071: Pharmacokinetics, Safety & Tolerability of HZN-825, a LPAR-1 Antagonist, Following Single & Multiple Doses in Healthy Japanese Subjects

Statement of Purpose: HZN-825 is a potent, selective, allosteric antagonist of lysophosphatidic acid receptor 1 (LPAR-1), with anti-fibrotic potential demonstrated in a Ph2a study of patients with diffuse cutaneous systemic sclerosis (dcSSc)(Allanore et al. Arthritis Rheumatol. 2018; Ellery et al. Eur J Pharmacol.2018). It is under evaluation for the treatment of dcSSc and idiopathic pulmonary fibrosis (IPF) in ongoing trials. The current study evaluated pharmacokinetics (PK), safety and tolerability of HZN-825 in Japanese subjects.

Description of Methods & Materials: This was a 2-part open-label Phase 1 study with 2-period, 2-way crossover design in 24 healthy adult first-generation Japanese subjects. Part 1 evaluated the multiple-dose PK of HZN-825 150 mg and 300 BID under fed conditions (standard Japanese meals, containing 13 g of fat, 633 total calories, 17% of calories from fat) for 5 days. Part 2 evaluated single dose PK of HZN 825 at a dose of 300 mg under fed (high fat, high calorie meals) and fasted conditions.

Data & Results: In Japanese healthy subjects, with standard Japanese meals, systemic exposures of HZN-825 increased less than dose proportionally from 150 mg to 300 mg, with AUC and C_max increasing by 70% and 87%, respectively. Median T_max of HZN-825 was approximately 4 hours. Median HZN-825 t½ values following the last dose on Day 6 were approximately 26 to 27 hours. Food increased HZN-825 exposure after a high-fat, high-calorie meal, with AUC_0-inf and C_max increasing approximately 68% and 72%, respectively, following administration of 300 mg HZN-825 compared to fasting conditions. No clinically meaningful ethnic difference in HZN-825 PK was observed when HZN-825 exposures in Japanese subjects were compared to the exposures in non-Japanese subjects from previous trials. HZN-825 was safe and well tolerated by the healthy adult Japanese subjects. There were no serious or severe AEs and no remarkable findings regarding vital signs, ECGs, physical examination and laboratory assessments.

Interpretation, Conclusion or Significance: PK parameters under fed conditions in Japanese subjects were comparable to those previously observed in non-Japanese subjects. These results support the selection of the same dose regimen for further evaluation in Phase 2 global trials for all patients.

Disclosures: Y. Song, F.N. Ali, A. Kanchi, Z. Ye, W. Chen, J. Zarzoso, J Rogowski, Y. Sun and Y. Xin are employees of Horizon Therapeutics and own stock.