Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial
Kiminori Kimura,
Akemi Ikoma,
Maki Shibakawa,
Shinji Shimoda,
Kenichi Harada,
Masanao Saio,
Jun Imamura,
Yosuke Osawa,
Masamichi Kimura,
Koji Nishikawa,
Takuji Okusaka,
Satoshi Morita,
Kazuaki Inoue,
Tatsuya Kanto,
Koji Todaka,
Yoichi Nakanishi,
Michinori Kohara,
Masashi Mizokami
Affiliations
Kiminori Kimura
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Akemi Ikoma
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Maki Shibakawa
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Shinji Shimoda
Department of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Kenichi Harada
Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
Masanao Saio
Department of Pathology, University of the Ryukyus Hospital, Okinawa, Japan
Jun Imamura
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Yosuke Osawa
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Masamichi Kimura
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Koji Nishikawa
Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
Takuji Okusaka
Department of Hepatobilliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
Satoshi Morita
Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Kazuaki Inoue
Department of Gastroenterology, Showa University Fujigaoka Hospital, Kanagawa, Japan
Tatsuya Kanto
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Koji Todaka
Center for Clinical and Translational Research, Kyushu University, Fukuoka, Japan
Yoichi Nakanishi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Michinori Kohara
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Masashi Mizokami
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Background: There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. Methods: In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160 mg/m2/day for six cycles of 1 week on and 1 week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). Findings: Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160 mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10 mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40 mg/m2/day cohort, and improved in one patient by 3 points in the 160 mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10 mg/m2/day cohort, and improved in one patient in the 40 mg/m2/day cohort. Interpretation: This study showed that administration of 10 or 40 mg/m2/day intravenous PRI-724 over 12 weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160 mg/m2/day cohort. Funding Source: AMED.
