百时美施贵宝（BMS）4月10日公布了丙肝鸡尾酒疗法（daclatasvir+asunaprevir，即DCV+ASV）一项国际性III期研究HALLMARK-DUAL的数据。DCV+ASV是一种实验性全口服、无干扰素、无利巴韦林丙肝治疗方案。该项研究在基因型1b丙型肝炎病毒（HCV）感染者中开展，数据表明，接受DCV+ASV方案治疗后，初治患者组有90%的患者实现SVR12（完成治疗后12周的持续病毒学应答，即功能性治愈），聚乙二醇干扰素/利巴韦林无响应患者组SVR12数据为82%，聚乙二醇干扰素/利巴韦林不适合/不耐受患者组SVR12数据为82%，肝硬化患者组和非肝硬化患者组SVR12数据分别为84%和85%。该项研究中DCV+ASV方案一般耐受性良好。该项研究的数据将提交至本周在英国伦敦举行的第49届欧洲肝脏研究协会年会（EASL 2014-49th）。
本周早些时候，百时美向FDA提交了daclatasvir（DCV）和asunaprevir（ASV）的新药申请（NDA），daclatasvir是一种实验性NS5A复制复合物抑制剂，asunaprevir则是一种实验性NS3蛋白酶抑制剂。NDAs中所包含的数据，支持了丙肝鸡尾酒疗法DCV+ASV用于基因型1b丙型肝炎（HCV）的治疗。此外，DCV的NDA，也寻求批准daclatasvir与其他制剂联合用于多种基因型HCV的治疗。目前，欧洲药品管理局（EMA）正在审查daclatasvir的上市许可申请（MAA），同时daclatasvir和asunaprevir的NDAs也正在接受日本监管机构的审查。
此前，FDA已授予丙肝鸡尾酒疗法（DCV+ASV）突破性疗法认定。而去年，鸡尾酒疗法（全口服3DAA方案，DCV/ASV/BMS-791325）也获得了突破性疗法认定，百时美计划于2015年第一季度向FDA提交3DAA方案的监管文件。
在世界各地，慢性丙型肝炎（HCV）是导致肝癌和肝移植的主要原因。全球有1.7亿丙型肝炎患者，基因型1最为普遍。在欧洲有900万感染者，基因型1b HCV最为流行。当前的HCV标准护理涉及长达48周的含聚乙二醇干扰素（peg-IFN）/利巴韦林（RBV）方案。这些方案并不总是有效，而且具有显著的副作用，并与其他药物具有用药禁忌。
英文原文：
-Results of the HALLMARK-Dual study include data among genotype 1b cirrhotic and non-cirrhotic, treatment-naïve, non-responder, and peginterferon/ribavirin ineligible and intolerant patients
-Study reinforces the potential of daclatasvir-based regimens to treat HCV patients with high unmet needs
-Data to be presented during late-breaker session at EASL The International Liver CongressTM
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced Phase III results from the global HALLMARK-Dual study investigating the all-oral, interferon- and ribavirin-free regimen of daclatasvir (DCV), a NS5A inhibitor, and asunaprevir (ASV), a NS3 inhibitor, among genotype 1b hepatitis C virus (HCV) infected patients. Results showed that the 24-week regimen achieved an overall sustained virologic response (a functional cure) 12 weeks after the end of treatment (SVR12) among treatment-naïve (90%), peginterferon/ribavirin non-responder (82%), and peginterferon/ribavirin ineligible/intolerant (82%) patients, including cirrhotic and non-cirrhotic patients (84% and 85%). In the study the DCV+ASV regimen was generally well tolerated. These data will be presented this week at the 49th annual meeting of the European Association for the Study of the Liver (EASL) The International Liver CongressTM in London, April 9-13.
Globally, there are 170 million people infected with HCV, with genotype 1 being the most preva1ent. There are 9 million people infected in Europe, where there is a high preva1ence of HCV genotype 1b.
“Not only was the daclatasvir and asunaprevir regimen highly effective among study participants, it was also very well tolerated, even among sicker patients with more advanced liver disease and higher unmet needs,” said lead study investigator Professor Michael P. Manns, director of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, Germany. “Despite a rapidly evolving HCV treatment paradigm, physicians and patients remain in need of new all-oral, interferon- and ribavirin-free regimens that have the potential to achieve virologic cure across a broad range of patients, including those with advanced liver disease and cirrhosis.”
