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

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/m2; 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.

• Authors: Ednan K Bajwa, Dawn Cislak, John Palcza, Hwa-Ping Feng, Eric J Messina, Tom Reynders, Jean-François Denef, Vasile Corcea, Eseng Lai, S Aubrey Stoch
• Journal: Respiratory medicine (Respir Med) Vol. 206 Pg. 107065 (01 2023) ISSN: 1532-3064 [Electronic] England
• PMID: 36521262 (Publication Type: Randomized Controlled Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Soluble Guanylyl Cyclase
• Vasodilator Agents

Topics

• Adult
• Humans
• Pulmonary Arterial Hypertension (drug therapy)
• Soluble Guanylyl Cyclase (administration & dosage)
• Vasodilator Agents (therapeutic use)
• Adolescent
• Young Adult
• Middle Aged
• Aged