ELATIVE and PBC

The ELATIVE trial was a clinical study designed to evaluate the efficacy and safety of **elafibranor**, a dual PPAR-α/δ agonist, as a potential second-line treatment for **primary biliary cholangitis (PBC)**. PBC is a chronic autoimmune liver disease characterized by progressive destruction of bile ducts, leading to cholestasis, fibrosis, and eventually cirrhosis. The trial specifically targeted patients with PBC who had an inadequate response or intolerance to **ursodeoxycholic acid (UDCA)**, the current first-line therapy for the disease.

### Key Aspects of the ELATIVE Trial:

#### **Objective:**

The primary goal of the ELATIVE trial was to determine whether elafibranor could improve **biochemical markers of cholestasis** and serve as a safe and effective second-line therapy for PBC patients who could not achieve sufficient benefits from UDCA.

#### **Study Design:**

• **Type:** Multicenter, phase 3, double-blind, placebo-controlled trial.
• **Duration:** 52 weeks, with continuation into a long-term open-label extension.
• **Participants:** 161 patients randomized in a 2:1 ratio to receive either **elafibranor (80 mg once daily)** or placebo.
• Conducted across **14 countries**.

#### **Patient Demographics:**

• **Gender:** Majority were women (96%), reflecting the typical gender distribution in PBC.
• **Age:** Average age was 57 years.
• **UDCA Use:** Approximately 94% of patients continued UDCA during the trial, mimicking real-world management of PBC.
• **Disease Severity:** Around 39% of participants had **ALP levels >3× upper limit of normal (ULN)**, and 35% had fibrosis or cirrhosis at baseline.

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### **Primary Endpoint:**

The trial’s main endpoint was achieving a **biochemical response** at week 52, defined as:

1. **ALP <1.67× ULN**,

2. **≥15% reduction from baseline**, and

3. **Normal total bilirubin**.

This endpoint is strongly predictive of **improved transplant-free survival** in PBC patients.

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### **Results and Outcomes:**

#### **Primary Outcome:**

• **Biochemical Response:**
• **Elafibranor group:** 51% achieved biochemical response at week 52.
• **Placebo group:** Only 4% achieved biochemical response.
• **Statistical Significance:** Difference of 47 percentage points (**P<0.001**), demonstrating robust efficacy.

#### **ALP Normalization:**

• 15% of elafibranor-treated patients achieved **normalization of ALP**, compared to none in the placebo group (**P=0.002**).
• ALP reductions were evident as early as **4 weeks** and sustained throughout the trial.

#### **Liver Enzymes and Bilirubin:**

• **Elafibranor effects:**
• Significant reductions in **γ-glutamyl transferase (GGT)**, **ALT**, and **IgM** levels.
• **Stable bilirubin and albumin levels**, indicating improved liver function without hepatotoxicity.

#### **Pruritus (Itch):**

• **Moderate-to-severe itch:** No statistically significant differences in **WI-NRS scores** at weeks 24 or 52 compared to placebo.
• However, patient-reported outcomes using **PBC-40** and **5-D itch scales** showed **modest improvements** favoring elafibranor.
• Unlike **obeticholic acid**, which tends to worsen pruritus, elafibranor may reduce **itch-related burden**.

#### **Lipid Metabolism:**

• Elafibranor significantly lowered **triglycerides**, **VLDL cholesterol**, and **total cholesterol**, while maintaining stable **LDL** and **HDL cholesterol** levels.
• This contrasts favorably with **obeticholic acid**, which often raises **LDL levels**.

#### **Fibrosis and Liver Stiffness:**

• No significant changes in **enhanced liver fibrosis scores** or **liver stiffness** were observed after 52 weeks.
• Longer follow-up is required to assess potential antifibrotic effects.

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### **Safety Profile:**

#### **Adverse Events:**

• Overall, adverse events were similar between elafibranor and placebo groups.
• Most common treatment-related side effects were mild **gastrointestinal events**:
• **Abdominal pain**, **diarrhea**, **nausea**, and **vomiting** (each reported in ~10–12% of patients).

#### **Muscle-Related Effects:**

• **Creatine phosphokinase elevations** occurred more frequently in the elafibranor group (3.7%), occasionally leading to treatment discontinuation.
• One serious case of **rhabdomyolysis** was reported in a patient with advanced cirrhosis and concomitant use of atorvastatin.

#### **Hepatic and Renal Safety:**

• **Drug-induced liver injury** was rare and reversible upon discontinuation.
• Slight increases in **creatinine** were noted in 10% of patients, but without changes in **cystatin C** or **estimated glomerular filtration rate**, suggesting no significant renal impairment.

#### **Mortality and Serious Events:**

• Two deaths occurred in the elafibranor group:
• One postoperative death.
• One due to **biliary sepsis**.
• Neither death was considered treatment-related.
• Serious adverse events were similar between elafibranor and placebo groups (10% vs. 13%).

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### **Comparison to Other Agents:**

• Unlike **obeticholic acid**:
• Elafibranor improved **lipid parameters**.
• Did not worsen **pruritus**, suggesting a more favorable tolerability and metabolic profile for long-term management of PBC.

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### **Mechanism of Action:**

Elafibranor works by activating **PPAR-α** and **PPAR-δ**, which are nuclear receptors involved in:

1. **Bile acid metabolism**: Reducing toxic bile acid accumulation.

2. **Inflammation**: Mitigating liver inflammation associated with PBC.

3. **Lipid oxidation**: Improving lipid profiles.

This mechanism helps reduce **hepatic injury** and improve **cholestatic liver function**.

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### **Clinical Significance:**

• Rapid and sustained biochemical improvements were observed within the first month of treatment and persisted through 52 weeks.
• **Normalization of ALP and bilirubin levels** correlates with **improved long-term outcomes** in PBC.
• The ELATIVE trial results position elafibranor as a promising **second-line therapy** for patients who fail or cannot tolerate UDCA.

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### **Future Outlook:**

• Long-term studies and open-label extensions are ongoing to further evaluate:
• Effects on **clinical outcomes**.
• **Fibrosis regression**.
• Overall **survival** in PBC patients.

Elafibranor represents a significant advancement in the treatment landscape for PBC, offering a safe and effective alternative for patients with unmet therapeutic needs.