FDA批准Gilead公司的Hepsera™（adefovir商标）用于慢性乙肝治疗
首种用于慢性乙肝治疗的核苷类似物
第二个在少于一年内批准的一种新的Gilead公司抗病毒药物
加州福斯特市，2002年9月20日
Gilead公司(Nasdaq: GILD) 今天宣布已收到美国FDA的正式批文，批准其抗病毒药剂Hepsera™ (adefovir dipivoxil) 用于慢性乙肝治疗。该药下周早些时候将开始向批发商供应。
Hepsera按口服10mg片剂用药，它是第一种被美国FDA批准用于慢性乙肝治疗的核苷类似物。它通过阻断体内的乙肝病毒(HBV)复制来发挥作用。在临床研究中，Hepsera与肝脏组织学和纤维化的改善相关，降低了血清中的HBVDNA水平，与使用安慰剂组未经任何治疗的病人以及先前用过干扰素治疗的病人相比，提高了血清转换率和ALT的复常率。关键性的研究范围包括肝功代偿病人，e抗原阳性或者e抗原阴性（或PreC区突变）。在一项为期48周的双盲、安慰剂受控的研究中，Hepsera被证实是第一种对e抗原阴性病人有效的药物。研究表明该药对曾经采用拉米夫定治疗并产生抗药性的病人有效，包括列入（肝移植）申请名单或接受过肝移植的病人。关键性的研究表明，在整个48周的治疗期间，未检测到与Hepsera抗药性相关的突变(n=467)。
“FDA今天批准Hepsera，这给医生及其病人提供了一种对抗慢性乙肝的新武器。”佛罗里达州迈阿密大学肝病中心主任、肝脏病学部主任、医学博士Eugene Schiff说道。“Hepsera对于有着不同分级的活动性肝病患者来说是一项重要的进展，包括那些e抗原阴性或PreC区突变的慢性乙肝病人。同时对那些不适合或者在先前可用的治疗中产生抗药性的人来说也提供了一种选择。可以使用Hepsera的病人范围是空前的，他们将可能从治疗中获益。”
“全球范围有超过2000名的病人和卫生保健专业人员参与了Hepsera的临床研究，我们应当感谢他们帮助我们达到今天这个重要的里程碑。”Gilead科技公司总经理、执行总裁John C. Martin谈到。“Gilead人的使命就是增进对那些受到威胁生命的传染病感染的患者的治疗，我们为研制出了Hepsera而自豪，它将有助于满足对那些慢性乙肝携带者来说未能解决的治疗需求。”
这是FDA第二次在少于一年内批准Gilead的一种新抗病毒药物。Viread™ (tenofovir disoproxil fumarate)，该公司用于艾滋病(HIV)治疗的一种抗逆转录酶病毒药剂，于2001年10月在美国得到批准、2002年2月在欧盟得到批准。2002年3月，Gilead 公司向欧洲药物审核处递交了有关慢性乙肝治疗药物adefovir dipivoxil的行销权申请，该申请正在审查中。
Hepsera适应症
Hepsera适用于有检测结果显示病毒复制活跃，以及血清转氨酶(ALT或AST)持续升高或肝脏组织有活动病变的成年慢性乙肝患者的治疗。
该适应症范围基于HBeAg阳性和阴性、具有肝功代偿的成年慢性乙肝病人的组织学、病毒学、生物学、血清学反应，以及用于临床显示体内乙肝病毒已产生拉米夫定抗药性的、肝功代偿或失代偿的成年患者。
安全性描述
48周的临床研究表明，在使用Hepsera和那些使用安慰剂的病人之间，副作用的停止率和特性、严重程度和发生率与试验室异常是相似的。在这些研究中观察到大部分人的不良反应包括衰弱（虚弱）、头痛、腹痛、恶心、肠胃气胀、腹泻以及消化不良。这些副作用的报告在使用Hepsera和安慰剂的患者之间是相似的。整个48周研究期间，安慰剂组没有病人的血清肌氨酸酐升高到比正常值大于或等于0.5 mg/dL，4%接受Hepsera治疗的病人和2%接受安慰剂的病人升高到大于或等于0.3 mg/dL。延长治疗超过一年时，492人中有2例（少于1%）血清肌氨酸酐升高到大于或等于0.5 mg/dL，492人中有29例升高到大于或等于0.3 mg/dL。这种升高在持续治疗或停止治疗时或者消退或者仍然保持不变。
其他在肝移植前或已做过肝移植的病人中报道的不良反应有发热、呕吐、肝衰竭、ALT和AST升高、肝功能反常、咳嗽增加、咽炎、窦炎、搔痒症、皮疹、血清肌氨酸酐升高、肾衰竭以及肾功能不足。48周的治疗期间，13%的病人（41/324）血清肌氨酸酐升高到大于或等于0.5 mg/dL，26%的病人血清肌氨酸酐升高到大于或等于0.3 mg/dL。Hepsera在血清肌氨酸酐变化方面所起的作用难于评价，因为在治疗期间大多数病人具有一定程度潜在的肾功能不足和其他肾功能紊乱的风险因素。这些病人应当小心监控，并可能需要进行间隔用药调节。
与以前那些进行抗病毒治疗的慢性乙肝病人一样，医生需要监控肝炎引起的肝功恶化并停止治疗。另外，对于受到未被识别或未治疗过的HIV感染的慢性乙肝病人，可能出现HIV抗药性，这类人接受抗乙肝病毒治疗可能激活对HIV的对抗。在单纯使用核苷类似物或者与其他抗逆转录酶病毒药物联合使用时，有报告出现乳酸毒症和严重的脂肪变性肝肿大、包括致命的病例。
关于乙肝
乙肝是一种严重的疾病，病毒袭击肝脏，在高达三分之一的病人中能引起传染性肝炎（终身的）、肝硬化、肝癌和死亡。在美国，据估计相信有125万人有乙肝，每年大约有10万新感染者。全球范围内，慢性乙肝是肝癌的首要原因，1/10会导致死亡（今年大约有一百万人死于该病的并发症）。
