LB-005 - A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF AMX0035 IN PARTICIPANTS WITH AMYOTROPHIC LATERAL SCLEROSIS

A. Keshavarz¹, M. Gutierrez², P. Yeramian², A. Yeo², M. St Pierre², W. McNeely³, J. Steshyn³, J. Wymer⁴; ¹Amylyx Pharmaceuticals, Inc., Cambridge, MA, , ²Amylyx Pharmaceuticals, Inc., , , ³University of Florida, , , ⁴The University of Florida, , .

Background: AMX0035, an oral, fixed-dose combination of 1 g sodium phenylbutyrate (PB) and 3 g taurursodiol (TURSO) significantly slowed the rate of functional decline in participants with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. The study objectives were to determine the pharmacokinetics (PK), pharmacodynamics (PD), safety and effects of demographic characteristics on PK of PB and TURSO after single and multiple oral administrations of AMX0035 in 11 participants with ALS.

Methods: This study was a Phase 2, open-label, two sequential period study with blood and urine collection after AMX0035 single dose on period 1 day 1 (P1D1), 15 days once daily (QD) doses on P2D1, and 15 days twice daily (BID) doses on P2D15. The data was not analyzed until September 20, 2023 due to delay of bioanalytical data.

Results: PB was rapidly absorbed with Tmax occurring at 0.5 hour while TURSO Tmax occurred around 4.0 hours. The PB profiles showed similar apparent volume of distribution (Vd) (14- 15 L) and clearance (CL) (18-22 L/h) and rapid elimination (T1/2= 0.5 hour) across the periods. PB and TURSO reached steady state (SS) after BID doses of AMX0035. There were no significant differences in PB and TURSO Cmax and AUC0-last following single and multiple dosing of AMX0035 (Table 1). PB and TURSO Cmax accumulation ratios (AR) were 0.92 and 0.98, indicating no accumulation at SS. The metabolite/parent (MR) for PB and PB metabolite renal CL was high, suggesting urine excretion of PB metabolite. MR for TURSO was high, indicating extensive metabolism of TURSO to its metabolites. There were no significant differences in PB and TURSO peak, exposure, Tmax, and AR between males and females after multiple QD and BID doses of AMX0035. There were no effects of age and weight on the exposure parameters of PB, TURSO, and their metabolites. There were no clinically relevant findings for clinical safety lab results, vital signs, electrocardiograms, and physical examinations in the study.

Conclusion: There were no statistically significant differences in peak and extent of exposure of TURSO, PB and its metabolites after single or multiple doses of AMX0035. There was no PB or TURSO accumulation at SS. Demographic characteristics (sex, age, and weight) did not have significant effect on peak and exposure of PB and TURSO. AMX0035 was generally well tolerated and safe for participants with ALS.