Investigational drugs in early clinical development for portal hypertension

ABSTRACT

Introduction

Advanced chronic liver disease is considered a reversible condition after removal of the primary etiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH.

Areas covered

This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trial sites and PubMed from the last 10 years.

Expert Opinion

A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis, thus eliminating the need for treatment or screening of PH.

KEYWORDS:

• Cirrhosis
• chronic liver disease
• portal pressure
• hepatic
• hepatic venous pressure gradient

Article highlights

• The complications of liver cirrhosis are determined largely by the presence of clinically significant portal hypertension (CSPH).

• The paradigm of current pharmacologic management of portal hypertension (PH) has shifted beyond prevention of major complications of PH, to modifying the natural history of cirrhosis and PH, such as prevention of clinical decompensation, and ultimately reversing cirrhosis and subsequently PH.

• In recent years, the development of new therapies to treat portal hypertension have focused primarily on reducing increased intrahepatic resistance.

• The complex interaction between structural and hemodynamic mechanisms that lead to PH makes the development of new drugs targeting several potential pathways, such as decreasing fibrogenesis and angiogenesis more attractive.

• The future panorama of therapy of portal hypertension together with aetiology-specific treatments, are likely to lead to decrease in decompensation and increased benefit on survival and quality of life.

• Some drugs are closer to clinical use. These include a group of drugs decreasing portal pressure by reducing intrahepatic vascular resistance and reversing liver microvascular dysfunction that comprise the statins, simvastatin and atorvastatin, and soluble guanyl-cyclase (sGC) activators and stimulators (mainly, riociguat).

• Anticoagulants such as enoxaparin and ribaroxaban are promising, as well as the FXR agonists such as obeticholic acid, the glucagon-like peptide-1 (GLP-1) agonists liraglutide and semaglutide, and the pan-peroxisome proliferator-activated receptor (PPAR) agonist lanifibranor.

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Declaration of interest

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

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

Additional information

Funding

This paper was not funded.