ATXA Therapeutics have published a new paper detailing results of its lead drug candidate NTP42 in a further preclinical model of pulmonary arterial hypertension (PAH).
NTP42 targets a novel pathway in PAH, namely the thromboxane receptor (TP) signaling axis. In this seminal study, NTP42 used in mono-therapy or, in line with current treatment guidelines, in combination with other existing PAH drug therapies, has the potential to attenuate multiple key PAH disease features and to address many of the limitations of existing therapies.
As a TP antagonist, NTP42 is targeting a pathway with a distinct yet complimentary mechanism of action to that of the other PAH drug classes and, thus, it is likely that further synergistic benefits may become evident through combination therapy, where such therapies would be guided by the evolving therapeutic algorithms of PAH clinical management. The manuscript, entitled Efficacy of the Thromboxane Receptor Antagonist NTP42 alone, or in Combination with Sildenafil, in the Sugen/hypoxia-induced Model of Pulmonary Arterial Hypertension, was recently accepted for publication in the European Journal of Pharmacology. Read the abstract below and click here to view the complete Open Access manuscript.
Abstract NTP42 is a novel antagonist of the thromboxane A2 receptor (TP) in development for the treatment of pulmonary arterial hypertension (PAH). Recent studies demonstrated that NTP42 and TP antagonism have a role in alleviating PAH pathophysiology. However, the efficacy of NTP42 when used in combination with existing PAH therapies has not yet been investigated. Herein, the Sugen 5416/hypoxia (SuHx)-induced PAH model was employed to evaluate the efficacy of NTP42 when used alone or in dual-therapy with Sildenafil, a PAH standard-of-care. PAH was induced in rats by injection of Sugen 5416 and exposure to hypoxia for 21 days. Thereafter, animals were treated orally twice-daily for 28 days with either vehicle, NTP42 (0.05 mg/kg), Sildenafil (50 mg/kg), or NTP42+Sildenafil (0.05 mg/kg + 50 mg/kg, respectively). While Sildenafil or NTP42 mono-therapy led to non-significant reductions in the SuHx-induced rises in mean pulmonary arterial pressure (mPAP) or right ventricular systolic pressure (RSVP), combined use of NTP42+Sildenafil significantly reduced these increases in mPAP and RVSP. Detailed histologic analyses of pulmonary vessel remodelling, right ventricular hypertrophy and fibrosis demonstrated that while NTP42 and Sildenafil in mono-therapy resulted in significant benefits, NTP42+Sildenafil in dual-therapy showed an even greater benefit over either drug used alone. In summary, combined use of NTP42+Sildenafil in dual-therapy confers an even greater benefit in treating or offsetting key aetiologies underlying PAH. These findings corroborate earlier preclinical findings suggesting that, through antagonism of TP signalling, NTP42 attenuates PAH pathophysiology, positioning it as a novel therapeutic for use alone or in combination therapy regimens.