乙肝通过血液和体液、性接触、注射药物或母婴围产期传播。早期症状包括食欲欠佳、不明显的疼痛、疲劳、痒、风疹（麻疹）和关节痛。随后的症状包括恶心、呕吐、口臭（难闻的气味）、茶褐色尿、黄疸（皮肤和眼睛变黄）以及右侧腹部疼痛（尤其是在外压或心悸的时候）。
使用Hepsera
Gilead公司保证大多数处于危急中的病人能够用到其产品。在该药按规定批准之前的2002年3月，Gilead公司就启动了“早期使用计划”，向那些急需一种新治疗选择的病人提供Hepsera用于治疗慢性乙肝。类似的计划在澳大利亚、加拿大和欧洲的许多国家也得到实施，该计划将持续到该药在这些地区进行商业应用时为止。
在美国，Hepsera的批发价为440美元每瓶（30片/瓶），每瓶可供一个月的治疗之用。
随着今天FDA的批准，为了促进公司的承诺实现，帮助所有病人能够从Hepsera受益，Gilead公司为那些没有保险或不能负担治疗费用的人建立了一项“美国患者援助计划”。关于该计划或“早期使用计划”的更进一步信息，请致电1-800-GILEAD-5或1-650-574-3000。
Gilead科技公司
Gilead科技公司是一家生物制药公司，研究、开发以及商业化治疗药物，在全球范围内提高对受到生命威胁的病人的保健。公司拥有6个已上市的产品，并集中研究力量和临床计划于抗传染性药物，包括抗病毒、抗真菌剂、抗菌药物等。总部位于加州福斯特市，公司在美国、欧洲和澳洲运营。
本新闻稿包含前瞻性的陈述，在1995年的《个人证券诉讼改革法案》有效范围内，遭受风险、不确定的或其他因素影响，可能引起实际结果与前瞻性陈述有着本质的不同。警告读者不要依赖这些前瞻性的陈述。在Gilead公司2001年12月31日截止的10-K形式的年度报告中，以及Gilead公司10-Q形式的季度报告中，详细描述了这些风险，所有这些文件都在美国证券交易委员会存档备查。所有前瞻性陈述均基于当前对Gilead公司可用的信息，Gilead公司不对更新这些前瞻性陈述承担义务。
Hepsera是Gilead科技公司的一个商标，Viread是该公司的一个注册商标。
需要有关Hepsera的完整的处方信息，请致电Gilead公司公共事务部：1-800-GILEAD-5 (1-800-445-3235) ，或访问www.hepsera.com。
（本译文若有不妥之处，敬请指出。）
附原文如下：（原文由HBV论坛 liver411提供）
FDA Approves Gilead’s Hepsera™ for the Treatment of Chronic Hepatitis B
First nucleotide analogue for the treatment of chronic hepatitis B
Second novel Gilead antiviral approved in less than one year
Foster City, CA, September 20, 2002 -
Gilead Sciences (Nasdaq: GILD) today announced that it received U.S. Food and Drug Administration (FDA) approval for its antiviral agent Hepsera™ (adefovir dipivoxil) for the treatment of chronic hepatitis B. The drug will be shipped to wholesalers early next week.
Hepsera, administered as an oral 10 mg tablet, is the first nucleotide analogue to receive FDA approval for the treatment of chronic hepatitis B. It works by blocking the replication of the hepatitis B virus (HBV) in the body. In clinical studies, Hepsera treatment was associated with significant improvements in liver histology and fibrosis, reduction in serum HBV DNA levels, increased rates of seroconversion and normalization of alanine aminotransferase (ALT) levels as compared to placebo in treatment-naïve patients and in patients with prior interferon experience. These pivotal studies included patients with compensated liver function and either "e" antigen-positive (HBeAg-positive) or "e" antigen-negative (HBeAg-negative, or