1. In this randomized controlled trial, primary biliary cholangitis (PBC) patients who received elafibranor had significantly improved serum markers of cholestasis compared to those who received a placebo.
2. Adverse events occurred at similar rates in both groups, but gastrointestinal events were more frequent in the treatment group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: PBC is an autoimmune disorder characterized by the destruction of interlobular bile ducts. As the serum concentrations of alkaline phosphatase and bilirubin rise, PBC can result in cirrhosis and death. Ursodeoxycholic acid, the only first-line therapy for this condition, and obeticholic acid, the only second-line treatment, are both associated with either poor efficacy or an unacceptable side effect profile in approximately half of patients. Elafibranor is a novel dual peroxisome proliferator-activated receptor agonist (PPAR) that has been shown in a previous phase-two trial to reduce biomarkers of disease activity significantly. In this new phase three study of patients with PBC who were unresponsive to ursodeoxycholic acid, it was found that a biochemical response was observed in over half of those who received elafibranor, a significantly greater proportion than in the placebo group. Normalization of alkaline phosphatase also occurred more frequently among those who received elafibranor than those who received placebo. There was no meaningful change in renal function in either group. Adverse events, including those judged to be severe, generally occurred at similar rates between groups. However, gastrointestinal adverse events such as abdominal pain, nausea, vomiting, and diarrhea were more frequent in the elafibranor group. This study was limited by the underrepresentation of racial diversity and a short-term design. Nonetheless, these results indicate that elafibranor may effectively manage primary biliary cholangitis.
Click here to read the study in NEJM
Relevant Reading: A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis
In-Depth [randomized controlled trial]: In this multinational, phase three, placebo-controlled trial, 161 adult patients were randomly assigned in a 2:1 ratio to receive daily oral treatment with either 80 mg of elafibranor or placebo. The mean age was 57 years, 95% of patients were female, and 91% were White. The mean alkaline phosphatase at baseline was 322 U per liter. The primary outcome was defined as an alkaline phosphatase level <1.67 times the upper limit of normal (ULN), with a reduction of ≥15% from baseline and total bilirubin at or below the ULN. At 52 weeks, this outcome was observed in 51% of the treatment group versus 4% of the control group (difference, 47 percentage points; p<0.001). This response was realized within four weeks of initiation of treatment and was sustained over the full duration of the study. Greater reductions in alkaline phosphatase levels were observed in the elafibranor group than those in the placebo group (between-group difference, -40.6 percentage points), and full normalization of the alkaline phosphatase level at week 52 occurred in 15% of the elafibranor group versus 0% of the control group (p=0.002). Among patients with moderate-to-severe pruritus, elafibranor was also associated with greater reductions in patient-reported itch scores (mean difference for itch domain of PBC-40 questionnaire, -2.3; mean difference for 5-D itch scale, -3.0). Regarding adverse events, increases in serum creatinine levels of 25% above baseline were observed in 10.2% of those receiving elafibranor and 7.5% of those receiving placebo. Of note, four patients discontinued treatment with elafibranor because of increased creatinine phosphokinase levels. In summary, elafibranor may be an effective and tolerable second-line treatment for patients with primary biliary cholangitis.
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