A randomized, proof-of-concept clinical trial on repurposing chlorcyclizine for the treatment of chronic hepatitis C

Highlights

• Chlorcyclizine HCl is a first-generation piperazine-class antihistamine.

• It has demonstrated anti-hepatitis C virus activity in vitro and in vivo.

• In a pilot study, it has anti-hepatitis C effects, in combination with ribavirin.

• More potent CCZ derivatives may be suitable for future development.

Abstract

Background & aims

Chlorcyclizine HCl (CCZ) is a piperazine-class antihistamine with anti-hepatitis C virus (HCV) activity in vitro and in vivo. In a first-in-humans study for HCV, we evaluated the antiviral effects and safety of CCZ±ribavirin (RBV), characterized pharmacokinetic (PK) and viral kinetic (VK) patterns, and provide insights into CCZs mode of action against HCV.

Methods

Chronic HCV patients were randomized to CCZ (75 mg twice daily) or CCZ+weight-based RBV (1000/1200 mg daily) for 28 days. Therapy started with a loading dose of CCZ 150 mg ± RBV. Serial assessments of safety, liver tests, PK and VK markers were obtained.

Results

24 HCV patients were treated; 54% male, median age 56 years, median HCV RNA 6.30 log IU/ml, without baseline differences between groups. At the end of therapy, subjects treated with CCZ monotherapy did not show any significant or sustained reduction in viremia (p = 0.69), whereas 7/12 (58%) subjects treated with CCZ+RBV had a >3-fold decline in HCV RNA. Subjects who responded demonstrated monophasic (n = 2), biphasic (n = 2) and triphasic (n = 3) VK responses. Contrary to historical RBV monotherapy response, CCZ+RBV demonstrated a continued viral decline suggesting a possible synergistic effect of CCZ+RBV. Mathematical modeling predicts a median effectiveness of CCZ+RBV in blocking viral production (ε) of 59% (Interquartile range, IQR: 50%) and blocking infection (η) of 78% (IQR: 23%). Adverse events (AEs) were mild-moderate without treatment discontinuations for AEs.

Conclusions

In this human pilot study, CCZ demonstrated some anti-HCV effects, mostly in combination with RBV. More potent CCZ derivatives with optimal PK features may be more suitable for future therapeutic development. ClinicalTrials.gov number: NCT02118012.

Introduction

Chronic hepatitis C virus (HCV) infection affects approximately 80 million people worldwide and when left untreated can lead to cirrhosis, hepatic failure and hepatocellular carcinoma (HCC) (Polaris Observatory, 2017; Gower et al., 2014). In the United States (U.S.), hepatitis C-related liver disease remains the leading cause for liver transplantation and HCV-related HCC continues to be the fastest-growing cause of cancer related death (Liang et al., 2000; Thomas, 2013; Kim et al., 2015). Given the importance of identifying those infected, the U.S. Centers for Disease Control has recommended screening of all “baby boomers” for HCV with the expectation that a large number of individuals from diverse socioeconomic backgrounds will be identified for treatment (Smith et al., 2012).

With the revolutionization of HCV treatment with all-oral IFN-free regimens, today's therapies demonstrate response rates >90%, broad genotypic activity, once daily dosing, and minimal side-effects (Panel, 2015). However, despite the significant advances in HCV therapy, it is widely acknowledged that cost remains a major barrier in treating the populations that are most affected by HCV (Lo Re et al., 2016; Callaway, 2014). Thus, there still exists a need for affordable therapy with similar attributes and efficacy to the currently available DAAs.

One strategy for achieving affordability and facilitating pharmaceutical development involves the evaluation of existing drugs for new therapeutic indications (Collins, 2011). Various studies have reported drugs used for other purposes that have antiviral activity against various viral infections (Simanjuntak et al., 2015; Boonyasuppayakorn et al., 2014; Clouser et al., 2010; Sainz et al., 2012; Rolt et al., 2018). Recently, via high-throughput screening (HTS) of pharmaceutical collections, we and others discovered that the antihistamine chlorcyclizine HCl (CCZ) has anti-HCV activity (Huang et al., 2011; He et al., 2016; Chamoun-Emanuelli et al., 2014). CCZ is a first-generation over-the-counter piperazine class antihistamine that demonstrated high anti-HCV activity in vitro and in vivo with high liver distribution, synergy with various approved anti-HCV drugs and no evidence of drug resistance (He et al., 2015, 2016). The anti-HCV mechanism of action identified in cell culture was inhibition of late-stage HCV entry while not affecting viral replication or assembly/secretion (Chamoun-Emanuelli et al., 2014; He et al., 2015).

In this proof-of-concept study, we examined the antiviral effect of CCZ (with and without ribavirin (RBV)) in patients with chronic HCV infection and evaluated its safety and tolerability. We characterized the pharmacokinetic (PK) parameters and viral kinetic (VK) patterns of CCZ±RBV, and further used mathematical modeling to provide insights into the viral-host interactions, as well as CCZ+RBV efficacy and its mechanism of action (MOA) in humans. Finally, we performed a kinetic and modeling analysis in a previously described in vivo mouse model of CCZ monotherapy (He et al., 2015) and describe the similarities and differences in response patterns compared to human subjects in this study.