precore mutant) chronic hepatitis B. Hepsera is the first drug for which efficacy has been demonstrated in HBeAg-negative patients in a 48-week double-blind, placebo-controlled study. The drug was studied and proven effective in patients who were treated with and developed resistance to lamivudine, including patients wait-listed for or who had received a liver transplant. Mutations associated with resistance to Hepsera have not been identified through 48 weeks of treatment in pivotal studies (n=467).
"Today's FDA approval of Hepsera gives physicians and their patients a new weapon in the fight against chronic hepatitis B," said Eugene Schiff, MD, Chief, Division of Hepatology and Director, Center for Liver Diseases, University of Miami, Florida. "Hepsera is an important development for people who have varying stages of active liver disease, including those with the HBeAg-negative or precore mutant strain of chronic hepatitis B. It is also an option for patients who aren't candidates for or have developed resistance to previously available therapies. With Hepsera, an unprecedented range of patients will have the potential to benefit from treatment."
"We extend our thanks to the more than 2000 patients and the health care professionals from around the world who participated in clinical studies of Hepsera, helping us to reach this important milestone today," said John C. Martin, PhD, President and CEO, Gilead Sciences. "Our mission at Gilead is to advance therapeutics for patients suffering from life-threatening infectious diseases, and we are proud to have developed a drug with the profile of Hepsera that will help to address the unmet medical needs of people living with chronic hepatitis B."
This is the second FDA approval for a novel Gilead antiviral in less than one year. Viread® (tenofovir disoproxil fumarate), the company's antiretroviral agent for the treatment of human immunodeficiency virus (HIV) infection, was approved in the United States in October 2001 and in the European Union in February 2002. In March 2002, Gilead submitted a Marketing Authorisation Application for adefovir dipivoxil for the treatment of chronic hepatitis B to the European Medicines Evaluation Agency. That application currently is under review.
