Further testing with other approved treatments is warranted, its researchers wrote, as the paired treatment showed more benefit than either sildenafil (sold as Revatio, or as a generic alternative) or NTP42 alone. This suggests the investigative therapy, through its distinct way of working, may provide “synergistic benefits” in such combinations.
The study, “Efficacy of the thromboxane receptor antagonist NTP42 alone, or in combination with sildenafil, in the sugen/hypoxia-induced model of pulmonary arterial hypertension,” was published in The European Journal of Pharmacology.
PAH patients often use combination therapies, but many of these operate through overlapping mechanisms, which can limit their effectiveness and exacerbate side effects. Safer and more complementary combo treatments are needed.
NTP42, being developed by Axta Therapeutics, is designed to block prostanoid thromboxane A2 (TXA2), a molecule that causes blood vessels to narrow. By binding to the T prostanoid (TP) receptor, it aims to lessen vascular remodeling, inflammation, and fibrosis.
A team led by researchers at Atxa (a University College Dublin spinoff) recently showed that NTP42 eased signs of PAH in a rat model of the disease, with some findings showing greater benefit than was seen with sildenafil. Notably, sildenafil inhibits an enzyme called phosphodiesterase-5 (PDE-5) in the walls of arteries and the lungs to widen arteries and reduce blood pressure.
Now the Atxa team, partnered with scientists at University of Porto, in Portugal, assessed NTP42’s efficacy when used alone or in combination with sildenafil in a different PAH rat model. Specifically, PAH was induced by injecting a molecule known as Sugen 5416, which blocks the vascular endothelial growth factor receptor; most animals were also exposing to low oxygen for three weeks.
“It is accepted that no one model of PAH fully recapitulates the pathologies of the human disease,” the study noted.
These animals developed typical PAH symptoms, such as substantial increases in mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) — a measure of the pressure inside the artery that supplies blood to the lungs — without significant changes in heart rate or mean arterial pressure.
After 28 days of treatment with either or both medications, or no treatment as control groups, investigators found the NTP42–sildenafil combination eased the increase in mPAP (40.9 mmHg vs. 52.7 mmHg in untreated rats) and in RVSP (70.7 mmHg vs. 92 mmHg) in the rats.
Combination therapy also significantly eased the deterioration in tricuspid annular plane systolic excursion, a measure of heart function analyzed via echocardiography.
The dual therapy also eased pulmonary inflammation relative to untreated animals, and significantly reduced cardiac enlargement and small blood vessel density, while also showing lesser fibrosis (scarring).
In contrast, neither sildenafil nor NTP42 alone led to significant benefits in any of these measures.
The dual therapy also eased pulmonary inflammation relative to untreated animals, and significantly reduced cardiac enlargement and small blood vessel density, while also showing lesser fibrosis (scarring). These treatments, used alone, did not produce significant changes.
Given these results, the investigators said that NTP42 should also be tested in combination with other PAH therapies, such as endothelin receptor antagonists.
“In conclusion,” the scientists wrote, “NTP42 would represent a first-in-class drug targeting a novel pathway, namely the TXA2-TP signaling axis.
“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.”
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