Efficacy and Safety of Alfosbuvir Plus Daclatasvir in Chinese Patients With Hepatitis C Virus Genotypes 1, 2, 3, and 6 Infection

An Open-label, Phase 2 Study

Rui Hua; Fei Kong; Xiaofeng Wen; Qingfang Xiong; Jiayu Chen; Chenxin Meng; Hong Ma; Youwen Tan; Yan Huang; Yongfang Jiang; Yujuan Guan; Xiaorong Mao; Jiefei Wang; Yongning Xin; Hainv Gao; Bin Xu; Cheng Li; Qiong Wu; Xian Zhang; Zhiqiang Wang; Liwen Zhao; Yuexin Zhang; Guangming Li; Junqi Niu

Disclosures

J Viral Hepat. 2022;29(6):455-464. 

In This Article

Abstract and Introduction

Abstract

Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. Our previous studies indicated that alfosbuvir monotherapy was well-tolerated and druggable in healthy subjects and HCV-infected patients. Here, we evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV genotype 1, 2, 3 or 6. In this open-label study, patients with chronic HCV infection were randomly assigned with a 1:1:1 ratio to receive 12 weeks of daclatasvir 60 mg plus alfosbuvir at a dose of 400, 600 or 800 mg (Cohort A, B or C) daily. Randomization was stratified by HCV genotype and the presence or absence of cirrhosis at screening. The primary endpoint was a sustained virologic response 12 weeks after the end of treatment (SVR12). A total of 124 patients were enrolled in the study, all of whom were available for post-treatment week 12 assessments. SVR12 was achieved in 92.7% (38/41), 95.2% (40/42) and 100% (41/41) of patients in Cohort A, B and C respectively. The most common adverse events were hepatic steatosis, upper respiratory tract infection, hypercholesterolaemia, hypertriglyceridaemia, blood bilirubin increased, and total bile acids increased. There were no discontinuations due to adverse events, and no treatment-related serious adverse events were reported. Once-daily oral administration of alfosbuvir plus daclatasvir were highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3 or 6, suggesting this regimen could be a promising drug candidate for HCV treatment irrespective of genotype.

(ClinicalTrials.gov number, NCT04070235).

Introduction

There are at least 10 million patients chronically infected with hepatitis C virus (HCV) in China.[1] Genotype 1 was the most common HCV genotype across China, comprising 57% of the overall population, followed by genotypes 2, 3 and 6 with approximate prevalence of 24%, 9% and 6% respectively.[2–4]

From the year of 2017, with the successive launch of several direct-acting antiviral drugs (DAAs) in mainland China (e.g. sofosbuvir, ledipasvir, elbasvir and grazoprevir), interferon-free antiviral therapy began to be available to patients, and a new era of chronic HCV treatment has arrived.[5–7] However, most of the DAAs launched in China are specific for HCV genotype 1, which means approximately 40% of HCV-infected Chinese patients are lack of therapeutic choices and a pan-genotypic regimen is in urgent need.

Alfosbuvir (formerly named as SH229) is a phosphoramidate nucleotide prodrug that potently and selectively inhibits HCV NS5B polymerase showing an in vitro activity with the half maximal effective concentration (EC50) value of 10.4–38.4 nM in HCV replicons. In the hepatocytes, alfosbuvir is metabolized to an active triphosphate form (SH229M3) with NS5B inhibitory activity (Figure S1).[8,9] Data from two Phase 1 studies demonstrated that alfosbuvir is generally safe and well-tolerated with a favourable pharmacokinetic profile. In patients with HCV infection, alfosbuvir monotherapy for 3 days resulted in median maximum HCV RNA reductions >3.5 log10 IU/ml at doses of 400, 600 and 800 mg, suggesting alfosbuvir could be evaluable for further HCV clinical development in combination with other DAAs (unpublished data).

Daclatasvir is a pan-genotypic HCV NS5A inhibitor which has been already approved in China for the treatment of chronic hepatitis C.[10–12] Our previous studies indicated that daclatasvir shows synergy antiviral activity when combined with alfosbuvir in HCV replicons without complicated pharmacokinetic interactions. Thus, it is anticipated that the combination of alfosbuvir and daclatasvir may be a potential pan-genotypic regimen. Therefore, we conducted a Phase 2 study to evaluate the efficacy and safety of 12 weeks of treatment with alfosbuvir plus daclatasvir in Chinese patients with HCV of all genotypes, including both previously treated and untreated patients, and those with compensated cirrhosis or without cirrhosis.

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