Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study

Kiminori Kimura, Tatsuya Kanto, Shinji Shimoda, Kenichi Harada, Masamichi Kimura, Koji Nishikawa, Jun Imamura, Eiichi Ogawa, Masanao Saio, Yoshihiro Ikura, Takuji Okusaka, Kazuaki Inoue, Tetsuya Ishikawa, Ichiro Ieiri, Junji Kishimoto, Koji Todaka, Terumi Kamisawa, Kiminori Kimura, Tatsuya Kanto, Shinji Shimoda, Kenichi Harada, Masamichi Kimura, Koji Nishikawa, Jun Imamura, Eiichi Ogawa, Masanao Saio, Yoshihiro Ikura, Takuji Okusaka, Kazuaki Inoue, Tetsuya Ishikawa, Ichiro Ieiri, Junji Kishimoto, Koji Todaka, Terumi Kamisawa

Abstract

Background: 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.

Methods: 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/m2/4 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).

Findings: 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.

Interpretation: Intravenous administration of 280 mg/m2/4 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.

Funding: AMED, Ohara Pharmaceutical.

Keywords: Anti-fibrotic drug; HBV; HCV; Liver cirrhosis; PRI-724.

Conflict of interest statement

There are no conflicts of interest.

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile (Phase 1/2a). Consort diagram.
Figure 2
Figure 2
Pharmacokinetics of PRI-724 and C-82 after intravenous infusion of PRI-724 (Phase 1). (a) Mean concentration profiles of PRI-724 in plasma from patients with HCV and HBV liver cirrhosis during intravenous infusion of PRI-724. (b) Mean plasma concentration profiles of C-82, a PRI-724 metabolite, in the same patients.
Figure 3
Figure 3
Effects of PRI-724 treatment on liver function and liver stiffness measure (Phase 2a).Changes in (a) serum ALB, PT, and TBIL before, during, and after 12 weeks of PRI-724 administration. (b) Change in LSM from baseline to post-treatment following 12 weeks of PRI-724 administration (n = 13). The graph (right) shows the results of analysing patients with liver cirrhosis and a baseline LSM of ≥ 20 kPa. Statistical analyses were performed using paired t-tests.

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