Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease
Ednan K Bajwa,1 Dawn Cislak,1 Amit Kumar,1 Dan Li,1 Eric J Messina,1 Tom Reynders,2 Jean-François Denef,2 Vasile Corcea,3 Ketan P Buch,4 Eseng Lai,1 S Aubrey Stoch1 1MRL, Merck & Co., Inc., Rahway, NJ, USA; 2Translational Medicine, MSD Belgium, Brussels, Belgium; 3PMSI Republican Clinical Hospital “T. Mosneaga”, ARENSIA EM Unit, Chisinau, Republic of Moldova; 4Department of Internal Medicine, Pulmonary and Critical Care Medicine, Lexington VA Healthcare, Lexington, KY, USACorrespondence: Ednan K Bajwa, Translational Medicine, Merck Research Laboratories Massachusetts LLC, 33 Avenue Louis Pasteur, MAILSTOP BMB-3-420, Boston, MA, 02115-5727, USA, Tel +1 617 992-3470, Email [email protected]: 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 (FEV1/FVC 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 μg) or 28 days in Part 2 (380 μg). 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 between-group 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%]). MK-5475 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.Keywords: pulmonary hypertension, chronic obstructive pulmonary disease, MK-5475, soluble guanylate cyclase stimulator, dry powder inhaler, pulmonary vascular resistanc