Hepsera Indication
Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
This indication is based on histological, virological, biochemical and serological responses in adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
Safety Profile
In clinical studies, the discontinuation rates and nature, severity and incidence of side effects and laboratory abnormalities were similar between people taking Hepsera and those taking placebo through 48 weeks. The most common adverse events observed in these studies were asthenia (weakness), headache, abdominal pain, nausea, flatulence, diarrhea and dyspepsia. These side effects were reported with similar frequency in Hepsera and placebo-treated patients. Through 48 weeks, no patients in the placebo-controlled studies had elevations in serum creatinine greater than or equal to 0.5 mg/dL from baseline. Four percent of patients receiving Hepsera and two percent of patients receiving placebo had increases greater than or equal to 0.3 mg/dL. With extended treatment beyond one year, two of 492 patients (less than one percent) had elevations in serum creatinine greater than or equal to 0.5 mg/dL from baseline and 29 of 492 had elevations greater than or equal to 0.3 mg/dL. These elevations resolved or remained unchanged with either continued treatment or discontinuation.
Additional adverse events reported in pre-and post-liver transplant patients include fever, vomiting, hepatic failure, increases in ALT and AST levels, abnormal liver function, increased cough, pharyngitis, sinusitis, pruritus, rash, increases in serum creatinine, renal failure and renal insufficiency. Thirteen percent of patients (41 of 324) developed an elevation in serum creatinine greater than or equal to 0.5 mg/dL from baseline and 26 percent developed an increase greater than or equal to 0.3 mg/dL through 48 weeks. The contribution of Hepsera to changes in serum creatinine is difficult to assess as the majority of these patients had some degree of underlying renal insufficiency at baseline and other risk factors for renal dysfunction during treatment. These patients should be carefully monitored and may require dose interval adjustments.
As is the case with other antiviral therapies for chronic hepatitis B, physicians need to monitor liver function for exacerbation of hepatitis following discontinuation of therapy. Additionally, HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection who receive anti-hepatitis B therapies that may have activity against HIV. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals.
About Hepatitis B
Hepatitis B is a serious disease that attacks the liver and can cause chronic (lifelong) infection, cirrhosis of the liver, liver cancer and death in up to a third of patients. In the United States, an estimated 1.25 million people are believed to have chronic hepatitis B, with approximately 100,000 new infections occurring annually. Worldwide, chronic hepatitis B is the leading cause of liver cancer and the tenth leading cause of death (approximately one million people will die this year from complications from the disease).
Hepatitis B is spread through infected blood or body fluids, sexual contact, injection drug use or perinatally from mother to child. Early symptoms include loss of appetite, fever, generalized aches and pains, fatigue, itching, urticaria (hives) and joint pain. Later symptoms may include nausea and vomiting, halitosis (bad breath), dark brown urine, jaundice (yellowing of the skin and eyes) and right-sided abdominal pain (especially with external pressure or palpitation).
Access to Hepsera
Gilead is committed to ensuring access to its products for patients most in need. Prior to regulatory approval of the drug, in March 2002, Gilead initiated an Early Access Program to provide Hepsera to patients in urgent need of a new treatment option for chronic hepatitis B. Similar programs are in place in Australia, Canada and many countries in Europe and will continue until the drug is commercially available in those areas.
In the United States, the wholesaler acquisition cost for Hepsera is $440 for a bottle of 30 tablets, or one month of therapy.
With today's FDA approval, and to further its commitment to helping all patients who can benefit from Hepsera, Gilead has established a U.S. Patient Assistance Program for people who do not have insurance or cannot afford to pay for treatment. For more information about the Patient Assistance Program or the Early Access Program, please call 1-800-GILEAD-5 or 1-650-574-3000.
Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases worldwide. The company has six marketed products and focuses its research and clinical programs on anti-infectives, including antivirals, antifungals and antibacterials. Headquartered in Foster City, CA, Gilead has operations in the United States, Europe and Australia.
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in the Gilead Annual Report on Form 10-K for the year ended December 31, 2001 and in Gilead's Quarterly Reports on Form 10-Q, all of which are on file with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead and Gilead assumes no obligation to update any such forward-looking statements.
Hepsera is a trademark and Viread is a registered trademark of Gilead Sciences, Inc.
For full prescribing information on Hepsera, please call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit www.hepsera.com.