{
  "abstract": "Introduction Elafibranor is a peroxisome proliferator-activated receptor (PPAR) α and δ agonist approved for treatment of adults with PBC. In the phase III ELATIVE® trial, elafibranor significantly improved biochemical response rate and markers of disease progression compared with placebo in patients with PBC. We investigated the effect of body mass index (BMI) on elafibranor pharmacokinetics using population modelling, and on efficacy in healthy, overweight and obese subgroups of ELATIVE®.Methods Population pharmacokinetic models for elafibranor and its active metabolite GFT1007 were developed using data from 17 phase 1–3 clinical studies (including ELATIVE and a phase 2 trial in patients with PBC). In ELATIVE, patients with PBC and an inadequate response to or intolerable side effects with ursodeoxycholic acid were randomized 2:1 to receive elafibranor 80mg daily or placebo for 52 weeks. The primary endpoint was biochemical response at Week 52 (alkaline phosphatase [ALP] <1.67 × upper limit of normal [ULN] with ≥15% reduction from baseline and total bilirubin ≤ULN). Change in ALP levels from baseline to Week 52 was a secondary efficacy endpoint. Randomized patients were classified post hoc into subgroups of healthy weight (BMI ≥18.5 to <25 kg/m2), overweight (BMI ≥25 to <30 kg/m2) or obese (BMI ≥30 kg/m2); those with BMI <18.5 kg/m2 (n = 5) were not included. Statistical tests were post hoc and non-inferential; p values were nominal.Results In the pharmacokinetic models, BMI had no clinically relevant effect on exposure (AUC and C max) to elafibranor or GFT1007 in patients with PBC. In ELATIVE, 161 patients were randomised to elafibranor (n = 108) or placebo (n = 53). In the elafibranor arm, biochemical response rates at week 52 were 56.3% (n = 27/48), 46.4% (n = 13/28) and 44.8% (n = 13/29) in the healthy weight, overweight and obese subgroups, respectively. Risk difference (95% CI) compared with placebo was 56.3% (35.4, 69.3) (p < 0.001), 46.4% (19.9, 64.2) (p = 0.006), and 35.6% (4.8, 56.2) (p = 0.0343) in the healthy weight, overweight, and obese subgroups, respectively. Mean (SD) changes in ALP levels from baseline to week 52 in the elafibranor arm were –41.5% (26.7), –41.8% (23.0) and –32.3% (22.3) for elafibranor in the healthy weight, overweight and obese subgroups respectively, compared with a mean (SD) change of +1.8% (19.5), +1.5% (15.4) and +0.2% (21.5) in healthy weight, overweight and obese subgroups in the placebo arm, respectively.Conclusion(s) The pharmacokinetics of elafibranor are not clinically meaningfully affected by BMI in patients with PBC. The efficacy of the clinical dose of elafibranor is stable in patients with PBC, regardless of baseline BMI or weight changes during the course of treatment.",
  "authors": [
    {
      "affiliations": [
        "Ipsen, London, United Kingdom"
      ],
      "name": "Mohammad Raja"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland"
      ],
      "name": "Andreas E Kremer"
    },
    {
      "affiliations": [
        "Schiff Center for Liver Diseases, University of Miami, Miami, USA",
        "Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, USA"
      ],
      "name": "Cynthia Levy"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, UC Davis School of Medicine, Sacramento, USA"
      ],
      "name": "Christopher L Bowlus"
    },
    {
      "affiliations": [
        "University of Milano-Bicocca, Milan, Italy",
        "The Niguarda Liver Transplant Centre, Milan, Italy"
      ],
      "name": "Marco Carbone"
    },
    {
      "affiliations": [
        "Ipsen, Paris, France"
      ],
      "name": "Marwan Sleiman"
    },
    {
      "affiliations": [
        "Ipsen, Cambridge, USA"
      ],
      "name": "Nuno Antunes"
    },
    {
      "affiliations": [
        "Ipsen, Paris, France"
      ],
      "name": "Marion Dehez"
    },
    {
      "affiliations": [
        "Ipsen, Paris, France"
      ],
      "name": "Hugo Gomes da Silva"
    },
    {
      "affiliations": [
        "CHU de Grenoble, Pôle Digidune, Clinique Universitaire d’Hépato-Gastroentérologie, Grenoble, France",
        "Unité INSERM /Université Grenoble, IAPC Institut Albert Bonniot, Grenoble, France"
      ],
      "name": "Vincent Leroy"
    }
  ],
  "title": "P56 The efficacy of elafibranor is not affected by body mass index in patients with primary biliary cholangitis (PBC)",
  "uid": "bba772ba-b6f0-5563-822b-9ed2c9efa696"
}