Elafibranor, a dual peroxisome proliferator-activated receptor (PPAR) alpha and delta agonist, appears to be a safe and effective treatment of primary biliary cholangitis, according to a new clinical trial.
At week 52, more than half of patients with the disease had a biochemical response after receiving oral elafibranor compared with 4% who received the placebo.
"The results of the current trial showed that elafibranor may provide an effective, new second-line treatment for patients with primary biliary cholangitis," Kris Kowdley, MD, director of the Liver Institute Northwest in Seattle, Washington, and colleagues wrote.
The study was published online in the New England Journal of Medicine.
Testing Second-Line Treatment
Primary biliary cholangitis — a rare, chronic cholestatic liver disease — destroys interlobular bile ducts and leads to cholestasis and liver fibrosis. Left untreated, the disease can progress to cirrhosis, require liver transplantation, and end in premature death. Increasing in prevalence worldwide, the disease occurs predominantly in women aged ≥ 40 years.
Ursodeoxycholic acid, a tertiary hydrophilic bile acid, is the only approved first-line therapy for the disease. However, up to 40% of patients have an inadequate response, and between 3% and 5% report unacceptable adverse events, Kowdley and authors wrote.
Obeticholic acid, a selective farnesoid X receptor agonist, is the only approved second-line treatment of the disease. However, fewer than half of patients show a biochemical response, and pruritus can be exacerbated.
In a multinational, phase 3, double-blind, placebo-controlled trial, Kowdley and colleagues evaluated the efficacy and safety of elafibranor, which decreases the toxic effects of bile acid and inflammation through downstream modulation of the nuclear receptor target of PPAR-alpha and PPAR-delta.
Between September 2020 and June 2022, the researchers randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive either once-daily 80 mg of elafibranor or a placebo. Overall, 96% were women, and the average age was 57 years.
At week 52, the research team looked for a biochemical response, defined as an alkaline phosphate level of < 1.67 times the upper limit of the normal range, with a reduction of ≥ 15% from baseline, as well as normal total bilirubin levels.
Secondary endpoints included normalization of the alkaline phosphatase level at week 52 and a change in pruritis intensity, as measured on the Worst Itch Numeric Rating Scale (WI-NRS), from baseline through weeks 24 and 52.
Among 161 patients, a biochemical response was seen in 55 of 108 patients (51%) who received elafibranor and two of 53 patients (4%) who received the placebo. At week 52, the alkaline phosphate level normalized in 15% of patients in the elafibranor group and none of the patients in the placebo group.
Among patients with moderate to severe pruritis (44 elafibranor patients and 22 placebo patients), the least-squares mean change on the WI-NRS from baseline to week 52 didn't differ significantly between the groups.
Across the study population, the elafibranor and placebo groups had similar percentages of patients with adverse events, severe or serious adverse events, or adverse events leading to discontinuation. Adverse events that occurred in > 10% of patients and more frequently in those receiving elafibranor predominantly related to gastrointestinal events, particularly abdominal pain, diarrhea, nausea, and vomiting.
Considering Additional Factors
A response to elafibranor appeared to occur within 4 weeks after initiation and was maintained through week 52, Kowdley and colleagues noted. Liver-related variables, immunoglobulins, biomarkers of bile acid synthesis (7alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor-1), and lipid variables (total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglycerides) also appeared to be lower in patients who received elafibranor.
"In contrast, among patients treated with obeticholic acid, increases in the levels of total cholesterol and LDL cholesterol and decreases in the level of HDL cholesterol have been observed," the authors wrote.
In an ongoing open-label extension and confirmatory phase 3 trial, the researchers will continue to assess the long-term safety and clinical outcomes of elafibranor.
The majority of patients enrolled in this trial were White patients, the authors noted.
"Although this feature aligns with the general epidemiology of the disease, racial minorities appeared to be underrepresented and ethnicity was not recorded," they wrote.
The study was sponsored by GENFIT and Ipsen. The authors declared numerous research grants, consulting roles, and speaking fees for several pharmaceutical companies and research foundations not related to this study.
Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape, MDedge, and WebMD.
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