Ipsen and GENFIT announced compelling results from their pivotal Phase III ELATIVE trial of elafibranor in primary biliary cholangitis (PBC), demonstrating statistically significant improvements in disease biomarkers that could establish the investigational drug as a paradigm-changing second-line treatment for this rare liver condition.
The randomized, double-blind, placebo-controlled trial enrolled 161 patients with PBC who had inadequate response or intolerance to ursodeoxycholic acid (UDCA), the current first-line therapy. Results presented at the American Association for the Study of Liver Disease (AASLD) congress and simultaneously published in the New England Journal of Medicine showed a remarkable 47% placebo-adjusted difference (P<0.001) in the primary composite endpoint.
Primary Efficacy Results
The trial achieved its primary endpoint with 51% of patients receiving elafibranor 80mg once daily achieving biochemical response compared to just 4% of placebo patients. A biochemical response was defined as alkaline phosphatase (ALP) <1.67 x upper limit of normal (ULN), an ALP decrease ≥15% and total bilirubin ≤ULN at 52 weeks.
"When managing PBC our first goal is to effectively control the disease progression which can lead to liver failure. The results from ELATIVE provide compelling evidence that elafibranor has the potential to achieve this goal, with evidence of a highly significant treatment benefit that is associated with improved clinical outcomes," said Dr. Christopher Bowlus, Professor of Gastroenterology and Hepatology at University of California Davis.
ALP Normalization Achievement
A particularly notable finding was that only patients receiving elafibranor achieved normalization of ALP levels at Week 52, with 15% of elafibranor patients versus 0% of placebo patients reaching normal ALP levels (P=0.002). The upper limit of normal was defined as 104 U/L in females and 129 U/L in males. The biochemical effects were rapid, with ALP reductions observed as early as Week 4 in the elafibranor group and sustained through Week 52, showing a 41% decrease compared to placebo.
Symptom Management Potential
The trial investigated elafibranor's effect on pruritus (severe itch) across three patient-reported outcome measures. While the primary pruritus endpoint using the PBC Worst Itch NRS score did not reach statistical significance (LS mean difference -0.78; 95% CI, -1.99 to 0.42; P=0.20), two other measures showed promising results. Greater reductions in pruritus were observed with elafibranor compared to placebo according to the PBC-40 quality of life questionnaire itch domain (LS mean difference -2.3; 95% CI, -4.0 to -0.7) and 5-D Itch total score (LS mean difference -3.0; 95% CI, -5.5 to -0.5).
Safety Profile
Elafibranor demonstrated a favorable safety profile consistent with previous trials. Similar percentages of patients in both treatment and placebo groups experienced adverse events, treatment-related adverse events, severe or serious adverse events, or adverse events leading to discontinuation. The most common adverse events occurring in >10% of patients and more frequently with elafibranor versus placebo included abdominal pain, diarrhea, nausea, and vomiting.
Disease Context and Unmet Need
PBC is a rare, autoimmune, cholestatic liver disease affecting approximately nine women for every one man. The condition involves bile and toxin buildup (cholestasis) and chronic inflammation that causes irreversible liver fibrosis and bile duct destruction. Without effective treatment, PBC can progress to liver transplant requirement and premature death.
"Living with PBC can be very challenging for many people. The fear of the disease progressing hangs over you, and you have to manage as best you can with the daily symptom burden, symptoms that can sometimes be so debilitating it takes every ounce of strength to get through another day," explained Mo Christie, Head of Patient Services at PBC Foundation, UK.
Currently, no approved treatments can effectively manage both disease progression and life-impacting symptoms, representing a significant unmet medical need in this patient population.
Regulatory Path Forward
"We believe these data suggest that elafibranor could be a paradigm-changing treatment meeting the unmet need for an effective second-line option," said Christelle Huguet, EVP and Head of Research and Development at Ipsen. Data from ELATIVE are being used to support regulatory submissions for elafibranor as a PBC treatment with authorities worldwide.
Elafibranor, a novel oral dual peroxisome activated receptor (PPAR) α,δ agonist, received FDA Breakthrough Therapy Designation in 2019 for adults with PBC who have inadequate response to UDCA. The drug's concurrent α,δ activation targets inflammation, cholestasis, and fibrosis in PBC, representing a first-in-class mechanism for this indication.
