LB-013 - EVALUATION OF SINGLE DOSE AND STEADY STATE PHARMACOKINETICS AND SAFETY OF AMX0035 IN CAUCASIAN AND JAPANESE HEALTHY MALE AND FEMALE PARTICIPANTS.

M. Gutierrez, P. Yeramian, A. Yeo, M. St Pierre; Amylyx Pharmaceuticals, Inc., , .

Background: AMX0035, an oral, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO) significantly slowed functional decline and prolonged survival in people with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. The study objectives were to compare the pharmacokinetics (PK) and safety of AMX0035 (single and multiple doses) in 15 healthy Japanese (JAP) and 15 Caucasian (CAU) participants and evaluate gender differences in the PK of each ethnic group.

Methods: This was an open-label study of AMX0035 given as a single oral dose of AMX0035 (3 g PB, 1 g TURSO) on Day 1, followed by twice a day dosing from Day 2 to Day 6, and a single dose on Day 7. Serial blood sampling occurred on Days 1 and 7. The data was not analyzed until September 20, 2023 due to delay of bioanalytical data.

Results: There were 15 JAP (7 male [M], 8 female [F]) and 14 CAU (8 M, 6 F) PK evaluable participants. Following a single dose of AMX0035, PB was rapidly absorbed with Tmax around 0.5 hour while TURSO Tmax was around 4-6 hours in both ethnic groups. At steady state (Table 1), the respective geometric mean [%CV] Cmax and AUCinf of JAP PB (188.2 µg/mL [23] and 235.2 µg*h/mL [38]) were higher than those of CAU PB (154.0 µg/mL [34] and 169.4 µg*h/mL [26]). Similarly, Cmax and AUCinf of JAP TURSO (1.2 µg/mL [100] and 13.5 µg*h/mL [91]) were higher than those of CAU TURSO 1.0 [41] µg/mL and 10.3 µg*h/mL [44]. There was no PB and minimal TURSO accumulation as AUClast accumulation ratio was 0.84 and 1.7, respectively. PB and TURSO metabolic ratios were not affected by ethnic background. PB, TURSO, and their metabolites show relative increase of exposure in female and lower body weight subjects. However, following weight adjustment, exposure is similar between the two ethnic groups and between M and F within each group. T1/2 values for PB and TURSO were around 0.5 and 5 hours, respectively for both groups. No participants reported severe adverse events (AEs), or AEs leading to death. There were no clinically relevant findings for clinical safety lab results, vital signs, ECGs, or physical examinations.

Conclusion: AMX0035 exposure was higher in JAP compared to CAU and in F compared to M in each ethnic group. Following weight adjustment, the PK between the two ethnic groups and between M and F in each ethnic group were similar. The safety and tolerability of AMX0035 were similar between JAP and CAU participants.