Gilead's Hepatitis C Drug Vosevi (Sofosbuvir/Velpatasvir/Voxilaprevir) Expected to Gain Approval This Month in China

Recently, Gilead’s hepatitis C drug Vosevi (Application No.: JXHS1900078) has entered the “under review” status for its marketing application, with approval expected this month. Vosevi consists of three fixed-dose components: sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg), and is referred to by industry insiders as “Gilead’s fourth-generation therapy.”

(Source: NMPA)

Compared with “Epclusa” (the third-generation regimen), “Vosevi” (the fourth-generation regimen) is indicated for adult patients with genotype 1, 2, 3, 4, 5, or 6 chronic hepatitis C virus (HCV) infection who have previously failed treatment with an NS5A inhibitor-containing regimen, as well as for adult patients with genotype 1a or 3 infection who have previously failed treatment with a sofosbuvir-containing regimen without an NS5A inhibitor. In July 2017, Vosevi was approved by the U.S. FDA for the treatment of adults with genotype 1–6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A), becoming the first approved once-daily, single-tablet regimen.

(Source: FDA)

The Global Hepatitis C Market Is Shrinking, but the Domestic Market in China Is Rising

Globally, hepatitis C (HCV) is one of the most common liver diseases and a public health challenge facing all of humanity. According to statistics from the World Health Organization (WHO), approximately 3% of the global population (around 150 million people) is affected by hepatitis C.

According to the “2018 National Overview of Statutory Infectious Disease Epidemics” released by the Bureau of Disease Prevention and Control under the National Health Commission, there are currently nearly 19 million HCV patients in China, making it one of the countries with the highest number of infections globally. Among these cases, HCV genotypes 1, 2, 3, and 6 account for more than 96% of all cases.

In 2018, the global hepatitis C market size fell below $10 billion, reaching only $7.767 billion. Compared to the peak of the global hepatitis C drug market in 2015, it has dropped by $15.996 billion (-67.32%). There is a mismatch between the development of the global liver disease drug market and the domestic market. The main reason for this phenomenon is that the introduction of sofosbuvir directly pushed the entire hepatitis C market into a curable stage, significantly reducing the number of existing patients, and stabilizing the international market landscape.

Meanwhile, in 2018, the number of new hepatitis C cases in China reached 250,000, with 115 deaths, marking a significant increase compared to previous years. In the domestic market, due to patent issues that delayed the entry of such products into China, there is an approximately 3- to 5-year generational gap compared to the global market. Currently, local pharmaceutical companies are accelerating their strategic layouts. Behind the increasingly fierce competition lies, on one hand, the substantial potential demand from the large population of hepatitis C patients in China coupled with declining demand for hepatitis C drugs in developed countries; on the other hand, it is driven by favorable policies introduced by the Chinese government.

Hepatitis C Treatment in China Enters the DAA Era

As is well known, interferon and ribavirin were once the first-line therapies for hepatitis C. In particular, after the launch of pegylated interferon alfa-2a and pegylated interferon alfa-2b, they dominated the entire hepatitis C market. Starting in 2017, multinational pharmaceutical companies and Chinese domestic pharmaceutical companies increasingly focused on the hepatitis C treatment market in China. In May 2017, Bristol-Myers Squibb’s daclatasvir hydrochloride tablets (Daclatasvir, DCV) and asunaprevir soft capsules (Asunaprevir, ASV) were approved for marketing in China for the combination treatment of chronic hepatitis C in adults, becoming the first oral direct-acting antiviral (DAA) drugs for hepatitis C launched in the country.

DAA drugs are protein inhibitors that directly target proteins involved in the hepatitis C virus replication process to prevent further viral infection. The traditional international treatment regimen for hepatitis C primarily employs interferon, which requires injection and often leads to poor patient compliance.

Oral direct-acting antiviral (DAA) agents have altered this characteristic. DAAs primarily include NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A inhibitors, all of which target three sites on the HCV non-structural proteins.

