Elsevier

EBioMedicine

Volume 23, September 2017, Pages 79-87
EBioMedicine

Research Paper
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

https://doi.org/10.1016/j.ebiom.2017.08.016Get rights and content
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Highlights

  • 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 12 weeks after PRI-724 treatment (40 mg/m2/day) in 3 CP class B patients.

Liver cirrhosis is one of the leading causes of morbidity and mortality in developed countries and is the 14th most common cause of death in adults worldwide. However, there is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. This study showed that intravenous PRI-724 at 10 or 40 mg/m2/day over 12 weeks was well-tolerated by patients with HCV cirrhosis and resulted in an improvement of liver histology and CP class in several patients.

Abstract

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 Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160 mg/m2/day dose cohort and one withdrew for personal reasons.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.

Keywords

PRI-724
Liver cirrhosis
HCV
Wnt inhibitor

Abbreviations

ALT
alanine aminotransferase
ALB
albumin
AUC
area under the concentration curve
CBP
CREB binding protein
CREB
cAMP-response element-binding protein
Cmax
maximum concentration
CP
Child-Pugh
HAI
histology activity index
HCV
hepatitis C virus
HTLV
human T-cell leukemia virus
PT
prothrombin time
Tmax
time of maximum observed serum

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