PII-071 - PHARMACOKINETICS (PK) OF HZN-825, A SMALL MOLECULE SELECTIVE ANTAGONIST OF LPAR1, AND THE EFFECT OF FOOD IN HEALTHY ADULT SUBJECTS.

Y. Song¹, F. Ali², Z. Ye², J. Zarzoso¹, J. Rogowski¹, Y. Sun¹, Y. Xin¹; ¹Horizon Therapeutics, South San Francisco, CA, USA, ²Horizon Therapeutics, Chicago, IL, USA.

Background: HZN-825, a potent selective antagonist of lysophosphatidic acid receptor 1 (LPAR1), suggested efficacy in a Ph2a study of patients with diffuse cutaneous systemic sclerosis (dcSSc) (Allanore et al. Arthritis Rheumatol. 2018) and is being evaluated for treatment of dcSSc and idiopathic pulmonary fibrosis in ongoing trials.

Methods: The PK of HZN-825 and food effect were evaluated in an open-label study in healthy volunteers to inform the dose and dosing condition of a new tablet formulation. Dose proportionality and food effect were evaluated using a 2-way, 2-period crossover design in two cohorts:150 mg and 300 mg single dose under fasting condition in Cohort 1 and 450 mg single dose under fasting and high-fat, high calorie meal condition in Cohort 2. Multiple-dose PK was evaluated using a 2-period, fixed sequence crossover design. Subjects received HZN-825 twice a day (BID) of 300 mg (Cohort 3) or 450 mg (Cohort 4) administered with low-fat meals in Period 1 and with high-fat meals in Period 2.

Results: HZN-825 was safe and well-tolerated when administered after single and multiple doses up to 450 mg, with no SAEs or AESIs reported. HZN-825 Cmax and AUC increased in a less than dose-proportional manner from 150 to 450 mg, with minimal exposure increase from 300 mg to 450 mg. At 450 mg, high-fat, high-calorie meal increased the Cmax and the AUC by approximately 1.9-fold and 2.2-fold, respectively. Similar HZN-825 exposure was achieved following administration of 300 mg BID with meal compared to results seen in the Ph2a study. Therefore, 300 mg BID with meal was selected as the top dose for Ph2b studies, with 300 mg QD dose also included to inform the dose-response relationship for HZN-825.

Conclusion: The study results informed dose selection of HZN-825 for further trials.

Allanore, Y. et al. Lysophosphatidic Acid Receptor 1 Antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis: A Double-Blind, Randomized, Eight-Week Placebo-Controlled Study Followed by a Sixteen-Week Open-Label Extension Study. Arthritis Rheumatol. 70(10):1634-1643 (2018)