Emerging pharmacotherapies for the treatment of pulmonary arterial hypertension

ABSTRACT

Introduction

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin.

Areas covered

Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved.

Expert opinion

Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.

KEYWORDS:

• Pulmonary arterial hypertension
• idiopathic pulmonary arterial hypertension
• pulmonary arterial hypertension pathogenesis
• clinical trials
• randomized controlled trials
• novel therapeutics
• pulmonary vascular remodeling
• sotatercept

Article highlights

• Pharmacologic therapy for treating PAH has expanded rapidly since the approval of intravenous prostacyclin less than 30 years ago

• Available therapies reduce pulmonary arterial pressures by compensating for alterations in prostacyclin, cGMP, and endothelin signaling

• They do prevent disease progression because they fail to address the underlying pathogenesis that drives the disease

• Repurposing currently available PAH medications to be used at different doses or via other routes of administration may result in therapies that are easier for patients to use but are not likely to result in substantial improvements in clinical outcomes

• Encouraging results from recently completed phase 2 and 3 trials with sotatercept suggest that this drug may soon be approved for treating PAH

• As the armamentarium for PAH treatments continues to grow, it will be essential to conduct future studies to determine which drugs most likely benefit individual patients with PAH

• Recent calls for studies that aim to develop a precision medicine approach to treating PAH will likely become increasingly relevant in this rapidly expanding area

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have served as a consultant for J and J. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.