Mechanism of Action of DAA Drugs

(Source: JAMA)

Multiple Blockbuster DAA Drugs Enter China

Since the National Medical Products Administration (NMPA) implemented reforms to the drug review and approval system, the time lag for the entry of overseas new drugs into China has been gradually shortening, with multiple blockbuster hepatitis C drugs/therapies approved in China.

Blockbuster Hepatitis C Drugs Approved by the NMPA Since 2017

(Source: NMPA)

Gilead Ushered in the Era of Hepatitis C Cure in China

On September 20, 2017, Gilead’s Sovaldi (sofosbuvir tablets) was approved for marketing in China, indicated for use in combination with other agents to treat genotype 1–6 hepatitis C virus (HCV) infection in adults and adolescents aged 12 to 18 years. The advent of this direct-acting antiviral agent for hepatitis C marked the beginning of the end for the disease.

On May 30, 2018, Epclusa ("Sofosbuvir 400 mg/Velpatasvir 100 mg," known as "Ji San Dai" in China) was approved in China for the treatment of all genotypes (1–6) of hepatitis C. At a press conference titled "Hepatitis C Treatment Enters the Pan-Genotypic Era," Gilead Sciences announced that Epclusa is the first pan-genotypic, single-tablet regimen for hepatitis C virus (HCV) approved in China. It is indicated for adult patients with chronic HCV infection, including those with genotypes 1–6, mixed genotypes, or unknown genotypes.

On November 27, 2018, Harvoni (ledipasvir 90 mg/sofosbuvir 400 mg), known as the “second-generation Gilead product,” was approved in China for the treatment of adults and adolescents aged 12 to 18 years with chronic hepatitis C virus (HCV) infection genotypes 1–6. According to reports, in multicenter clinical trials conducted in China, a once-daily, single-tablet regimen achieved a 100% SVR12 rate (defined as undetectable HCV RNA 12 weeks after completion of therapy) in patients with genotype 1 HCV.

Ascletis Pharma Ushers in the Era of Domestic DAAs

On June 8, 2018, Ganovo (danoprevir, ASC08), a Class 1 innovative drug for hepatitis C developed by Ascletis Pharma, received marketing approval from the National Medical Products Administration (NMPA). Danoprevir is the first direct-acting antiviral agent developed by a domestic Chinese company, indicated for use in combination with other drugs to treat treatment-naïve, non-cirrhotic patients with chronic genotype 1 hepatitis C.

Ravidasvir, another hepatitis C drug developed by Ascletis Pharma, had its marketing application submitted in August 2018. It is reported that the first all-oral, interferon-free regimen originally developed in China, consisting of ravidasvir combined with danoprevir, achieved a cure rate (SVR12) of 99% in patients with genotype 1 non-cirrhotic hepatitis C. Furthermore, 100% of patients with baseline NS5A resistance-associated substitutions achieved SVR12.

Merck & Co. and Gilead Sciences Included in National Reimbursement Drug List

According to the 2019 National Reimbursement Drug List (NRDL) negotiation catalogue, Merck’s Zepatier (elbasvir/grazoprevir), Gilead’s Epclusa (sofosbuvir/velpatasvir), and Harvoni (ledipasvir/sofosbuvir) were included in Category B of the National Reimbursement Drug List with price reductions exceeding 85%. The agreement is valid from January 1, 2020, to December 31, 2021.

Meanwhile, the other two pharmaceutical companies involved in the hepatitis C drug price negotiations—AbbVie and Ascletis Pharma—were eliminated. Following the announcement of the national medical insurance negotiation results, Ascletis Pharma’s stock price plummeted, closing at HK$3.42 on November 28, a drop of 25.00%.

Original Title: Listing | Breaking! Gilead’s Hepatitis C Drug “Fourth-Generation” Vosevi Set for Imminent Approval and Launch