2014年6月18讯 /生物谷BIOON/ --吉利德科学（Gilead Sciences）6月15日公布了丙型肝炎ledipasvir/sofosbuvir固定剂量复方片（LDV/SOF，90mg/400mg，每日一次）日本III期研究（GS-US-337-0113）的顶线数据。该研究调查了LDV/SOF（有或无利巴韦林，RBV）用于基因型1慢性丙型肝炎病毒（HCV）感染的治疗。接受LDV/SOF（无RBV）治疗12周的患者中，初治治疗组（n=83/83，100%）和经治治疗组（n=88/88，100%）在完成治疗12周后均实现了100%的持续的病毒学应答（SVR12）。接受LDV/SOF+RBV治疗12周的患者中，初治治疗组（n=80/83，96%）和经治治疗组（n=87/87，100%）分别有96%和100%的患者实现了SVR12。在横跨研究的所有组中，肝硬化患者群体有99%（n=75/76）实现了SVR12。与预先定义的历史SVR12百分率相比，该项研究达到了优越性主要疗效终点，实现SVR12的患者被认为已治愈HCV感染。
LDV/SOF为每日一次的固定剂量复方片，其中ledipasvir（LDV）为NS5A抑制剂，sofosbuvir（SOF）为核苷酸类似物聚合酶抑制剂。
基于以上数据，吉利德计划于2014年底向日本药品和医疗器械管理局（PMDA）提交LDV/SOF固定剂量组合的新药申请（NDA）。目前LDV/SOF正在接受FDA和欧盟的审查。此前，FDA已授予LDV/SOF突破性疗法认定，并授予优先审查资格。
2014年4月2日，吉利德公布了在日本开展的另一项III期研究的顶线数据，该研究评价了SOF+RBV用于基因型2 HCV感染的治疗。吉利德计划于2014年年中向PMDA提交SOF的单药申请。目前，SOF已获FDA、欧盟、加拿大批准，商品名为Sovaldi。
在日本，基因型1 HCV是最常见的毒株，约占所有HCV感染病例的70%，大部分为基因型1b HCV。目前日本有超过100万HCV感染者。当前，基因型1 HCV感染的标准治疗方案，涉及长达48周的聚乙二醇化干扰素注射、口服RBV片剂其他药物，对于某些特定患者可能不适合。
关于Sovaldi（sofosbuvir）：
Sovaldi（400mg片剂）为每日一次的口服核苷类似物聚合酶抑制剂，分别于2013年12月和2014年1月获FDA和欧盟批准，作为抗病毒治疗方案的一部分，用于慢性丙型肝炎（HCV）的治疗。
Sovaldi是首个获批可用于C型肝炎全口服治疗方案的药物，在用于特定基因型慢性丙型肝炎治疗时，可消除对传统注射药物干扰素（IFN）的需求。
具体而言，FDA已批准sofosbuvir联合利巴韦林（ribavirin）用于基因型2和基因型3慢性丙型肝炎（hepatitis C）成人患者的治疗。同时，FDA还批准sofosbuvir联合聚乙二醇干扰素（PEG-IFN）和利巴韦林，用于基因型1和基因型4慢性丙型肝炎初治（treat-naive）成人患者的治疗。（生物谷Bioon.com）
英文原文：Gilead Announces Phase 3 Data Showing That the Fixed-Dose Combination of Ledipasvir/Sofosbuvir Achieved 100 Percent Sustained Virologic Response (SVR12) Among Patients with Chronic Hepatitis C in Japan
-- Interferon- and Ribavirin-Free Therapy Effective against Genotype 1 HCV, Japan’s Most Prevalent Strain of the Disease --
-- Japanese Regulatory Submission for Ledipasvir/Sofosbuvir Anticipated by Year End --
FOSTER CITY, Calif.--(BUSINESS WIRE)--Jun. 15, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline results from a Phase 3 clinical trial (GS-US-337-0113) in Japan evaluating the investigational once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection. Among patients receiving 12 weeks of LDV/SOF without RBV, 100 percent (n=83/83) of treatment-naïve and 100 percent (n=88/88) of treatment-experienced patients achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Among patients receiving LDV/SOF plus RBV, 96 percent (n=80/83) of treatment-naïve and 100 percent of treatment-experienced patients (n=87/87) achieved SVR12. Across all arms of the study, patients with cirrhosis achieved a 99 percent (n=75/76) SVR12. The study met its primary endpoint of superiority compared to a predefined historical SVR12 rate. Patients who achieve SVR12 are considered cured of HCV infection.
