Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial

Primary biliary cholangitis (PBC) is a chronic autoimmune disease of the liver that damages the bile ducts, resulting in cholestasis and fibrosis if left untreated.^1,2 Patients are also at higher risk for hepato-cellular carcinoma, osteoporosis, and osteopenia. The disease is rare and mainly diagnosed in women in their 40s. Importantly, the incidence appears to be steadily increasing in the United States, Europe, and Asia.^3-5 Urso deoxycholic acid (UDCA), the standard first-line treatment, alters the course of the disease, but approximately 40% of patients do not benefit from this approach.^6,7

Obeticholic acid (OCA) is a modified bile acid farnesoid X receptor agonist that was first approved by the US Food and Drug Administration (FDA) in May 2016 for use in conjunction with UDCA.² OCA acts on several steps in bile acid homeostasis, ultimately improving the clearance of bile acid from the body and decreasing the amount being made. It also reduces inflammation and cholestasis in the liver.⁸ In addition, OCA is antifibrotic.

The phase 3 POISE trial evaluated OCA in patients with PBC. In the 12-month double-blind phase, patients were randomized to 1 of 3 arms: placebo with or without UDCA (73 patients), 5 mg of OCA with allowed adjustment to 10 mg with or without UDCA (70 patients), or 10 mg of OCA with or without UDCA (73 patients). Key inclusion criteria included a diagnosis of PBC; alkaline phosphatase (ALP) of at least 1.67 times the upper limit of normal (ULN) or total bilirubin greater than the ULN to less than 2 times the ULN; and inadequate response to UDCA or inability to tolerate it.⁹ The primary POISE endpoint was ALP of less than 1.67 times the ULN, a reduction of at least 15% in ALP from baseline, and normal total bilirubin (≤ ULN) at 12 months.

The primary endpoint was met by 46% of patients in the 5-mg to 10-mg OCA arm and by 47% of patients in the 10-mg OCA arm, compared with 10% of patients in the placebo arm. In addition, PBC patients who received OCA for 12 months experienced significantly decreased levels of ALP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), compared with those on placebo, as well as stabilization of total bilirubin.⁹

Following the 12-month double-blind phase of the POISE trial, patients were eligible to enter an open-label extension. All patients were treated with OCA 5 mg for 3 months, after which the dose could be titrated based on tolerability.

At the American College of Gastroenterology 2020 Virtual Annual Scientific Meeting, Dr Christopher L. Bowlus presented results from an analysis of the long-term efficacy and safety of OCA in demographic subgroups of patients who had been treated for 5 or more years in the POISE trial.¹⁰ This analysis pooled double-blind placebo and double-blind OCA patients, and the demographic subgroups included age at study entry (≤55 years vs >55 years), age when diagnosed with PBC (≤47.5 years vs >47.5 years), and sex (male vs female).

A total of 193 of the 198 patients who completed the double-blind phase of the study enrolled in the open-label extension. Of these, 116 completed 5 years of OCA treatment, including 52 who received OCA in the double-blind phase and thus received a total of 6 years of OCA treatment. Figure 1 shows the POISE primary endpoint from OCA baseline by demographic subgroup for years 1, 5, and 6. Total bilirubin remained stabilized and the improvements in ALP were maintained across all subgroups after 6 years of treatment with OCA. Likewise, all of the subgroups sustained the improvements in both ALT and GGT that they achieved during the early phase of the study. In general, both ALT and AST were higher in the 2 younger-age subgroups. The most common side effect was mild to moderate pruritus, which occurred at similar rates in all demographic subgroups.

Figure 1.

POISE primary endpoint (ALP <1.67 × ULN, total bilirubin ≤ ULN, and ALP reduction ≥15%) from OCA baseline by demographic subgroup. For patients who received placebo in the double-blind phase, OCA baseline was the last assessment prior to the first OCA dose in OLE. For patients who received OCA in the double-blind phase, OCA baseline was the mean of all available evaluations prior to double-blind treatment. ALP, alkaline phosphatase; OCA, obeticholic acid; OLE, open-label extension; ULN, upper limit of normal. Adapted from Bowlus CL et al. ACG abstract 58. Presented at the American College of Gastroenterology 2020 Virtual Annual Scientific Meeting; October 23-28, 2020.¹⁰

OCA led to sustained improvements in ALP, ALT, AST, and GGT as well as stabilization of total bilirubin through 5 years across demographic subgroups. Adverse events were consistent with OCA’s established safety profile, and there were no new safety observations during long-term treatment. The researchers concluded that long-term OCA treatment is associated with durable improvements or stabilization in markers of disease severity in PBC patients, regardless of age or sex.