POISE Study

The POISE study is a phase 3 clinical trial designed to evaluate the efficacy and safety of obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, in patients with primary biliary cholangitis (PBC) who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA). Below is a detailed breakdown of the study:

### **Purpose**

The study aimed to address the unmet need in PBC patients who do not respond adequately to UDCA, the first-line treatment for PBC. OCA was investigated as a second-line therapy to improve biochemical markers associated with disease progression, particularly alkaline phosphatase (ALP) and bilirubin levels, which are strongly linked to improved transplant-free survival in PBC.

---

### **Study Design**

• **Type:** 12-month, double-blind, randomized, placebo-controlled, multicenter trial.
• **Participants:** 217 patients with PBC.
• **Treatment Groups:**
• OCA 10 mg daily.
• OCA 5 mg daily titrated to 10 mg.
• Placebo.
• Patients were allowed to continue UDCA therapy during the trial, with 93% of participants doing so.

---

### **Patient Profile**

• **Demographics:** Predominantly middle-aged women (91% female, mean age 56 years).
• **Ethnicity:** Mostly White (94%).
• **Disease Characteristics:** Long-standing PBC with elevated ALP levels (≥1.67× the upper limit of normal [ULN]).

---

### **Primary Endpoint**

The main composite endpoint was achieving:

1. ALP <1.67× ULN.

2. A ≥15% reduction in ALP from baseline.

3. Normal total bilirubin levels at 12 months.

These parameters are strongly associated with improved transplant-free survival in PBC patients.

---

### **Key Results**

#### **Achievement of Primary Endpoint**

• **OCA 5 mg titrated to 10 mg:** 46% of patients achieved the primary endpoint.
• **OCA 10 mg:** 47% of patients achieved the primary endpoint.
• **Placebo:** Only 10% of patients achieved the endpoint.
• Statistical significance: P<0.001 for both OCA groups compared to placebo.

#### **ALP and Bilirubin Reduction**

• **ALP Reduction:** Substantial decreases in ALP were observed in the OCA groups (−113 to −130 U/L) compared to placebo (−14 U/L).
• **Total Bilirubin:** Levels decreased in the OCA groups but slightly increased in the placebo group, indicating improved cholestasis control.

#### **Rapid and Sustained Response**

• Biochemical improvements were seen as early as two weeks after starting OCA and were maintained throughout the study.
• Sustained effects were observed in the open-label extension study over two years.

#### **Other Liver Enzyme Effects**

OCA significantly reduced gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and conjugated bilirubin levels, reinforcing its role in improving markers of hepatocellular and cholestatic injury.

#### **Inflammatory and Immune Modulation**

Exploratory analyses showed decreased levels of inflammatory and immune markers (e.g., C-reactive protein, TNF-α, IgM, IgG, and IL-12) in OCA-treated patients, suggesting systemic anti-inflammatory and immune-regulating effects through FXR activation.

#### **Mechanistic Biomarker Support**

OCA increased circulating fibroblast growth factor-19 (FGF-19) and reduced total bile acids, consistent with FXR activation. This mechanism suppresses bile acid synthesis and reduces hepatocellular bile acid load.

---

### **Safety and Adverse Events**

#### **Pruritus**

• Pruritus (itching) was the most common side effect:
• **OCA 5 mg titrated to 10 mg:** 56% of patients.
• **OCA 10 mg:** 68% of patients.
• **Placebo:** 38% of patients.
• Pruritus was dose-dependent and occasionally required dose reduction or treatment discontinuation.

#### **Other Adverse Events**

• Serious adverse events occurred in:
• **OCA 5 mg titrated to 10 mg:** 16%.
• **OCA 10 mg:** 11%.
• **Placebo:** 4%.
• Most adverse events were mild-to-moderate and resolved without long-term effects.
• One death occurred during the study but was unrelated to OCA treatment.

#### **Lipid Profile Effects**

• **HDL Cholesterol:** Dose-related decreases.
• **LDL Cholesterol:** Transient increases.
• **Triglycerides:** Reductions.

These changes are attributed to FXR-mediated regulation of bile acid and cholesterol metabolism.

#### **Bone Mineral Density**

DEXA scans showed smaller declines in femoral bone mineral density in OCA-treated patients compared to placebo, suggesting potential protective effects on skeletal health.

---

### **Limitations**

1. **Duration:** The 12-month trial was insufficient to assess long-term clinical outcomes, including fibrosis improvement.

2. **Pruritus:** It remains a significant tolerability issue, requiring optimized dose titration strategies.

3. **Multiplicity Corrections:** Limited to primary endpoints.

---

### **Open-Label Extension Outcomes**

In the 5-year extension study:

• Patients continuing OCA maintained biochemical improvements.
• Patients switching from placebo experienced similar benefits.

This confirmed the reproducibility and durability of OCA’s efficacy.

---

### **Clinical Significance**

Although fibrosis improvement was not demonstrated within the trial duration, the observed biochemical responses strongly predict reduced risk of liver failure, transplantation, and death based on established prognostic models.

---

### **Conclusion**

The POISE study established that obeticholic acid significantly improves key biochemical markers of disease progression in PBC patients unresponsive to UDCA. Despite challenges with pruritus, OCA demonstrated robust efficacy and established FXR agonism as a viable disease-modifying mechanism for PBC. Long-term outcome trials, such as COBALT, were initiated to confirm survival benefits and refine dosing strategies for broader clinical use.