Metabolic Liver Research Program, I. Department of Medicine, University Medical Centre Mainz, Germany.
Hospital Clinic, University of Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain.
J Hepatol. 2021 Jun;74(6):1344-1354. doi: 10.1016/j.jhep.2021.01.013. Epub 2021 Jan 21.
BACKGROUND & AIMS: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC.
This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108).
At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate.
In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid.
Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy.
Clinical Trials.gov NCT03124108.
原发性胆汁性胆管炎（PBC）患者对熊去氧胆酸治疗不完全应答仍存在疾病进展风险。我们研究了双重过氧化物酶体增殖物激活受体α/δ（PPARα/δ）激动剂 Elafibranor 在 PBC 患者中的安全性和疗效。
这是一项为期 12 周的双盲 II 期临床试验，纳入了 45 例对熊去氧胆酸治疗应答不完全（碱性磷酸酶（ALP）水平≥正常值上限（ULN）的 1.67 倍）的 PBC 成年患者。患者被随机分配至 Elafibranor 80 mg 组、Elafibranor 120 mg 组或安慰剂组。主要终点为 12 周时 ALP 的相对变化（NCT03124108）。
在 12 周时，Elafibranor 80 mg 组的 ALP 降低了-48.3±14.8%（p<0.001 与安慰剂），Elafibranor 120 mg 组降低了-40.6±17.4%（p<0.001），而安慰剂组则增加了+3.2±14.8%。Elafibranor 80 mg 组有 67%的患者和 Elafibranor 120 mg 组有 79%的患者达到 ALP≤1.67 倍 ULN、ALP 降低>15%和总胆红素低于 ULN 的复合终点，而安慰剂组仅有 6.7%的患者达到该终点。Elafibranor 80 mg 组的γ-谷氨酰转移酶降低了 37.0±25.5%（p<0.001），Elafibranor 120 mg 组降低了 40.0±24.1%（p<0.01），而安慰剂组则无变化（+0.2±26.0%）。Elafibranor 同样降低了疾病标志物如 IgM、5'-核苷酸酶或高敏 C 反应蛋白的水平。Elafibranor 未引起或加重瘙痒，基线时有瘙痒症状的患者在治疗结束时报告的瘙痒症状更少。所有可能与药物相关的非严重不良事件均为轻度至中度。
在这项随机 II 期试验中，Elafibranor 通常安全且耐受良好，可显著降低 ALP 水平、胆红素和 ALP 的复合终点以及 PBC 患者和对熊去氧胆酸应答不完全的其他疾病活动标志物的水平。
原发性胆汁性胆管炎（一种罕见的慢性肝脏疾病）患者对标准治疗无应答仍存在疾病进展为肝硬化和生活质量下降的风险。Elafibranor 是一种核受体激动剂，我们在一项为期 12 周的随机临床试验中对其进行了测试。它成功降低了疾病活动标志物的水平，包括碱性磷酸酶。因此，这项研究为一项更大规模的前瞻性研究奠定了基础，该研究将确定这种药物作为二线治疗的疗效和安全性。
ClinicalTrials.gov NCT03124108。
