A65-11 Study Design of a Phase 2a Randomized, Placebo-controlled Trial of Inhaled Frespaciguat (MK-5475) in Adults with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease (INSIGNIA PH-COPD)

Abstract Rationale Pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) correlates with impaired functional capacity, poor quality of life, and increased mortality (Shlobin et al., Eur Respir J 2024). No therapies are currently approved for PH-COPD. Vasodilators indicated to treat pulmonary arterial hypertension (PAH) can cause systemic hypotension and worsen ventilation-perfusion mismatch. Frespaciguat (MK-5475) is a pulmonary-selective, inhaled soluble guanylate cyclase stimulator with minimal systemic exposure. In a phase 1 study in PH-COPD, inhaled frespaciguat was well tolerated and improved pulmonary hemodynamics without systemic vasodilation (Bajwa et al., Int J Chron Obstruct Pulmon Dis 2024). In the INSIGNIA-PAH Phase 2 trial in PAH, inhaled frespaciguat significantly reduced pulmonary vascular resistance (PVR) with acceptable safety (Humbert et al., Eur Respir J 2024), supporting evaluation in PH-COPD. Methods The objective of this study is to evaluate the efficacy and safety of once-daily inhaled frespaciguat versus placebo over 24 weeks in adults with PH-COPD. This phase 2a, double-blind, placebo-controlled trial (NCT05612035) enrolled 129 adults, 40-85 years, with right heart catheterization-confirmed Group 3.1 PH-COPD (mean pulmonary arterial pressure ≥25 mmHg; pulmonary capillary wedge pressure ≤15 mmHg; and PVR ≥3 Wood units WU or PVR ≥4 WU depending on COPD severity). Eligible participants had a physician diagnosis of COPD, a spirometrically confirmed diagnosis of COPD with forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) 70% and had moderate-to-severe airflow obstruction with FEV1 ≥30% and 80% of predicted after bronchodilator administration. Participants were randomized 2:1 to frespaciguat 380 µg or placebo once daily via dry powder inhaler for 24 weeks, stratified by PVR (3 WU ≤ PVR 4 WU versus ≥4 WU) and phosphodiesterase 5 inhibitor use (PDE5i; yes versus no). An open-label extension study of frespaciguat 380 µg daily will follow for up to 42 months. Results The primary endpoint is change from baseline in 6-minute walk distance (6MWD) at Week 24. Secondary endpoints include change in 6MWD at Week 12, N-terminal pro-B-type natriuretic peptide at Weeks 12 and 24, World Health Organization functional class at Weeks 12 and 24, and safety and tolerability. Key safety outcomes include adverse events of symptomatic hypotension, pulmonary hemorrhage, and hemoptysis. An internal data monitoring committee oversees safety. The last patient was randomized in the study in October 2025. Conclusions Upon completion, this trial will determine whether inhaled frespaciguat improves exercise capacity with acceptable safety in adults with PH-COPD, including those on background PDE5i therapy. This abstract is funded by: Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA