Advances in the discovery of drugs that treat pulmonary arterial hypertension

ABSTRACT

Introduction

Distal pulmonary arterial remodeling and elevated pulmonary vascular resistance are characteristic of pulmonary arterial hypertension (PAH). Current approved vasodilator-specific PAH therapy that includes phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids has demonstrated dramatic enhancement in functional capacity, quality of life, and invasive hemodynamics. However, none of these treatments are curative, underscoring the need to identify new pathophysiologic signaling pathways.

Areas covered

The author provides a comprehensive review on current knowledge and recent development in the understanding of PAH. Furthermore, the author discusses PAH potential genetic causes as well as novel molecular signaling pathways. This article also reviews the currently approved PAH specific therapy based on pivotal clinical trials and ongoing clinical trials using novel compounds that specifically target PAH pathogenesis.

Expert opinion

The discovery of novel signaling pathways – growth factors, tyrosine kinases, BMPs, estrogen, and serotonin – involved in the PAH pathobiology will lead within the next 5 years to the approval of new therapeutic agents targeting these different pathways. If proven beneficial, these new agents may reverse or at least prevent the progression of this devastating and lethal disease.

KEYWORDS:

• PAH
• Prostanoids
• Endothelin Receptor Antagonists
• Nitric Oxide
• Combination therapy
• TGF ‐ β superfamily
• BMPs
• growth factors/tyrosine kinases
• serotonin
• estrogen

Article highlights

• PAH is a deadly disease with a 5-year survival estimated to be at 30% with no PAH specific treatment.

• Current approved specific PAH therapy including prostacyclins, prostacyclin receptor analogues, ERAs, PDE5si, and sGC stimulators act essentially as vasodilators and do not reverse the disease process.

• The major histopathological characteristic of PAH is vascular wall remodeling with proliferation of PASMCs and fibroblasts as well as endothelial cell dysfunction.

• There is an urgent need for novel therapies able to stop the process of the disease and improve the outcome of PAH.

• There are several new molecules, currently being tested in Phases II and III clinical trial targeting new pathways which are promising and appear capable of interrupting and might even reverse the disease process.

Declaration of Interest

R Zolty is a consultant for Actelion, Bayer Healthcare, United Therapeutics and Johnson and Johnson. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.