Novel Therapies Targeting Vasoconstriction and Vascular Remodeling May Improve Outcomes in PAH

Pulmonary arterial hypertension (PAH) is currently an incurable disease that progresses rapidly and has a limited therapeutic landscape. But a recent article in press in Drug Discovery Today suggests changing the current treatment strategy from either vasodilation or vascular remodeling to a combination of these methods for potential increased efficacy.

PAH is a devastating and fast-moving disease characterized by persistent increases in mean pulmonary artery pressure (mPAP) and elevated pulmonary vascular resistance (PVR), leading to right heart dysfunction and heart failure or death when untreated. The 1-, 3-, and 5-year survival rates for patients with PAH are 85%, 68%, and 57%, respectively, according to the review.

While drugs currently marketed for PAH have been able to extend the lives of patients, they have shown limitations in their ability to prevent or reverse PAH. “These drugs fail to prevent or reverse the pathological process and, thus, most patients with PAH will still die from this disease,” the authors wrote.

PAH is multifaceted, making it a challenging disease to cure. Vasoconstriction followed by vascular remodeling was the initial concept of pathological progression, but pulmonary vascular remodeling driven by abnormal vascular cell proliferation and cell death is now accepted as having a major role in disease progression. One potentially curative approach to PAH treatment is therefore vascular remodeling inhibition via cell proliferation inhibition.

The focus of most current PAH treatments is vasodilation, with 3 main targets including the endothelin (ET), prostacyclin (PGI2), and nitric oxide (NO) signaling pathways to relax constriction in pulmonary arteries. More recently, novel drugs in preclinical and clinical research aim to inhibit vascular remodeling.

Combination therapies have become more common in clinical practice, but they do not come without potential side effects and decreased tolerability compared with single-drug treatments. However, a novel therapeutic strategy targeting different pathways to treat vasodilation and vascular remodeling at once has recently been considered a feasible approach to PAH treatment.

While new drugs targeting ET, PGI2, and NO pathways have been approved in the past 2 decades, these drugs mainly decrease PAP without affecting the vascular remodeling that furthers disease progression. Because vascular remodeling inhibition does not relax active vasoconstriction and elevated PAP —the most urgent symptom for patients—it stands to reason new treatments should address both facets of PAH.

Study authors present options, the first of which are natural products, or drugs derived from plants. In recent years, convincing clinical trials have shown efficacy in cancer and vascular disease treatment, including for COVID-19. “Natural products tend to be multitarget drugs that generally have multiple roles, including vasodilation and vascular remodeling inhibition,” the authors wrote.

One example, ligustrazine, reduced mPAP and PVR in dog models to improve vessel wall thickness. Plumbagin, dehydroepiandrosterone, rhodiola extract, resveratrol, and tetrandrine have also shown effects on PAP and PVR that may prove effective in PAH.

Another potential treatment approach is combined administrations of previously available PAH treatments that target different pathways. “Initial combination therapy with tadalafil and ambrisentan, a phosphodiesterase type 5 inhibitor and endothelin-receptor antagonist, respectively, demonstrated improved efficacy compared with monotherapy with either agent alone,” the authors wrote, “demonstrating the feasibility of combination therapies that exploit different pathways and targets to mediate multiple pathological processes.”

Many patients continue to have limited vascular function despite improvements while on these combinations, though, and drugs targeting ET, PGI2, and NO pathways at once are under consideration as a potential treatment option in severe disease. Thus far, triple therapies have shown improved long-term outcomes compared with double therapies.

Hybridization candidates are the final suggestion in the review. “Given the considerable improved outcomes of the simultaneous regulation of vasodilation and vascular remodeling, especially with the administration of natural products and combination therapies, it would be even more advantageous to synthesize small molecules that perform the dual activities of vascular remodeling inhibition and vasodilation,” the authors wrote.

One attempt at creating such a treatment was MN-08, which in rat studies was confirmed to inhibit N-methyl-D-aspartate, a target for vascular remodeling inhibition, while also releasing NO to reduce vasoconstriction. This and a selection of other drugs being researched shows the potential utility of higher vascular remodeling inhibition potency and moderate vasodilation ability in treatment of PAH.

An important aspect of PAH therapy improvement will be the shift from a symptom-based strategy to one that addresses disease pathology throughout treatment, the review concludes. Advances in technology will also speed the development of novel therapies.

“In the coming years, additional data are expected to fill the gaps in our knowledge,” the authors concluded, “ensuring that this novel therapeutic strategy for PAH can be used to its full potential, providing patients with the best long-term outcomes.”

Reference

Hu L, Zhao C, Chen Z, Hu G, Li X, Li Q. An emerging strategy for targeted therapy of pulmonary arterial hypertension: Vasodilation plus vascular remodeling inhibition. Drug Discov Today. Published online January 29, 2022. doi:10.1016/j.drudis.2022.01.011