187: A Phase 1, Open-label, Single Ascending Dose Study to Evaluate the Pharmacokinetics of Vorasidenib in Healthy Japanese & Non-Asian Participants

Statement of Purpose: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. Mutations in IDH1/2 occur in various cancer types including gliomas, glioblastomas, and hematological malignancies. Vorasidenib is a potent inhibitor of two mutant forms of IDH (mIDH) and has shown preliminary antitumor activity in patients with glioma. The aim of this study was to compare the pharmacokinetics (PK) and safety of vorasidenib in healthy Japanese and non-Asian individuals.

Description of Methods & Materials: This was a Phase 1, single ascending dose study conducted between October 2019 and December 2020 (NCT04145128). After screening, healthy Japanese and non-Asian adults [non-childbearing potential], aged 18–55 years received vorasidenib 10 mg p.o. on Day 1, followed by a washout period of 20 days, and then vorasidenib 50 mg p.o. on Day 22. Blood samples for the assessment of plasma PK parameters were collected pre-dose and serially up to 504 hours post-dose. Safety assessments, including treatment-emergent adverse events (TEAEs), were conducted throughout the study. Descriptive statistics were used to summarize PK and safety data. The PK obtained from Japanese and non-Asian participants were compared using a mixed effects model with race, dose and race-by-dose as fixed effects and subject as a random effect. Geometric mean ratios (GMR) and corresponding 90% confidence intervals (CIs) were estimated.

Data & Results: Overall, 16 Japanese and 16 non-Asian individuals (median [range] age: 35 [18–54] years; male: 94%) enrolled in the study. All 32 participants received vorasidenib 10 mg on Day 1; 26 (81%) received vorasidenib 50 mg on Day 22 (15/16 Japanese participants; 11/16 non-Asian participants). Vorasidenib was rapidly absorbed (median plasma t_max range: 1.01 to 2.50 hours) and had a biphasic elimination pattern with rapid elimination 12 hours after dosing and a long terminal phase (mean terminal t_1/2 range: 75.97 to 212.10 hours). Vorasidenib exposure was similar for Japanese vs non-Asian participants with 90% CIs for the GMRs of AUC_0–inf, AUC_0–last, and C_max all including 1 (Table); exposures remained similar between the two groups when normalized for dose and weight. No deaths, serious AEs, or discontinuations due to AEs were reported. After receiving vorasidenib 10 mg, 3 non-Asian participants experienced ≥1TEAE (diarrhea; food poisoning; vomiting and headache). After receiving vorasidenib 50 mg, 1 Japanese participant (cough and upper respiratory tract infection) and two non-Asian participants (upper respiratory tract infection; mild increased alanine and aspartate aminotransferase, severe increased blood creatine phosphokinase) experienced ≥1 TEAE. None of these TEAEs were considered to be related to vorasidenib.

Interpretation, Conclusion or Significance: The PK of vorasidenib in Japanese and non-Asian participants who received single-dose oral administration of vorasidenib 10 mg and 50 mg, were similar. Vorasidenib 10 mg or 50 mg was also generally safe and well tolerated in both healthy Japanese and non-Asian adults.

Disclosures: This study was supported by Agios Pharmaceuticals Inc. Servier Pharmaceuticals LLC has completed the acquisition of Agios’ oncology business. Editorial assistance was provided by Martin Gilmour of Empowering Strategic Performance, and supported by Servier Pharmaceuticals LLC. Tharin Limsakun, Jian Zhu and Mohammad Hossain are employees of Servier Pharmaceuticals and may own stocks/shares in the company. David Nguyen is an employee of Altasciences and may own stocks/shares in the company.