PII-035 - PHARMACOKINETICS OF AMG 193 (A SMALL MOLECULE MTA-COOPERATIVE PRMT5 INHIBITOR) AFTER SINGLE AND MULTIPLE DOSING IN THE FASTED AND FED IN STATE PATIENTS WITH MTAP DELETED TUMORS

M. McComb¹, A. Murphy², K. Penning¹, T. Eggert³, B. Houk⁴; ¹Amgen, Thousand Oaks, CA, United States, ²Clinical Pharmacology Modeling and Simulation, Amgen, Thousand Oaks, CA, USA, ³Amgen, Thousand Oaks, California, United States, ⁴Amgen Inc., Thousand Oaks, CA, USA.

Background: AMG 193 is a small molecule methylthioadenosine (MTA) cooperative protein arginine methyltransferase 5 inhibitor in development for treatment of patients with MTA phosphorylase (MTAP) -deleted tumors. The first-in-human (FIH) study included evaluation of the pharmacokinetics (PK) and effect of food on AMG 193.

Methods: This phase 1, FIH, multi-center, open-label study included patients with advanced tumors with MTAP-loss expression. All patients (N = 80) received daily AMG 193 orally in 28-day cycles under fasted conditions. PK samples were obtained on Days 1 and 15 of Cycle 1 at doses ranging from 40 – 1600 mg once daily (QD) and 600 mg twice daily (BID).
The effect of food on AMG 193 PK was evaluated with the 1200 mg dose at steady-state between three days. AMG 193 was administered under fasted conditions on Day 1 and fed conditions on Day 2. Patients were provided a standardized 800 to 1000 calorie high-fat meal (~50% fat calories). Blood samples were collected pre-dose up to 24 hours on Day 1 and 2. AMG 193 plasma concentrations were measured using a validated HPLC-MS/MS method. PK parameters were estimated using non-compartmental methods.

Results: A total of 80 and 51 patients had evaluable fasted PK profiles after single and multiple dosing, respectively. QD dosing within the range of 40 – 1200 mg resulted in a dose-proportional increase in plasma exposure, while 1600 mg QD plasma exposure was not greater than at 1200 mg. The highest tolerated dose was 1200 mg QD (N = 6) resulting in a multiple-dose mean Cmax, AUC0-24HR, t1/2, and median Tmax, of 7740 ng/mL (38% CV), 89300 hr∙ng/mL (48% CV), 8.57 hours (63% CV), and 3.0 hours (2.0 – 6.0), respectively. Steady-state plasma concentrations were achieved within 2 weeks with a mean accumulation ratio of 1.42 (71%). Exposure was similar in males and females as well as high and low body weight individuals.
A total of 7 patients were evaluable in the food effect PK sub-study. The geometric mean ratio (90% CI) of dose normalized Cmax and AUC0-24HR for fed state compared to fasted state were 0.975 (0.866, 1.10) and 1.10 (0.982, 1.23), respectively.

Conclusion: AMG 193 is eliminated with a terminal half-life of 8.57 hours and amenable to QD dosing in either the fasted or fed state. There is minimal accumulation with multiple QD dosing. No dose adjustment for sex or body weight is warranted.