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

• Published in: EBioMedicine 2017-09, Vol.23 (C), p.79-87
• Main Authors: Kimura, Kiminori, Ikoma, Akemi, Shibakawa, Maki, Shimoda, Shinji, Harada, Kenichi, Saio, Masanao, Imamura, Jun, Osawa, Yosuke, Kimura, Masamichi, Nishikawa, Koji, Okusaka, Takuji, Morita, Satoshi, Inoue, Kazuaki, Kanto, Tatsuya, Todaka, Koji, Nakanishi, Yoichi, Kohara, Michinori, Mizokami, Masashi
• Format: Article
• Language: English
• Subjects: Adult; Aged; beta Catenin - antagonists & inhibitors; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Female; Genotype; HCV; Hepacivirus - genetics; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - diagnosis; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - virology; Humans; Liver cirrhosis; Liver Cirrhosis - diagnosis; Liver Cirrhosis - drug therapy; Liver Cirrhosis - etiology; Liver Function Tests; Male; Middle Aged; PRI-724; Pyrimidinones - administration & dosage; Pyrimidinones - adverse effects; Pyrimidinones - therapeutic use; Research Paper; Treatment Outcome; Viral Load; Wnt inhibitor
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.08.016

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. 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 160mg/m2/day for six cycles of 1week on and 1week 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). 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 Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons.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 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort. This study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort. AMED. •Safety, tolerability, pharmacokinetics, and anti-fibrotic effect of PRI-724 were assessed in patients with HCV cirrhosis.•PRI-724 was well tolerated, suggesting that the treatment is relatively safe against HCV liver cirrhosis.•Significant fibrosis reduction in hepatic lobules 12weeks after PRI-724 treatment (40mg/m2/day) in 3 CP class B patients. Liver cirrhosis is one of the leading causes of morbidity and mortality in develo