Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). (January 2023)

• Record Type: Journal Article
• Authors: Bajwa, Ednan K.; Cislak, Dawn; Palcza, John; Feng, Hwa-ping; Messina, Eric J.; Reynders, Tom; Denef, Jean-François; Corcea, Vasile; Lai, Eseng; Stoch, S. Aubrey
• Is Part Of: Respiratory medicine. Volume 206(2023)
• Publication Date: 2023-01
• Subjects: Pulmonary vascular resistance -- Functional respiratory imaging -- Dry-powder inhaler -- Pulmonary blood volume -- Pulmonary selectivity; Chest -- Diseases -- Periodicals; Chest -- Diseases -- Great Britain -- Periodicals; Respiratory organs -- Diseases -- Periodicals; Respiratory Tract Diseases -- Periodicals; Appareil respiratoire -- Maladies -- Périodiques; Thorax -- Maladies -- Périodiques; Appareil respiratoire -- Maladies -- Traitement -- Périodiques; Electronic journals; 616.2
• DOI: 10.1016/j.rmed.2022.107065
• Languages: English
• ISSNs: 0954-6111

Abstract

Abstract: Background: Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality. Methods: This Phase 1 study evaluated efficacy/safety of inhaled single-dose MK-5475, an investigational, small-molecule stimulator of soluble guanylate cyclase designed for inhaled delivery via a dry-powder inhaler device, in participants with PAH (Clinicaltrials.gov: NCT03744637). Eligible participants were 18–70 years of age; body mass index ≤35 kg/m 2 ; diagnosis of PAH (Group 1 pulmonary hypertension). In Part 1, participants received double-blind MK-5475 or placebo for safety assessment (primary outcome). In Part 2, 4 panels participated in ≤3 open-label periods. Part 2/Period 1 assessed safety/tolerability. Part 2/Periods 2 and 3, respectively, involved functional respiratory imaging for measuring pulmonary blood volume (secondary outcome) and right heart catheterization for measuring pulmonary vascular resistance (primary outcome). Results: MK-5475 was generally well tolerated without systemic side effects on blood pressure or heart rate up to 24 h post dose. With respect to the primary pharmacodynamic outcome, mean reductions in pulmonary vascular resistance ranged from 21% to 30% across 120 μg and 360 μg doses. Conclusions: Treatment with inhaled single-dose MK-5475 showed rapid and sustained reductions in pulmonary vascular resistance and increases in pulmonary blood volume. MK-5475 was generally well tolerated versus placebo without vasodilatory systemic side effects. The promising pulmonary selectivity and favorable safety/tolerability profile of MK-5475 seen in this study of adult participants with PAH lays the foundation for further clinical development. Highlights: Current PAH therapies are administered systemically resulting in extrapulmonary effects. MK-5475 is an inhaled sGC stimulator under development for the treatment of PAH. This Phase 1 study evaluated single-dose MK-5475 in adult PAH participants. Single inhaled doses of MK-5475 had favorable effects on pulmonary vasodilation. Inhaled MK-5475 had a favorable safety profile without deleterious systemic effects.