Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
The Research Center for Hepatitis and Immunology, Gastroenterology Hepatology, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan.
EBioMedicine. 2022 Jun;80:104069. doi: 10.1016/j.ebiom.2022.104069. Epub 2022 May 20.
We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/β-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis.
This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child-Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT03620474).
Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level.
Intravenous administration of 280 mg/m/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted.
AMED, Ohara Pharmaceutical.
我们进行了一项探索性研究，以评估 CBP/β-连环蛋白抑制剂 PRI-724 在丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）引起的肝硬化患者中的安全性、耐受性和抗纤维化作用。
这项多中心、开放标签、非随机、非安慰剂对照的 1/2a 期临床试验在日本的三家医院进行。在 2018 年 7 月 27 日至 2021 年 7 月 13 日期间，我们招募了丙型肝炎和乙型肝炎引起的肝硬化患者，这些患者的分类为 Child-Pugh（CP）A级或 B 级。在 1 期，15 名患者接受了 PRI-724 的静脉输注，剂量为 140、280 和 380mg/m/4h，每周两次，共 12 周。在 2a 期，12 名患者接受了推荐剂量的 PRI-724。1 期和 2a 期的主要终点是根据肝活检评估治疗肝硬化的不良反应的频率和严重程度以及疗效。这项研究在 ClinicalTrials.gov 注册（编号：NCT03620474）。
在 2a 期，对接受推荐剂量的 PRI-724 的 1 期的 3 名患者进行了评估，以获得疗效和安全性数据。3 名患者发生了严重不良事件，其中 1 例可能与 PRI-724 有关。最常见的不良反应是腹泻和恶心。PRI-724 在 12 周时没有任何统计学意义上降低肝纤维化的程度，无论是通过序贯评分还是测量胶原比例区；然而，我们观察到肝脏硬度、终末期肝病模型评分和血清白蛋白水平有统计学意义上的改善。
初步评估每周 12 周内静脉给予 280mg/m/4h 的 PRI-724 耐受良好；然而，仍需要进一步评估该药物对肝硬化患者的抗纤维化作用。
AMED、大原制药。
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