Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC

Area of Science:

• Pharmacology
• Cardiopulmonary Medicine
• Drug Discovery

Background:

• Cardiopulmonary diseases induce oxidative stress, impairing nitric oxide/soluble guanylate cyclase (sGC) signaling.
• This impairment shifts native sGC to heme-free apo-soluble guanylate cyclase.
• A novel inhaled sGC activator is needed to target apo-sGC.

Purpose of the Study:

• To discover and characterize a novel inhaled sGC activator, mosliciguat (BAY 1237592).
• To evaluate its therapeutic potential for cardiopulmonary diseases.

Main Methods:

• Discovery and in vitro/in vivo characterization of mosliciguat.
• Inhaled and intravenous administration in minipig models of pulmonary hypertension.
• Assessment of pulmonary and systemic arterial pressure, ventilation/perfusion mismatch, and airway resistance.

Main Results:

• Mosliciguat specifically activates apo-sGC, improving cardiopulmonary circulation.
• Inhaled mosliciguat demonstrated lung-selective effects, reducing pulmonary artery pressure without affecting systemic pressure.
• Beneficial bronchodilatory effects and reduced pulmonary arterial pressure without V/Q mismatch were observed.

Conclusions:

• Inhaled mosliciguat offers a potential therapeutic advancement for pulmonary hypertension.
• It improves pulmonary circulation and airway resistance with minimal systemic exposure.
• Mosliciguat is under clinical development (Phase Ib) for pulmonary hypertension.