ATMOS, a Proof-of-Concept trial of inhaled mosliciguat in untreated PAH or CTEPH

<bold>Background:</bold> Mosliciguat is a soluble guanylate cyclase (sGC) activator for dry powder inhalation. Unlike sGC stimulators, mosliciguat also targets nitric oxide (NO) insensitive apo-sGC important in conditions of oxidative stress to increase cyclic guanosine monophosphate (cGMP). <bold>Objectives:</bold> Assess peak percent change (PPC) from baseline in pulmonary vascular resistance (PVR, primary) measured by right heart catheter (RHC), safety (secondary), pharmacodynamics (PD) and pharmacokinetics. <bold>Methods:</bold> Open-label, single-dose escalation (5 doses up to 4mg) multicenter trial in patients (pts) with untreated pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Per Protocol Set (PPS) consisted of the NO-nonresponsive pts with PVR≥5 Wood units at baseline (N=4/dose). <bold>Results:</bold> 38 pts received mosliciguat. For PPS (N=20), mean PPC of PVR from baseline [95%CI] was -21.0%[−31.6%,-10.4%], -16.1%[−32.8%,0.7%], -25.9%[−60.3%,8.4%], -38.1%[−55.9%,-20.3%] and -36.3%[−48.3%,-24.4%] for the 5 increasing doses, respectively. Reduced PVR persisted over the 3 hour RHC period at the highest doses. Pulmonary artery pressure decreased, plasma cGMP increased and, at the highest dose, mean cardiac output (CO) increased by ~25% from baseline. Effects were similar including non-PPS pts (PD Set, N=37). Most adverse events were mild, with headache (n=3;7.9%), decreased oxygen saturation and fatigue (n=2;5.3% each) reported most frequently (N=38). No safety relevant changes were seen in systemic vascular resistance or blood pressure. <bold>Conclusion:</bold> Mosliciguat had favorable tolerability and resulted in a sustained, substantial reduction in PVR after a single inhaled dose.