These data were part of the company’s recent DCV and ASV new drug application (NDA) submissions to the U.S. Food and Drug Administration (FDA), and helped support the validated marketing authorization application to the European Medicines Agency for the use of DCV in combination with other agents for the treatment of adults with HCV with compensated liver disease, including genotypes 1, 2, 3, and 4. These data are comparable to a similar Phase III study of this regimen in Japanese patients, which led to the submission of a New Drug Application with Japan’s Pharmaceutical and Medical Devices Agency.
“Daclatasvir has unique scientific characteristics that support ongoing research for its use in multiple all-oral HCV regimens,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “In addition to the HALLMARK-Dual study, we are pleased to be presenting data at EASL on our investigational 3DAA fixed-dose-combination, as well as daclatasvir in combination with other HCV compounds.”
Study Design and Results
This Phase III multinational clinical trial involved 116 sites in 18 countries, including countries that have a high preva1ence of genotype 1b such as Korea and Taiwan. In the study, treatment-naïve patients (n=205) received DCV 60 mg once daily plus ASV 100 mg twice daily for 12 weeks, and 102 patients received matching placebo for 12 weeks. The DCV+ASV treatment-naïve group continued treatment through week 24; placebo recipients entered another DCV+ASV study. The peginterferon/ribavirin-ineligible/intolerant (n=235) and non-responder patients (n=205) received the same doses of DCV and ASV for 24 weeks. The primary endpoint was the percentage of patients with a sustained virologic response at 12 weeks after the end of treatment (SVR12).
Virologic Response
90% of treatment-naïve patients achieved SVR12
82% of patients with prior null or partial response to peginterferon/ribavirin (non-responders) achieved SVR12
82% of peginterferon/ribavirin ineligible/intolerant patients achieved SVR12
Among peginterferon/ribavirin ineligible/intolerant patients, SVR12 was achieved by patients with anemia/neutropenia (91%); depression (80%) and compensated advanced fibrosis/cirrhosis with thrombocytopenia (73%).
Results among Cirrhotic Patients treated with DCV+ASV
At baseline, 33 treatment-naïve, 63 non-responders, and 111 ineligible/intolerant patients had cirrhosis. Cirrhotic patients made up ~32% of the study population.
SVR rates were similar in cirrhotic (84%) and non-cirrhotic (85%) patients.
The regimen used in this Phase III study resulted in low rates of discontinuation (1-3%) due to adverse events (AEs). In addition, the rate of serious adverse events (SAEs) was low (5-7%). Headache was the most common AE in the study (24-25%). No deaths occurred, and no clinically meaningful differences were observed in frequencies of SAEs, AEs leading to discontinuation, or grade 3/4 ALT/AST (liver enzymes) elevations in patients with or without cirrhosis. imp0rtantly, all grade 3/4 ALT/AST elevations observed were reversible and resolved off-treatment.
ab0ut Hepatitis C
Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 25 percent may progress to liver cancer.
ab0ut Bristol-Myers Squibb’s HCV Portfolio
Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir (DCV), an investigational NS5A replication complex inhibitor that has been studied in more than 5,500 patients as part of multiple direct-acting antiviral (DAA) based combination therapies. DCV has shown a low drug-drug interaction profile, supporting its potential use in multiple treatment regimens and in people with co-morbidities.
Daclatasvir is being investigated in combination with sofosbuvir in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients, and patients with genotype 3, as part of the ongoing Phase III ALLY Program.
In 2014, the U.S. Food and Drug Administration (FDA) granted Bristol-Myers Squibb’s investigational DCV Dual Regimen Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b HCV infection.
In 2013, Bristol-Myers Squibb’s investigational all-oral 3DAA Regimen (daclatasvir/ asunaprevir/BMS-791325) also received Breakthrough Therapy Designation, which helped to expedite the start of the ongoing Phase III UNITY Program. Study populations include non-cirrhotic naïve, cirrhotic naïve and previously treated patients. The daclatasvir 3DAA regimen is being studied as a fixed-dose-combination treatment with twice daily dosing.
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