近日，美国华裔生物科学家余芒研制的抗流感新药“Fludase”(流感酶)取得了突破性进展。这种新药针对患者本身，通过阻止病毒与人体结合的方式来达到治病的目的。它比“达菲”等常规药物更出色的地方在于，它不会产生抗药性，并且能对抗目前所知的所有流感病毒变种，包括甲型H1N1流感。

　文/Margo

　美国NexBio生物制药公司的首席执行官余芒博士又在案头上添了几叠资料，浏览完世界卫生组织每周更新的检测资料之后，便起身走向了实验室。七年前，为研发预防流感蛋白药物，华裔生物科学家余芒和妻子房芳一同创立了这间公司。在美国政府6300万美元的大力资助下，应对流感病毒的蛋白药物“Fludase”在近日取得了突破性进展，NexBio也因此被《科学美国人》杂志列为“最有影响力的50家公司”之一。

　余芒在接受媒体采访时表示，“Fludase”的主要成分是唾液酸酶融合蛋白，它由人体内自有的细菌中提取并加工合成。药物并不直接杀灭病毒，而是通过切断呼吸道上皮细胞表面的糖链受体，以阻止病毒与该人体的结合，从而达到防病治病的目的。“Fludase”的中文名为“流感酶”。在解释为何有如此中文名称时，他开玩笑说，“流感酶”，也就是“流感没了”的意思。

　为降低抗药性而进行的研究

　9月11日，一名来自珀斯的38岁男子被送进了西澳大利亚州立医院，在被确诊染上甲型H1N1后，医护人员让他服下了“达菲”，这是目前有效应对H1N1病毒的首选药物。然而，由于较弱的免疫系统，最初服药产生效果后不久，咳嗽与发热的病症再次复发，医生发现，病人产生了抗药性反应，这是澳洲出现首例对抗病毒药物达菲产生抗药性的甲流病例。

　事实上，最先的病例早在6月30日已经出现，丹麦一名甲型H1N1流感患者对“达菲”产生了同样的耐药反应，这是科学家首次检测到甲型H1N1流感病毒的抗药变异。之后，美国、加拿大、香港、日本、澳大利亚相继发现了对“达菲”有抗药性的甲流病例。根据瑞士罗氏公司最近公布的统计数字，全球范围内，对达菲产生耐药性的甲型H1N1流感病例已达26例。

　在甲型H1N1流感治疗手段方面，余芒表示，目前有效的首选药物是“达菲”和“乐感清”，它们属于同类药物，其中以“达菲”为主，根据临床试验，大约有0.5%的病例会出现抗药性。因为过度使用，抗药性H1N1甲型流感病毒的菌株很可能开始出现了。如产出抗药性，则意味着人们将没有现成的有效药物，流感也将成为无药可治的疾病，对人类威胁极大。

　正是“达菲”等药物潜在的抗药性，促使余芒进行新流感药物的研究。在禽流感肆虐全球的一年多以前，余芒的NexBio公司与联邦疾病控制中心联合，在小鼠生物模型上完成了“流感酶”防治H5N1病毒的实验。该实验证实“流感酶”可以保护小鼠抵御致命性禽流感病毒H5N1的感染。而在刚刚完成的一期临床实验中，结果也显示了药物在人体中的安全性。

　对预防和治病都有效的“流感酶”

　余芒与联邦疾病控制中心的洁奎琳。卡茨博士(Dr.Jacqueline Katz)及其同事将实验分为预防和治疗两大类。在防病实验中，从接触传染源之前一天起，每日以滴鼻方式给以“流感酶”(每公斤体重给一毫克)，连续给药七天，结果小白鼠均得以存活，并减少因病毒感染而出现的体重下降。反之，对照组中未给药的小白鼠都在感染后七天内陆续死亡，并在感染后第五天平均减重16%。

　在治病的实验中，研究人员将小鼠分3档，它们分别在接触病毒后24小时、48小时和72小时后开始接受药物治疗。结果显示，药物虽不能保护小鼠免于病毒感染，但却能减少它们的体重下降和延长它们的寿命。小鼠的存活率随开始治疗时间的早晚呈下滑趋势，分别为70%(24小时)、35%(48小时)以及15%(72小时)。

