Novel and Emerging Therapies for Cholestatic Liver Diseases

Jordan Goldstein; Cynthia Levy


Liver International. 2018;38(9):1520-1535. 

In This Article

Existing Therapies

Ursodeoxycholic Acid

Ursodeoxycholic acid was approved in 1997 for use in PBC at a dose of 13–15 mg/kg/d. The beneficial effects of UDCA are due to an increase in the ratio of hydrophilic to hydrophobic bile acids, stimulation of bile flow through BSEP, stabilization of the bicarbonate umbrella and antiapoptotic as well as anti-inflammatory effects.[16,19,20] In addition to improvement in liver biochemistries, studies have shown that UDCA delays histological progression, delays the development of oesophageal varices and improves survival free of liver transplantation.[21–23] UDCA should be used as the first-line therapy for all patients with PBC.

The American Association for the Study of Liver Diseases (AASLD) recommends against the use of UDCA as medical therapy in PSC, as beneficial data regarding its long-term use are lacking and doses >28 mg/kg/d have been associated with worse outcomes compared to placebo.[24,25] However, some experts still use UDCA for PSC in dosages of 17–23 mg/kg/d in hopes of decreasing serum alkaline phosphatase (ALP),[26] as studies have shown a survival benefit in patients who normalized ALP either spontaneously or as a result of treatment with UDCA.[27–29] Notably, recent guidelines from the American College of Gastroenterology (ACG) emphasize that doses greater than 28 mg/kg/d should not be used, but defer to the treating physician whether or not to use median doses (17–23 mg/kg/d).[30]

Obeticholic Acid

The natural ligand for FXR is chenodeoxycholic acid. Obeticholic acid (OCA), a 6-ethyl derivative of chenodeoxycholic acid with 100 times its potency, functions as a strong FXR agonist.[31] In addition to modulation of bile acid homeostasis, as previously discussed, FXR also regulates lipid metabolism and gluconeogenesis as well as inflammation and fibrosis pathways.[32]

Obeticholic acid was granted conditional approval in May 2016 for use in PBC. It should be prescribed in conjunction with UDCA for patients with inadequate response to UDCA, or as monotherapy for those who are unable to tolerate UDCA. This approval was based on results of the POISE trial, where 216 patients with PBC and an inadequate response to UDCA received either placebo, OCA 10 mg/d or OCA 5 mg/d with the possibility to titrate to 10 mg/d, for 12 months. In this study, OCA or placebo was given in combination with UDCA in 93% of patients and as monotherapy in 7%. The primary endpoint was a composite of 3 criteria: ALP < 1.67× upper limit of normal (ULN), total bilirubin ≤ULN and an ALP reduction of at least 15%. Nearly half of OCA-treated patients met the primary endpoint compared to only 10% of patients on placebo.[3] In a separate phase II study, ALP reductions of 53.9% and 37.2% were observed in patients receiving 10 mg/d and 50 mg/d of OCA monotherapy, respectively.[33]

The most common side effect of OCA is a dose-dependent development of itching. This is minimized by starting with the lowest recommended dose, 5 mg/d, and increasing to 10 mg/d after 3 months if the medication is well tolerated and the ALP remains elevated. Use of OCA has also been associated with a dose-dependent reduction in high-density lipoprotein (HDL) cholesterol and this should be monitored during treatment.[34] Importantly, the recommended starting dose is reduced in cirrhotics with moderate or severe hepatic impairment. Hepatic decompensation, liver failure and death have been reported when Child B or C cirrhotics are dosed more frequently than recommended. As a result, the FDA issued a black box warning to the OCA label highlighting prescribing recommendations for patients with decompensated liver disease ( These recommendations are listed in Table 2.

Further studies are needed to examine the long-term effect of OCA therapy on mortality and liver transplantation as well as its adequacy for patients with more advanced liver disease. Using data from the POISE trial in a microsimulation model, Samur and colleagues determined that the combination of UDCA and OCA could decrease the 15-year cumulative incidence of decompensated cirrhosis, hepatocellular carcinoma, liver transplants and liver-related deaths, thus increasing transplant-free survival. However, adding OCA to UDCA led to an incremental cost-effectiveness ratio of $473 400/quality-adjusted life year (QALY) gained, which is deemed not cost effective when using a willingness-to-pay threshold of $100 000/QALY.[35] While OCA is promising in terms of its ability to significantly decrease ALP levels in PBC patients and possibly improving survival free of liver transplantation, it is not economically feasible in the long term and a significant reduction in cost would be required to achieve cost-effectiveness.

In regard to the use of OCA in PSC, the phase II AESOP trial looked at the effect of OCA on 77 patients with PSC over 24 weeks (NCT02177136). Investigators noted a statistically significant decrease in baseline ALP of 22% in both the low-dose (1.5–3 mg) and high-dose (5–10 mg) groups,[36] and a long-term extension phase is ongoing. While encouraging, further trials are needed to assess if these results translate into a clinically significant endpoint such as increased time to transplantation or death.