Ratziu Vlad, Harrison Stephen A, Loustaud-Ratti Véronique, Bureau Christophe, Lawitz Eric, Abdelmalek Manal, Alkhouri Naim, Francque Sven, Girma Hugo, Darteil Raphaël, Couchoux Harold, Wolf Myles, Sanyal Arun, Vonderscher Jacky, Scalfaro Pietro
Sorbonne Université, ICAN, Hospital Pitié-Salpêtrière, INSERM UMRS 1138 CRC, Paris, France.
Pinnacle Clinical Research, San Antonio, TX, USA.
J Hepatol. 2023 Mar;78(3):479-492. doi: 10.1016/j.jhep.2022.10.023. Epub 2022 Nov 9.
BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).
This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12.
One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively.
In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit.
CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22.
NCT03812029.
Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.
LIVIFY试验研究了第二代非胆汁酸法尼醇X受体激动剂沃那法索在疑似纤维化非酒精性脂肪性肝炎（NASH）患者中的安全性、耐受性和疗效。
这项双盲IIa期研究分两部分进行。在A部分（安全性导入期、药代动力学/药效学），患者被随机分为（1:1:1:1）接受安慰剂、每日两次100mg沃那法索（VONA-100BID）、每日一次200mg沃那法索（VONA-200QD）或每日一次400mg沃那法索（VONA-400QD）；在B部分，患者被随机分为（1:1:1）接受安慰剂、每日一次100mg沃那法索（VONA-100QD）或VONA-200QD。主要疗效终点是通过磁共振成像-质子密度脂肪分数测量的肝脏脂肪含量（LFC）降低，次要终点包括从基线到第12周校正T1值和肝酶的降低。
120例患者被随机分组（A部分，n = 24；B部分，n = 96）。在B部分，与安慰剂组相比，VONA-100QD组（-6.3% [0.9]）和VONA-200QD组（-5.4% [0.9]）从基线到第12周LFC的最小二乘均值（SE）绝对变化显著降低，安慰剂组为（-
