Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK -5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV 1 /FVC <0.7; FEV 1 >30% predicted) and PH (mean pulmonary arterial pressure >= 25 mmHg). Participants were randomized 2:1 to MK -5475 or placebo via dry -powder inhaler once daily for 7 days in Part 1 (360 mu g) or 28 days in Part 2 (380 mu g). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part -2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non -informative prior was used to calculate posterior probability (PP) that the betweengroup difference (MK -5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate -to -severe COPD. Incidences of AEs were comparable between MK -5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug -related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK -5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between -group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK -5475 for PH-COPD treatment.