BACKGROUND: Mosliciguat, a soluble guanylate cyclase (sGC) activator, is designed for lung-targeted delivery via dry powder inhalation. Nitric oxide (NO) binds sGC's prosthetic heme group, catalysing cyclic guanosine monophosphate (cGMP) production, resulting in increased vasodilation, reduced inflammation/apoptosis, reverse vascular remodelling and antifibrotic effects. sGC is redox sensitive, losing heme in pulmonary hypertension (PH) oxidative stress conditions. Mosliciguat's novel 'activator' mechanism directly binds the sGC heme-binding pocket to induce cGMP, allowing it to target NO-insensitive heme-free sGC, potentially rescuing additional enzymatic activity. METHODS: A Proof-of-Concept Trial of Inhaled Mosliciguat, a First-in-Class Soluble Guanylate Cyclase Activator (ATMOS; non-randomised, open-label phase 1b trial) assessed single-dose escalation of mosliciguat in participants with pulmonary arterial hypertension or chronic thromboembolic PH. 38 participants received mosliciguat. The per protocol set (PPS, n=20) included NO-non-responsive participants with baseline pulmonary vascular resistance (PVR) >/=5 Wood units (n=4/dose). The pharmacodynamic set (PDS, n=37) included NO-responsive participants. Five PPS participants underwent a >/=24-hour washout from background therapy. RESULTS: In the PPS, doses of 0.24, 0.48, 1.0, 2.0 and 4.0 mg resulted in mean peak per cent PVR reductions from baseline (95% CI) of 21.0% (31.6% to 10.4%), 16.1% (32.8% to -0.7%), 25.9% (60.3% to -8.4%), 38.1% (55.9% to 20.3%) and 36.3% (48.3% to 24.4%), respectively, and generally persisted over the 3-hour observation period. Similar effects were seen in the PDS. The majority of adverse events were mild; most frequently reported were headache (n=3/38; 7.9%), decreased oxygen saturation and fatigue (n=2/38; 5.3% each). No safety-relevant changes were seen in systemic vascular resistance or blood pressure. CONCLUSIONS: Mosliciguat demonstrated a favourable safety profile and sustained, clinically meaningful reductions in PVR in participants with PH. TRIAL REGISTRATION NUMBER: NCT03754660.
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