Safety and Efficacy of Coblopasvir and Sofosbuvir in Patients With Genotypes 1, 2, 3 and 6 HCV Infections Without or With Compensated Cirrhosis

Huiying Rao; Guangjun Song; Guangming Li; Yongfeng Yang; Xiaofeng Wu; Yujuan Guan; Qing Mao; Xiangjun Jiang; Changyuan Wang; Ying Zhang; Jidong Jia; Xiaolin Guo; Chenghao Li; Jing Ning; Hong Qin; Hai Pan; Lai Wei

Disclosures

J Viral Hepat. 2019;27(1):45-51. 

In This Article

Abstract and Introduction

Abstract

A simple, pangenotypic and effective treatment regimen for patients with a broad range of chronic hepatitis C virus (HCV) infections remains an unmet medical need. We conducted a phase 2, randomized, open study involving untreated patients with chronic HCV genotypes 1, 2, 3, or 6 infections. Patients without cirrhosis were randomly assigned in a 1:2 ratio to receive capsules of the NS5A inhibitor coblopasvir at a dose of 30 or 60 mg plus tablets of the nucleotide polymerase inhibitor sofosbuvir (400 mg) once daily for 12 weeks. Patients with cirrhosis received 60 mg coblopasvir plus sofosbuvir for 12 weeks. The primary endpoint was the sustained virologic response at 12 weeks after the end of therapy (SVR12). Of the 110 patients who were enrolled in the study, 59 were male, 62.7% had HCV genotype 1, 24.5% had genotype 2, 6.4% had genotype 3, and 6.4% had genotype 6. The average age was 45.5 years. A total of 10.9% of patients had compensated cirrhosis. The rate of SVR12 was 98.2% in the intention-to-treat (ITT). One genotype 6 patient with cirrhosis experienced virologic relapse. One genotype 2 patient without cirrhosis failed to complete the follow-up and quit the study. Serious adverse events (SAEs) were reported in 2 patients and were not related to coblopasvir and sofosbuvir. Most adverse events (AEs) did not require treatment. Coblopasvir plus sofosbuvir taken once daily for 12 weeks provided high rates of sustained virologic response (SVR) and had a good safety profile among patients with HCV genotypes 1, 2, 3, or 6 infections, including those with compensated cirrhosis.

Introduction

It is estimated that the prevalence of chronic hepatitis C virus (HCV) infection in China is 0.7%, as approximately 10 million individuals are infected with HCV; the geographic distribution of HCV genotypes 1, 2, 3, and 6 is highly variable, and genotypes 4 and 5 are very rare.[1,2] Without effective antiviral treatment, patients can develop cirrhosis and even hepatocellular carcinoma.[3,4] Until April 2017, the only treatment option for patients with HCV infection in China was pegylated interferon plus ribavirin. Interferon-based therapies are poorly tolerated, and because of absolute and relative contraindications, a large number of patients remain untreated.[5]

The introduction of an all-oral direct-acting antiviral (DAA) therapy in China in 2017 and 2018 has improved the treatment options and outcomes for patients with HCV infection.[6] Four all-oral genotype-specific regimens have been approved for use in China: sofosbuvir, an HCV nonstructural protein (NS) 5B polymerase inhibitor, combined with ribavirin;[7] asunaprevir, an NS3 protease inhibitor (PI), combined with daclatasvir, an NS5A inhibitor; grazoprevir, an NS3 PI, combined with elbasvir, an NS5A inhibitor; and paritaprevir/ritonavir, an NS3 PI, and ombitasvir, an NS5A inhibitor, combined with dasabuvir, an NS5B polymerase inhibitor. Two all-oral pangenotypic regimens have been approved for use in China: sofosbuvir combined with daclatasvir and velpatasvir, an NS5A inhibitor, combined with sofosbuvir. All-oral pangenotypic regimens are simplified treatment options that were recommended by the World Health Organization (WHO) HCV guidelines (2018 version). A simple, affordable, universal, pangenotypic treatment regimen is preferred for anti-HCV treatment in clinical practice and public health efforts in China.[8] However, pangenotypic regimens, such as sofosbuvir, daclatasvir and sofosbuvir/velpatasvir, have not been covered by health insurance in China, and the price is high, so many patients cannot afford these treatments. Therefore, a simple, pangenotypic, effective and affordable treatment regimen for patients with a broad range of chronic HCV infections remains an unmet medical need in China.

KW-136 (WHO proposed International Nonproprietary Name: coblopasvir) is a pangenotypic inhibitor against HCV NS5A with picomolar antiviral activity against HCV replicons with genotypes 1a, 1b, 3a, 4a, 5a and 6a consensus sequences and in an HCV cell culture system with a genotype 2a strain in vitro, which is similar to or more potent than the first-in-class HCV NS5A inhibitor daclatasvir. The combination of coblopasvir and the NS5B polymerase inhibitor sofosbuvir has an additive effect against HCV genotype 1b in vitro without any observed cross-resistance to known major NS5A and NS5B amino acid substitutions. In noncirrhotic patients who are chronically monoinfected with genotype 1b HCV, an ultrashort duration (3 successive days) of once-daily oral coblopasvir monotherapy shows a maximal HCV RNA titre decline of greater than 2.5 (log10) IU/mL; a greater effect is observed with a 60 mg dose than that with 30 mg, but the effect of a 60 mg dose is similar to that of 90 and 120 mg doses. In phase 1 studies involving healthy adult volunteers and noncirrhotic patients with HCV monoinfections, coblopasvir monotherapy had a favourable safety profile and did not show treatment-emergent laboratory abnormalities that were clinically significant.

The combination regimen of coblopasvir and sofosbuvir is expected to completely suppress HCV replication in subjects who are chronically infected with HCV and to achieve a sustained virologic response (SVR). Because coblopasvir and sofosbuvir are both pangenotypic anti-HCV agents, the combination of these two agents is also predicted to be efficacious for the treatment of subjects who are chronically infected with HCV of all major genotypes and subtypes. An apparent clinical benefit of this pangenotypic anti-HCV treatment regimen is that complex, precise HCV genotype sequencing is not required to determine the genotype-specific treatment alternatives of choice before the initiation of treatment. This advantage is of great significance in the primary care setting. We conducted a phase 2 study to evaluate the safety and efficacy of coblopasvir combined with sofosbuvir for the treatment of Chinese adults who were chronically infected with HCV genotypes 1, 2, 3, and 6, with compensated cirrhosis or without cirrhosis.

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