COR-1389, a long-acting selective CRF-2 receptor agonist, in HFpEF with pulmonary hypertension due to left-heart disease: phase 1b randomised trial using wireless pulmonary artery pressure monitoring
M Ufnal, R L Benza, J Guichard, P Janiak, F Lawson, M L OzouxAbstract
Background
In HFpEF, pulmonary hypertension due to left-heart disease (PH-LHD; WHO group 2) increases right-ventricular afterload, contributes to right-ventricular dysfunction/failure, reduces exercise capacity, and is associated with adverse outcomes. No targeted therapy is currently approved for PH-LHD. COR-1389 is a long-acting, selective CRF-2 receptor agonist; preclinical studies suggest improvement in cardiopulmonary function in models of pulmonary hypertension. Implanted wireless pulmonary artery pressure monitoring devices (WPAPD) enable repeated, standardised assessment of pulmonary artery pressures at rest and in response to exercise.
Purpose
To evaluate the acute, dose-dependent effects of COR-1389 on pulmonary artery pressures at rest and following standardised submaximal exercise in HFpEF patients with PH-LHD, and to characterise safety/tolerability.
Methods
COR-PH (COR1389-102) is a phase 1b, randomised, double-blind, placebo-controlled study conducted at approximately 15 US sites. Approximately 40 participants with PH-LHD documented by prior right-heart catheterisation (resting pulmonary artery wedge pressure (PAWP) ≥ 15 mmHg, exercise PAWP ≥ 20 mmHg, PAWP/Cardiac output (CO) slope > 2 mmHg/L/min, or fluid-challenge PAWP > 18 mmHg), LVEF ≥50%, NYHA class II–III, WPAPD implanted for ≥3 months (mean pulmonary artery pressure (mPAP) > 25 mmHg within 2 weeks prior to randomisation), and stable guideline-directed HFpEF therapy will be enrolled. After confirmation of haemodynamic stability, participants will be randomised (2:2:1) to COR-1389 high dose, COR-1389 low dose, or placebo and receive a single subcutaneous dose on Day 1. WPAPD-derived pulmonary artery pressures will be assessed at baseline and post-dose at rest and immediately before and after a standardised 6-minute walk test (6MWT). Resting echocardiography will be performed in parallel to characterise cardiac structure and function. Safety assessments will be performed throughout the study.
Results / Endpoints
The primary endpoint is change from baseline in resting mPAP measured by WPAPD. Secondary endpoints include dose-related changes in systolic and diastolic pulmonary artery pressure (sPAP, dPAP), change from baseline in the pulmonary artery pressure response to the 6MWT (pre-/post-6MWT). Additional home WPAPD transmissions will be collected on Days 2, 4, 5, 6, 14 (±1), and 21 (±1) to characterise the time course of haemodynamic effects and support ongoing safety/tolerability evaluation.
Conclusions
COR-PH leverages high-frequency, device-based pulmonary artery pressure monitoring at rest and around a standardised 6MWT to characterise the acute, dose-dependent haemodynamic effects of COR-1389 in HFpEF with PH-LHD. Findings will inform dose selection and mechanistic understanding to support subsequent clinical development.