What are the details of landmark trials for obeticholic acid (Obeticholic acid) in Primary Biliary Cholangitis (PBC)?

Landmark Trials of Obeticholic Acid in Primary Biliary Cholangitis

Obeticholic acid (OCA) was approved in 2016 as a second-line therapy for patients with Primary Biliary Cholangitis (PBC) who have inadequate response to ursodeoxycholic acid (UDCA) or are intolerant to UDCA, based on several landmark clinical trials that demonstrated its efficacy in improving biochemical markers associated with disease progression and mortality. 1

POISE Trial: The Pivotal Phase 3 Study

The POISE trial was the landmark phase 3 clinical trial that led to FDA approval of obeticholic acid for PBC. Key features of this trial include:

• Design: Randomized, double-blind, placebo-controlled, 12-month clinical trial 2
• Participants: 216 patients with PBC who were taking UDCA for at least 12 months (93% of participants) or were unable to tolerate UDCA (7% of participants)
• Inclusion criteria: ALP ≥1.67× ULN and/or total bilirubin >1× ULN but <2× ULN
• Exclusion criteria: Other liver diseases, clinically significant hepatic decompensation, severe pruritus, or MELD score ≥15
• Treatment arms:
  • OCA 10 mg once daily for 12 months (n=73)
  • OCA titration (5 mg once daily for 6 months with option to increase to 10 mg) (n=70)
  • Placebo (n=73)
• Primary endpoint: Composite of ALP <1.67× ULN, total bilirubin ≤ULN, and ALP decrease ≥15% at 12 months 2

Long-term Extension of POISE

Following the initial 12-month double-blind phase, an open-label extension study was conducted:

• Duration: 5-year extension (3-year interim data published)
• Participants: 193 patients from the original POISE trial
• Key findings at 48 months:
  • Sustained reduction in ALP (mean change -95.6 U/L)
  • Stabilization of total bilirubin levels
  • Pruritus (77%) and fatigue (33%) were the most common adverse events
  • No serious adverse events were considered related to OCA 3

Real-World Evidence Studies

Several real-world studies have confirmed the efficacy and safety profile observed in clinical trials:

1. Italian PBC Registry Study (2021):

   • 191 patients followed for at least 12 months
   • 42.9% response rate according to POISE criteria
   • Significant median reductions in ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%)
   • Lower response in patients with cirrhosis (29.5% vs. 49.2%)
   • 17% discontinued due to adverse events, primarily pruritus 4

2. Southern European Multicenter Study (2021):

   • 120 patients from Spain and Portugal
   • Significant decrease in ALP (81.3 U/L), ALT (22.1 U/L), and bilirubin (0.12 mg/dL)
   • 29.5% achieved response according to POISE criteria
   • 11.67% discontinued treatment (8.3% due to pruritus) 5

Mechanism of Action Studies

A mechanistic study using positron emission tomography demonstrated that OCA:

• Increased hepatic blood perfusion by 11%
• Enhanced uptake clearance of bile acids from blood into hepatocytes by 11%
• Increased secretion of bile acids from hepatocytes into biliary canaliculi by 73%
• Reduced hepatocyte residence time of bile acids by 30% (from 11 to 8 minutes)

This confirms that OCA improves the transport of potentially cytotoxic bile acids from hepatocytes into biliary canaliculi, reducing their residence time in liver cells 6.

Combination Therapy Studies

A retrospective cohort study evaluated the combination of OCA with fibrates:

• 58 patients received triple therapy (UDCA + OCA + fibrates)
• Triple therapy was associated with:
  • 22% additional reduction in ALP compared to dual therapy
  • 3.4 times higher odds of reaching normal ALP
  • Significant improvements in GGT, ALT, AST, and total bilirubin
  • Improved pruritus in patients who received OCA before fibrates 7

Safety Considerations and Warnings

Important safety warnings from clinical trials and post-marketing surveillance:

• OCA is contraindicated in patients with PBC with decompensated cirrhosis, prior decompensation events, compensated cirrhosis with portal hypertension, or complete biliary obstruction 8
• The FDA has issued a boxed warning due to reports of hepatic decompensation and failure in PBC patients with cirrhosis, including 19 deaths and 11 cases of serious liver injury 8
• Dose adjustment is required for patients with advanced disease to avoid toxic drug exposure levels 1
• Pruritus is the most common adverse event and the leading cause of discontinuation 4, 3

Monitoring Recommendations

Based on landmark trials, monitoring should include:

• Liver biochemistry every 3 months (ALP, bilirubin, transaminases, albumin)
• Assessment of response at 12 months using validated criteria (Paris-II, GLOBE, UK-PBC scores)
• Monitoring for pruritus and other adverse events
• More frequent monitoring in patients with advanced disease 8

The landmark trials of obeticholic acid have established its role as an effective second-line therapy for PBC patients with inadequate response to UDCA, with consistent biochemical improvements across clinical trials and real-world studies, though with important safety considerations particularly in patients with advanced liver disease.