Search

Background: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation., Methods: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks., Objectives: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH., Results: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg)., Conclusions: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect., Competing Interests: Conflict of interest: M. Humbert reports grants/contracts from Gossamer Bio and Merck & Co., Inc., Rahway, NJ, USA, consultancy for 35 Pharma, Aerovate Therapeutics, Inc., AOP Orphan Pharmaceuticals, Bayer, Chiesi Farmaceutici SpA, Ferrer Internacional SA, Gossamer Bio, Janssen Pharmaceuticals, Keros Therapeutics, Liquidia Corp., Merck & Co., Inc., Rahway, NJ, USA, Novartis, Respira Therapeutics, Roivant Sciences Ltd and United Therapeutics Corp., honoraria from Janssen Pharmaceuticals and Merck & Co., Inc., Rahway, NJ, USA, and participation on a data safety monitoring or advisory board for 35 Pharma, Aerovate Therapeutics, Inc., Janssen Pharmaceuticals, Keros Therapeutics, Merck & Co., Inc., Rahway, NJ, USA, Novartis and United Therapeutics Corp. P.M. Hassoun reports participation on a scientific steering committee for MSD and participation on a scientific advisory board for ARIA-CV. K.M. Chin reports fees for work on steering, advisory or adjudication committees from Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, and research support to institution for clinical studies overseen by her from Altavant, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics. G. Bortman reports consultancy for Biosidus Argentina, Tuteur SA, Aerovate Therapeutics Inc., Baliarda Argentina, Merck & Co, Inc., Glaxo Inc. and Tecnopharma/Raffo, Inc. M.J. Patel, C. La Rosa, W. Fu and M.J. Loureiro are current employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. M.M. Hoeper reports consultancy for Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, AOP Orphan Pharmaceuticals, Bayer HealthCare, Ferrer Internacional SA, Gossamer Bio, Janssen Global Services, LLC, Keros, Merck & Co., Inc., Rahway, NJ, USA, and Novartis., (Copyright ©The authors 2024.)