Investigational drugs in early phase development for primary biliary cholangitis

ABSTRACT

Introduction: With a large percentage of patients having an incomplete response or intolerance to current FDA approved medications, new therapies for the treatment of primary biliary cholangitis are in great demand.

Areas covered: In this review, we assess currently available drugs as well as promising new therapies for the treatment of primary biliary cholangitis. A literature search was performed with the following search terms: ‘PBC treatment,’ ‘PBC therapeutics,’ ‘PBC clinical trials,’ and included original articles, meta-analyses, and systematic reviews from 1 January 1981, to 1 January 2020. ClinicalTrials.gov was accessed for data from ongoing trials.

Expert opinion: Targeted drug therapies offer an alternative for patients who are unable to meet their therapeutic goals with either of the two currently approved treatment options. Specifically, new drugs targeting bile-acid regulation, immune-modulation, and fibrogenic pathways are currently in development with multiple agents showing encouraging early results with the ultimate goal of developing therapies that will achieve high rates of biochemical remission, will be well tolerated, and improve symptoms and quality of life in patients with primary biliary cholangitis. Based on a review of the current literature, PPAR agonists appear to be promising agents, along with FGF19 analogs and FXR agonists.

KEYWORDS:

• Biliary
• cholangitis
• liver
• novel
• therapeutics
• phase 2
• phase 3

Article Highlights

• Ursodeoxycholic acid and obeticholic acid remain the first and second-line disease-modifying options, respectfully, for the treatment of primary biliary cholangitis; however, a significant percentage of patients need additional treatment to reach therapeutic goals.

• Novel therapies are currently in development, many of which have shown significant promise in ongoing clinical trials including PPAR agonists along with FGF19 analogs and FXR agonists.

• Treatment goals in PBC are evolving and the ideal therapy would achieve normalization of serum alkaline phosphatase and bilirubin and thus aim for a biochemical remission although biochemical remission does not always correlate with histological improvement in fibrosis.

• Challenges in finding an ideal treatment include the incomplete knowledge and complex pathophysiology of this disease and the rarity of primary biliary cholangitis limiting the number of patients eligible for enrollment in clinical trials.

• Future treatment strategies will likely incorporate stage-dependent therapies in addition to the use of combination therapies to create personalized treatment regimens for individual patients.

This box summarizes the key points contained in the article.

Declaration of Interests

K Kowdley receives research support from; Enanta, Genfit, Gilead, Cymabay, GlaxoSmithKline, Intercept, and Novartis. He also consults for; Intercept, Enanta, Genfit, Gilead, Cymabay, Novartis and Arena. He is also a speaker for Intercept and Gilead and has royalites with Up-To-Date (an educational website). The authors have 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.