NTP42, an antagonist of the thromboxane receptor, attenuates experimentally-induced pulmonary arterial hypertension

Abstract

NTP42 is a novel antagonist of the thromboxane (TX)A2 receptor (TP), in development for treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, fibrosis, inflammation, thrombosis and right ventricular hypertrophy. Signalling through the TP, TXA2 is a potent vasoconstrictor, is a driver of platelet aggregation, a pro-mitogenic and a pro-inflammatory mediator. Mechanistically, TP antagonists should treat many of the hallmarks of PAH, including the excess vasoconstriction, remodelling, in situ thrombosis, fibrosis and inflammation. This study investigated the efficacy of NTP42 in a monocrotaline (MCT)-induced PAH rat model. PAH was induced by subcutaneous injection of 60 mg/kg MCT. Rats were assigned to the groups: 1) No MCT, 2) MCT Only, 3) MCT+NTP42, 4) MCT+Sildenafil and 5) MCT+Selexipag, where 28-day treatment was initiated 24hr post-MCT. From hemodynamic measurements, NTP42 reduced MCT-induced PAH including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP). Moreover, NTP42 was superior to standard-of-care (SoC) drugs Sildenafil or Selexipag in reducing vessel remodelling, inflammation and fibrosis. A multiparameter score of key disease indices, including mPAP, RVSP, Fulton’s index, vessel remodelling, inflammation and fibrosis, shows that NTP42 has significant treatment benefits and superior to the SoCs tested. These findings suggest that NTP42 and antagonism of TP signalling may alleviate PAH pathophysiology, representing a novel therapeutic target with marked benefits over existing therapies.