Elafibranor, a dual alpha and delta agonist of the peroxisome proliferator-activated receptor (PPAR), appears to be a safe and effective treatment for primary biliary cholangitis, according to a recent clinical study.
In Week 52, more than half of the patients with this disease showed a biochemical response after taking oral Elafibranor, compared to 4% who received the placebo.
„The results of the current study showed that Elafibranor could represent an effective new second-line treatment for patients with primary biliary cholangitis,“ wrote Kris Kowdley, MD, Director of the Liver Institute Northwest in Seattle, Washington, and colleagues.
The study was published online in the New England Journal of Medicine.
Evaluating Second-Line Treatment
Primary biliary cholangitis, a rare chronic cholestatic liver disease, destroys interlobular bile ducts and leads to cholestasis and liver fibrosis. If left untreated, the disease can progress to liver cirrhosis, requiring a liver transplant and resulting in premature death. The disease is increasing worldwide and predominantly affects women aged 40 years and older.
Ursodeoxycholic acid, a tertiary hydrophilic bile acid, is the only approved first-line therapy for the disease. However, up to 40% of patients respond inadequately, and between 3 and 5% report unacceptable adverse events, write Kowdley and the authors.
Obeticholic acid, a selective farnesoid X receptor agonist, is the only approved second-line treatment for the disease. However, less than half of the patients show a biochemical response, and itching may worsen.
In a multinational, double-blind, placebo-controlled Phase 3 study, Kowdley and colleagues examined the efficacy and safety of Elafibranor, which reduces the toxic effects of bile acids and inflammation by downstream modulation of the PPAR-alpha PPAR-delta nuclear receptor target.
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 ursodeoxycholic acid or experienced unacceptable side effects to either once-daily 80 mg Elafibranor or a placebo. Overall, 96% were women, with an average age of 57 years.
At Week 52, the research team looked for a biochemical response, defined as an alkaline phosphatase level of <1.67 times the upper limit of normal range, with a reduction of ≥15% from baseline, as well as normal total bilirubin levels.
Secondary endpoints included normalization of alkaline phosphatase levels at Week 52 and a change in itch intensity, measured on the Worst Itch Numeric Rating Scale (WI-NRS), from baseline to Week 24 and Week 52.
Among the 161 patients, a biochemical response was observed in 55 out of 108 patients (51%) receiving Elafibranor and in two out of 53 patients (4%) receiving the placebo. At Week 52, alkaline phosphatase levels normalized in 15% of patients in the Elafibranor group and in none of the patients in the placebo group.
For patients with moderate to severe pruritus (44 Elafibranor patients and 22 placebo patients), the mean change from baseline to Week 52 in the smallest squares of the WI-NRS did not differ significantly between the groups.
In the overall 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 occurring in >10% of patients and more frequently in those receiving Elafibranor were mostly related to gastrointestinal events, particularly abdominal pain, diarrhea, nausea, and vomiting.
Considering Additional Factors
A response to Elafibranor appeared to occur within 4 weeks of initiation and continued until Week 52, noted Kowdley and colleagues. Liver-related variables, immunoglobulins, bile acid synthesis biomarkers (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 receiving Elafibranor.
„In contrast, patients treated with obeticholic acid experienced an increase in total cholesterol and LDL cholesterol levels and a decrease in HDL cholesterol levels,“ the authors write.
In an ongoing open-label extension and confirmation Phase 3 study, researchers will continue to evaluate the long-term safety and clinical outcomes of Elafibranor.
The majority of patients participating in this study were white, the authors noted.
„Although this characteristic is consistent with the overall epidemiology of the disease, ethnic minorities appeared to be underrepresented, and ethnic background was not captured,“ they wrote.
The study was sponsored by GENFIT and Ipsen. The authors disclosed numerous research grants, consulting roles, and speaking fees from several pharmaceutical companies and research foundations unrelated to this study.
Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape, MDedge, and WebMD.