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

Abstract

Background: Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential.

Methods: We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592).

Results: Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model.

Conclusion: Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Keywords: Mosliciguat; Nitric oxide-insensitive soluble guanylate cyclase; Pulmonary diseases; Soluble guanylate cyclase activator; Ventilation/perfusion mismatch.

Fig. 1

A NO and sGC activators target two different redox states of sGC: the NO-sensitive reduced native sGC and the NO-insensitive oxidized and finally heme-free apo-sGC, respectively. NO stabilizes the nitrosyl-heme complex of the reduced sGC to increase cGMP. Activators of sGC such as mosliciguat (B) bind to the unoccupied heme-binding complex or displace the prosthetic heme of sGC. The inhaled sGC activator is activating the heme-free apo-sGC to increase cGMP which mediates vasorelaxation and bronchodilation and blocks remodelling, apoptosis, and inflammation. ARDS acute respiratory distress syndrome, cGMP cyclic guanosine monophosphate, NO nitric oxide, PPHN persistent pulmonary hypertension in the neonate, sGC soluble guanylate cyclase

Fig. 2

The effect of mosliciguat with DEA/NO and ODQ on isolated HC and HF rat sGC in vitro specific activity (left) and stimulation (right). DEA/NO diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, HC heme-containing, HF heme-free, ODQ 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, sGC soluble guanylate cyclase

Fig. 3

A Percentage changes in PAP (mean) and BP (mean) versus vehicle-treated animals after inhaled cumulative application of mosliciguat under thromboxane A2-induced PH in minipigs observed 30 min after inhalation of cumulative doses. Data are mean ± SEM (n = 3). B Percentage changes on PAP (mean) and BP (mean) versus vehicle-treated animals after cumulative infusions of mosliciguat under thromboxane A2-induced PH in minipigs observed 30 min after infusion of cumulative doses. Data are mean ± SEM (n = 3). BP mean blood pressure, PH pulmonary hypertension, PAP mean pulmonary arterial pressure, SEM standard error of the mean

Fig. 4

A Effects of mosliciguat after inhaled application under thromboxane A2-induced PH in minipigs compared with iloprost inhalation as clinical reference. B Observed (symbols) and predicted (lines) PAP (mean) values after administration of 0.15, 0.5, 1.5, and 5 µg/kg mosliciguat (lung-deposited doses; figure shows inhalation doses) to minipigs (7-min inhalation as liquid aerosol). Data are mean ± SEM (n = 3–4). PAP (mean) reduction of 5% indicated as straight dotted line. BP mean blood pressure, PH pulmonary hypertension, PAP mean pulmonary arterial pressure, SEM standard error of the mean

Fig. 5

A Efficacy of inhaled mosliciguat on PAP (mean) and BP (mean) compared with efficacy of systemic applied bosentan and sildenafil at steady-state concentrations. B Efficacy of inhaled mosliciguat on PAP (mean) and BP (mean) in combination with bosentan or sildenafil under constant infusions. Results show percentage changes versus vehicle-treated control animals as mean ± SEM out of three or four experiments. BP mean blood pressure, PAP mean pulmonary arterial pressure, SEM standard error of the mean

Fig. 6

A Effects of inhaled mosliciguat under thromboxane A2-induced PH in minipigs with and without pretreatment by ODQ. B Effects of mosliciguat after inhaled application under thromboxane A2-induced PH in minipigs with and without pretreatment by L-NAME. Data are mean ± SEM (n = 3). BP mean blood pressure, L-NAME N(G)-Nitro-l-arginine methyl ester, ODQ 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, PAP mean pulmonary arterial pressure, SEM standard error of the mean, wo without

Fig. 7

A Effects of mosliciguat after inhaled application on systolic PAP during hypoxia-induced vasoconstriction in conscious dogs (n = 3). B Mean PAP decrease evoked by mosliciguat after inhaled application during hypoxia challenge in conscious dogs. PAP decrease for each animal is calculated as follows: PAP decrease = (SUM of mPAP from 10–40 min of mosliciguat-treated animal) ‒ (SUM of mPAP from 10–40 min of respective vehicle-treated animal)/number of time points. mPAP mean pulmonary arterial pressure, PAP mean pulmonary arterial pressure, SEM standard error of the mean, sPAP systolic pulmonary arterial pressure

Fig. 8

A Effects of mosliciguat after inhaled and intravenous application and vehicle administration on PAP (mean) and SaO₂ during eight broncho-occlusion cycles in minipigs. B Effects of mosliciguat after inhaled and intravenous application and vehicle administration on BP (mean) and HR during eight broncho-occlusion cycles in minipigs. Data are mean (n = 3 or 4). BP mean blood pressure, HR heart rate, PAP mean pulmonary arterial pressure, SaO₂ arterial oxygen saturation of hemoglobin

Fig. 9

Mosliciguat capacity to decrease maximal hypoxic PAP (mean) (positive treatment effect) and AUC SaO₂ (unwanted desaturation effect) based on effects of representative cycles (n = 4 animals); data are mean ± SEM (n = 4). Mosliciguat inhaled (100 µg/kg nominal dose); intravenous 30 and 100 µg/kg. AUC SaO₂ area under the SaO₂ curve, PAP mean pulmonary arterial pressure, SaO₂ arterial oxygen saturation of hemoglobin, SEM standard error of the mean, VQ ventilation/perfusion

Fig. 10

Left: bronchodilating effects on lung resistance at baseline prior to acetylcholine provocation (mean ± SEM, *p < 0.05, **p < 0.01 versus positive control group). Right: bronchoprotective effects after acetylcholine-induced bronchospasm: maximum lung resistance during and after provocation. Values are given as individual data and mean ± SEM with n = 11–17 animals/group and **p < 0.01 versus positive control group. RL lung resistance, SEM standard error of the mean