). AMS: advisory board (Relay Therapeutics/Mersana/Merus/PMV Pharmaceuticals/Schrodinger); consulting (Blueprint Bio/Flagship Pioneering/Redona Therapeutics); steering committee (Merus/Pfizer/Relay Therapeutics); institute research funding (AstraZeneca/ArQule/BeiGene/Springworks/Black Diamond Therapeutics/Elevation Oncology/Kura/Lilly/Merus/Northern Biologics/Pfizer/PMV Pharmaceuticals/Relay/Repare Therapeutics/Revolution Medicine/Surface Oncology); reimbursements (PUMA/Repare Therapeutics); acknowledgements (ASCO Conquer Cancer Foundation CDA/NCI P30CA008748 CCITLA/Cycle for Survival/MSKCC Support Grant [P30 CA008748]). ABK: Certara employee and shareholder.

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Funding: PMV Pharmaceuticals.