Emerging therapeutic targets for primary sclerosing cholangitis

ABSTRACT

Introduction: Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that can progress to end-stage cirrhotic liver disease and/or hepatobiliary malignancy. The etiopathogenesis of PSC remains unknown, and considerable heterogeneity is seen both phenotypically as well as genetically; this, together with its relative rarity and the lack of consensus regarding appropriate (surrogate) clinical endpoints, has hampered the development and implementation of effective pharmacologic therapies. Several different disease mechanisms have been proposed which have led to various potential therapeutic approaches. However, to date, no medical therapies short of liver transplantation have been proven to be effective for PSC, and as such, liver transplantation – an option for only a fraction of patients – remains the only potentially curative therapy.

Areas covered: This review will highlight the various different proposed mechanisms of the etiopathogenesis of PSC and explore the therapeutic targets corresponding to them which are anticipated to be or are already under clinical investigation.

Expert commentary: The development of new therapies for PSC remains challenging due to numerous factors, not the least of which are the rare and pathobiologically enigmatic nature of the disease. However, with recent advances in the understanding of potential mechanistic underpinnings and lateral insights from other liver diseases, new potential targets and novel therapeutic agents are being evaluated; we believe these have the potential to lead to the establishment of safe and effective medical therapies and thus better outcomes in PSC.

KEYWORDS:

• Biliary tract disease
• drug therapy
• bile acids
• endoscopy therapy
• survival

Article highlights

• PSC is an idiopathic, progressive, CLD for which there is no approved pharmacotherapy.

• Development and testing of medical therapies for PSC are hampered by the enigmatic etiopathogenesis of the disease, its phenotypic and genetic heterogeneity, the relative rarity of the disease, paucity of viable animal models, and lack of consensus regarding appropriate (surrogate) clinical endpoints.

• Given the morbidity and mortality of PSC, the lack of effective medical treatments, and the costs and challenges of LT and post-LT PSC or hepatobiliary carcinoma recurrence, novel targets and therapeutic options are critically needed.

• Presently, several agents belonging to a variety of pharmacologic and mechanistic classes seem promising as potential treatments for PSC based on ongoing preclinical studies and clinical trials.

We anticipate more data emerging in the near future about these agents as well as others, and as such, there is a new-found optimism for the emergence of safe and effective medical therapy for PSC on the horizon.

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.

Additional information

Funding

No funding was received