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: 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.

Inhalation of repurposed drugs to treat pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach. Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH.

The Effects of Prostacyclin Aerosol and Infusion on Pulmonary Hypertension / 대한마취과학회지

BACKGROUND: Prostacyclin administered intravenously has demonstrated intermediate pulmonary specificity and its aerosol form has an even greater pulmonary selectivity. There have been few systematic analyses of the difference in response according to the route of administration and the dose of administration of prostacyclin. So we have compared prostacyclin infusion versus inhalation in various concentrations in an animal model. METHODS: Pulmonary hypertension was induced by continuous intravenous infusion of the vasoconstrictor U46619 and prostacyclin solutions of 10, 50, 100, 200 mcg/ml were inhaled using a jet nebulizer. Prostacyclin infusion was done at a rate of 100, 200, 400 ng/kg/min. RESULTS: With inhalation of 10, 50, 100, 200 mcg/ml prostacyclin, PVR fell to values of 85%, 76%, 64%, 55% of the preinhalation value and SVR fell to values of 94%, 80%, 76%, 64% of the preinhalation value, respectively (p<0.05). PVR/SVR ratios decreased significantly in all inhalation doses (p<0.05). With infusion of prostacyclin at a rate of 100, 200, 400 ng/kg/min, PVR fell to values of 73%, 60%, 50% of the preinfusion value and SVR fell to values of 68%, 54%, 38% of the preinfusion value, respectively (p<0.05). PVR/SVR ratios increased at an infusion rate of 400 ng/kg/min. CONCLUSION: Prostacyclin inhalation did not result in selective pulmonary vasodilation without causing any efects on the systemic vascular bed (absolute pulmonary selectivity). But it did cause more predominant vasodilation on the pulmonary vascular bed (relative pulmonary selectivity). By contrast, prostacyclin infusion caused more predominant vasodilation on the systemic vascular bed, creating the risk of severe systemic hypotension.