Genotype 1 is the most common strain of HCV in Japan, accounting for approximately 70 percent of the more than one million people chronically infected with the disease. The majority of these infections are due to HCV genotype 1b. Current treatment options for genotype 1 HCV infection involve up to 48 weeks of therapy with pegylated interferon injections, RBV tablets and other oral medicines, which may not be suitable for certain patients.
“The cure rates observed with LDV/SOF in this study are impressive because they were achieved without the need for interferon or ribavirin, both of which involve more complex dosing requirements and may be associated with significant side effects,” said Norbert Bischofberger, PhD, Gilead’s Executive Vice President of Research and Development and Chief Scientific Officer. “These results suggest that a once-daily LDV/SOF tablet has the potential to be an efficacious and well-tolerated regimen for many HCV patients in Japan.”
In the study, 341 patients with genotype 1 HCV infection were randomized (1:1) to receive 12 weeks of all-oral therapy with LDV/SOF, with or without RBV. Of these, 166 patients were treatment-naïve, 175 were treatment-experienced and 76 had compensated cirrhosis. The intent-to-treat SVR12 rates in the study are summarized in the table below:
Population Treatment Duration SVR12 Rates
Genotype 1 treatment-naïve LDV/SOF 12 weeks 100% (83/83)
LDV/SOF + RBV 12 weeks 96% (80/83)
Genotype 1 treatment-experienced LDV/SOF 12 weeks 100% (88/88)
LDV/SOF + RBV 12 weeks 100% (87/87)
Overall, 338/341 patients (99 percent) in Study GS-US-337-0113 achieved SVR12. Of the three patients who failed to achieve SVR12, one patient relapsed after discontinuation of therapy, one patient discontinued therapy after one week of treatment due to rash and one patient died during the study.
Fewer adverse events were observed in the RBV-free arms compared to the RBV-containing arms in the study, most notably with regard to anemia, which was observed in 14 percent of patients taking LDV/SOF plus RBV compared to 2 percent of patients receiving LDV/SOF alone. Adverse events observed with LDV/SOF without RBV were generally mild and included nasopharyngitis (28 percent), headache (6 percent) and malaise (5 percent). Among those taking LDV/SOF plus RBV, in addition to anemia, the most common adverse events were nasopharyngitis (22 percent), pruritus (8 percent), rash (8 percent), headache (8 percent), stomatitis (6 percent), nausea (5 percent) and malaise (5 percent). No patients taking LDV/SOF and two patients taking LDV/SOF plus RBV discontinued treatment due to treatment-emergent adverse events. Full study results will be presented at a future scientific meeting.
Based on these data, Gilead plans to submit a New Drug Application for the LDV/SOF fixed-dose combination with the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by the end of 2014. The product is currently under regulatory review in the United States and European Union.
On April 2, 2014, Gilead announced topline results from another Phase 3 study in Japan evaluating SOF as a single agent in combination with RBV for the treatment of genotype 2 HCV infection. The company plans to file for approval of SOF with the PMDA by mid-2014. SOF as a single agent has been approved by regulatory authorities in the United States, European Union and Canada under the tradename Sovaldi®.
LDV/SOF and SOF are investigational products in Japan and their safety and efficacy have not yet been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.
