C64-14 Pharmacokinetic/Pharmacodynamic (PK/PD) Sub-study of UNISUS in Pulmonary Arterial Hypertension (PAH): Characteristics of Enrolled Patients

Rationale Macitentan 10 mg is a dual endothelin receptor antagonist that confers potent endothelin (ET) A and partial ETB receptor blockade and is approved for treatment of PAH. UNISUS, the first head-to-head superiority study in PAH will evaluate macitentan 75 mg (hypothesized to confer potent blockade of both ETA and ETB receptors) versus macitentan 10 mg, with time to first morbidity/mortality event as the primary endpoint. Blockade of ETB receptors leads to increased plasma levels of the ET-1 ligand, which can be used as a marker of ETB receptor inhibition. A dedicated UNISUS PK/PD sub-study will evaluate plasma levels of macitentan and ET-1 in response to macitentan treatment. The UNISUS PK/PD sub-study design and preliminary baseline characteristics of enrolled patients are reported. Methods UNISUS (NCT04273945) is an ongoing phase 3, prospective, multicenter, double-blind, double-dummy, randomized, active-controlled, parallel-group, group-sequential, adaptive, event-driven superiority study in patients with PAH, randomized 1:1 to receive macitentan 75 mg or 10 mg once-daily. Adult patients in WHO functional class II-IV, with or without prior PAH treatment, were eligible. During UNISUS, blood samples were collected pre-dose and 2-10 hours post-dose to measure plasma concentrations of macitentan, its active metabolite aprocitentan, and ET-1. Samples were taken at Day 1 of double-blind treatment, then at Weeks 4, 8, 24 and 52; for patients who had a run-in period with macitentan 10 mg, a pre-dose sample was taken. In the PK/PD sub-study, a 24-hour PK/PD profile was collected at Week 8. Using individual plasma concentration-time data, PK parameters (trough concentration [Ctrough], area under the curve over dosing interval [AUCτ], maximum concentration [Cmax], and time to maximum concentration [tmax]) will be derived for macitentan, aprocitentan and ET-1 using noncompartmental methods. Additionally, collected data will be analyzed by population PK/PD modelling. Results The UNISUS PK/PD sub-study includes 42 patients. At baseline, mean (SD) age was 45.4 (17.1) years; 73.8% were female. Patients were from Latin America (31.0%), South-East Asia (26.2%), Eastern Europe (26.2%) and Western Europe (16.7%). Mean (SD) body mass index was 25.9 (6.3) kg/m2. Conclusions The UNISUS PK/PD sub-study will provide insights into changes in ET-1 concentrations and ETB receptor inhibition following macitentan 10 mg and 75 mg treatment. Changes in ET-1 levels following potent blockade of the ETB receptor have not previously been characterized in PAH patients; these findings will enhance our understanding of the mechanistic impact of maximal dual ETA and ETB receptor inhibition in PAH.