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

BACKGROUND: Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality. METHODS: ; 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.