Elafibranor in primary biliary cholangitis: two-year placebo-controlled outcomes and long-term open-label data from the ELATIVE® phase III trial.

BACKGROUND & AIMS: We report 104-week placebo-controlled data and long-term open-label extension (OLE) data from the ongoing ELATIVE® phase III trial (NCT04526665) of elafibranor in primary biliary cholangitis (PBC). METHODS: 161 patients were randomized 2:1 to elafibranor 80 mg or placebo. The double-blind period (DBP) consisted of 52-week common (Part 1) and variable (Part 2) periods. Patients completing Part 1 continued into Part 2 until all patients completed Part 1, or for a maximum of 104 weeks. All patients completing Part 1 could enter the OLE and receive elafibranor. RESULTS: At Week 104 in the DBP Part 2, 64.3% (18/28) and 10.7% (3/28) of elafibranor-treated patients achieved biochemical response and alkaline phosphatase (ALP) normalization, versus no placebo-treated patients. In patients with moderate-to-severe fatigue or pruritus at baseline, mean (SE) changes to Week 104 in PROMIS Fatigue Short Form 7a (PFSF 7a) and PBC Worst-Itch Numeric Rating Scale (PBC WI NRS) were -6.3 (2.2) versus -0.4 (1.2) and -4.1 (1.0) versus 0.3 (1.2) with elafibranor versus placebo. 138 patients entered the OLE (continuous elafibranor: n=93; crossover elafibranor: n=45). In continuous patients at Weeks 104 and 156, 58.8% (47/80) and 65.0% (13/20) achieved biochemical response, and 15.0% (12/80) and 25.0% (5/20) achieved ALP normalization. In crossover patients, 51.2% (21/41) and 22.0% (9/41) achieved biochemical response and ALP normalization after 52 weeks. In continuous patients with baseline moderate-to-severe symptoms, mean (SE) changes to Week 130 in PFSF 7a and PBC WI NRS were -4.8 (1.5) and -4.0 (0.7). There were no unexpected safety findings. CONCLUSIONS: Through three years of treatment, elafibranor led to sustained biochemical improvements and was generally well tolerated, with numerical improvements in fatigue and pruritus. TRIAL REGISTRATION: NCT04526665 (https://clinicaltrials.gov/study/NCT04526665); first registered 08/26/2020 IMPACT AND IMPLICATIONS: • Given the chronic, progressive nature of primary biliary cholangitis (PBC), the long-term efficacy and tolerability of treatments is important.• Here, we present two-year results from the double-blind period, and long-term data from the ongoing open-label extension of the phase III ELATIVE® trial, wherein elafibranor (a peroxisome proliferator-activated receptor-α/δ agonist) treatment led to sustained biochemical improvements, stable non-invasive tests of fibrosis, and numerical improvements in fatigue and pruritus, through three years.• Elafibranor demonstrated a favorable safety profile up to a maximum treatment exposure of 3.5 years, including in patients crossing over from placebo.• These findings support elafibranor's role as a durable long-term treatment for patients with PBC, and are particularly relevant for clinicians managing patients with inadequate response or intolerance to first-line treatments.