Sodium/bile acid co-transporter inhibitors currently in preclinical or early clinical development for the treatment of primary biliary cholangitis

ABSTRACT

Introduction

Pruritus is common and often undertreated in patients with primary biliary cholangitis (PBC). Existing treatments largely have an aging and low-quality evidence base, and studies included only small numbers of patients. More recent data that has added to our understanding of pruritus treatments has often come from clinical trials where itching was a secondary outcome measure in a trial designed primarily to assess disease-modifying agents. This area represents an unmet clinical need in the management of PBC.

Areas covered

In this manuscript, we first summarize the proposed mechanisms for PBC-related pruritus and the current treatment paradigm. We then present an appraisal of the existing pre-clinical and clinical evidence for the use of ileal bile acid transporter inhibitors (IBATis) for this indication in PBC patients.

Expert opinion

Evidence for the efficacy of IBATis is promising but limited by the currently available volume of data. Furthermore, larger clinical trials with long-term data on efficacy, safety and tolerability are needed to confirm the role of using IBATis in clinical practice and their place on the itch treatment ladder. Additional focus should also be given to exploring the disease-modifying potential of IBATis in PBC.

KEYWORDS:

• Primary biliary cholangitis
• symptoms
• pruritus
• IBAT inhibitor
• ASBT inhibitor

Article highlights

• Pruritus in PBC is not well understood but remains a significant contributor to impaired quality of life and is associated with poorer outcomes. Many current therapies lack a robust, contemporary evidence base for their use.

• IBAT inhibitors effectively block the enterohepatic circulation of bile acids, one of several proposed pruritogens, leading to almost total fecal excretion.

• Preclinical and clinical trials have shown this class to be safe and well tolerated, while the phase 2 GLIMMER trial has demonstrated superiority over placebo in improving patient-reported measures of pruritus.

• Several factors continue to make progress in this area challenging: the placebo effect, the multifactorial pathogenesis of pruritus, and methodological limitations of rare disease research.

• Repeated and larger scale trials are required to clarify the role of this class in the management of pruritus.

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

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

Additional information

Funding

This paper was not funded.