Safety and pharmacokinetics of mosliciguat, a new, inhaled soluble guanylate cyclase activator, in healthy adult subjects.

AIM: Mosliciguat (BAY 1237592), the first soluble guanylate cyclase (sGC) activator in a dry powder inhaler (DPI), could potentially treat pulmonary hypertension with a more targeted delivery than systemic sGC stimulators. We report safety and tolerability of mosliciguat in healthy men.

METHODS

Three randomized, single-blinded, placebo-controlled Phase 1 studies of mosliciguat DPI: a single-dose escalation study (SDES) of mosliciguat 60-4000 μg (n = 78), a multiple-dose escalation study (MDES) of seven once-daily doses of 480-2000 μg over 8 days (n = 36) and a multiple-dose study (MDS) of mosliciguat 1000 μg for 14 days (n = 21).

RESULTS

Most adverse events (AEs) were mild, with no serious AEs or AEs leading to discontinuation. No clinically relevant lung function impairment or change in oxygen saturation was observed. In the MDES, body plethysmography indicated reduced airway resistance 6 h after dosing. Generally, no clinically relevant effect on blood pressure was seen; however, a few events of mild-to-moderate orthostatic hypotension occurred with higher doses in the SDES and MDS. In the SDES, there was a small, dose-dependent heart rate increase with mosliciguat. Increased plasma cyclic guanosine monophosphate levels confirmed target engagement by mosliciguat. Overall, the PK profile of mosliciguat was appropriate for an inhaled therapy, with low systemic exposures and an effect on airway resistance consistent with targeted inhaled lung-selective delivery.

CONCLUSION

Mosliciguat DPI was well tolerated in healthy subjects, without AEs related to bronchospasm or airway irritation, with a pharmacodynamic response indicating sGC activation and a bronchodilating action.