061: First-in-Human Evaluation of Pharmacokinetics & Safety of Tilpisertib Fosmecarbil, an Oral Prodrug of a Tumor Progression Locus 2 Inhibitor, in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: GS-4875, administered as the prodrug Tilpisertib Fosmecarbil (TIP), is a potent inhibitor of tumor progression locus 2 (TPL-2) currently in clinical development for the treatment of ulcerative colitis (UC). The aim of this Phase 1 First-in-Human study was to evaluate the pharmacokinetics, safety, and tolerability of escalating single and multiple oral doses of TIP in healthy participants.

Description of Methods & Materials: This was a double-blinded, randomized, placebo-controlled, parallel-group, single and multiple (once or twice daily for 10 days) dose escalation study. Healthy male and female participants were enrolled sequentially in ascending dose cohorts and randomized to receive TIP (75, 300, 600, 900, or 1500 mg; n = 6 per cohort) or placebo (n = 2 per cohort). TIP was administered under fasting conditions in both the single (up to 1500 mg) and multiple (up to 900 mg) ascending dose cohorts. Serial blood samples were collected up to 120 hours post last dose and GS-4875 plasma pharmacokinetic parameters were characterized from plasma concentrations quantified using validated LC-MS/MS bioanalytical methods. Safety was assessed by review of adverse events, clinical laboratory tests, vital signs, and electrocardiogram (ECG) data.

Data & Results: A total of 71 participants (n = 53 active; n = 18 placebo) enrolled and completed treatments in this study. Based on its mechanism as a prodrug of GS-4875, TIP was rapidly converted to its active form GS-4875 during absorption and TIP concentrations were not quantifiable in most participants. Following multiple once-daily doses of TIP (75 to 900 mg) under fasting conditions, GS-4875 steady-state plasma exposure (C_max and AUC) increased in a less than dose-proportional manner from 75 to 900 mg. GS-4875 showed low-to-moderate pharmacokinetic variability with median half-life of 19 to 28 hours and approximately 2-fold accumulation at steady-state with once-daily dosing, which was achieved by Day 7. TIP was generally well tolerated at all evaluated dose levels; all adverse events were mild (Grade 1) in severity and no dose-limiting toxicities, serious adverse events, clinically relevant abnormal ECGs or vital sign abnormalities were observed in participants administered TIP.

Interpretation, Conclusion or Significance: Single and multiple oral doses of TIP up to 1500 mg and 900 mg, respectively, were generally safe and well tolerated. TIP exhibited a favorable PK profile amenable to once-daily dosing. The overall pharmacokinetic and safety profiles of TIP supported its evaluation in an ongoing Phase 2 trial in UC (NCT06029972) and informed dose selection for that Phase 2 study.

Disclosures: Elijah J. Weber, Xin Qi, Ann Qin, Frank Hong, Ingrid J. Chang, Matthew McKevitt, and Ahmed A. Othman: Current employee, former employee, and/or shareholder of Gilead Sciences, Inc.

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Additional Information/Authors: This research was sponsored by Gilead Sciences, Inc.