　NexBio公司与疾病控制中心专家都认为，“流感酶”代表治疗呼吸道病毒感染的新进展，它不同于当前用于治疗禽流感的各种药物，它所针对的不是病毒，而是患病者自身，作用于保护人体细胞不受流感病毒侵害，因而比一般药物更有“治本”的功效。并且，“流感酶”还具有广泛的抗病毒活性以及降低抗药性的潜力，能有效识别同一宿主受体的呼吸道流感病毒，从而对抗目前所知的所有流感病毒变种，包括在全球范围内徘徊了五个月之久的甲型H1N1流感。对于已对达菲产生耐药性的流感病毒毒株，“流感酶”也能抵御其入侵细胞。美国国家卫生研究院(NIH)已高度肯定该项研究成果，一再提供高额经费，推动相关的研发进程。

　将在紧急情况下批准使用

　“流感酶”目前已完成“合标制造程序”(cGMP)的生产，并顺利结束一期临床实验。根据美国食品药物管理局(FDA)的规定，通常药物要完成三期临床试验后才有可能被批准上市。这往往需要花费数年甚至更长的时间。也许实验还未来得及完成，因H1N1变异引起的人类流感就会暴发。对此，余芒表示，迄今尚未发现真正意义上的“甲流”病毒变异并传染的案例。已经发现的“甲流”病毒抗药性病例，均为孤立现象。如果甲型H1N1流感对现有药物真的产生了抗药性，那么公司将申请美国食品和药品管理局(FDA)的紧急用药许可证，由政府购买药物进行战略储备。根据美国法律规定，在紧急情况下，如果实验药物满足动物实验有效且人体使用安全两个条件，那么FDA将准许使用该药物。

　余芒认为，病毒毒力及其变异方向存在不确定性，没有人能够确保甲型H1N1流感的耐药性病毒变体是否会产生，并大范围地传播。甲型H1N1流感可以在几周内肆虐全球，影响到每个人。有些人会自己痊愈，但对有些人却会是致命的。人们必须充分认清流感病毒潜在的杀伤力，提高防范意识，而作为研究者的他们也将加快实验进程，让“流感酶”尽快生产问世。

Fludase®(DAS181) is a broad-spectrum drug candidate for the prophylaxis and treatment of respiratory infections caused by all types of influenza virus, including the types of virus that may cause a potential influenza pandemic, as well as all types of parainfluenza virus. Fludase® is currently in phase I clinical development, and has successfully completed its First-In-Man trial.

MECHANISM OF ACTION: FLUDASE® BLOCKS IFV ENTRY INTO CELLS

Fludase®is a recombinant fusion protein (see figure 1) that inactivates viral receptors on the cells of the human respiratory tract, thereby preventing influenza and other viruses such as parainfluenza from both infecting the human body and amplifying in already-infected individuals.

In the human respiratory tract, cell-surface sialic acids act as the host cell receptors for all influenza A and B and parainfluenza viruses. Fludase®works by inactivating these sialic receptors in the airway epithelium, therefore preventing viral entry into cells.

Because these viruses primarily invade and replicate in cells of the upper and central respiratory tract, Fludase®is administered through oral inhalation to this same area. The fusion protein consists of two parts: a sialidase plus a cell-surface anchoring domain, designed to attach to the respiratory epithelium, thereby increasing retention time and drug potency.

Fludase is delivered by a simple generic device called “Cyclohaler,” click here to see it in action!

FLUDASE®EFFECTIVE

AGAINST ALL TYPES OF INFLUENZA INCLUDING H5N1

In a study preformed by the CDC, DAS181 was shown to prevent death in mice infected with the highly-lethal (to humans) A/VN/1203/04 strain of H5N1 influenza virus. DAS181 was used both as a prophylactic (see figure 2) and therapeutic agent (see figure 3) and showed remarkable efficacy in both applications.

FLUDASE® SHOWN EFFECTIVE AGAINST PARAINFLUENZA

Fludase®has shown efficacy against multiple parainfluenza (PIV) virus strains. This virus may cause serious respiratory infection similar to influenza in patients of all ages and is a known cause of community-acquired pneumonia. There is no approved vaccine or therapeutic for PIV. Other viruses may also show susceptibility to Fludase®.

FLUDASE® PRODUCT POSITIONING

Fludase®will be positioned for the prevention, treatment and containment of pandemic influenza due to strains such as H5N1. For seasonal use, Fludase®will be positioned for the prevention, treatment and containment of Influenza-Like Illness (ILI), the set of symptoms that drives a patient to seek medical attention complaining of “the Flu.” Extensive market research with physicians confirms the need for a broad-spectrum respiratory anti-viral agent. We believe Fludase® will offer an improved treatment option for all ILI patients, including those currently not treated, those treated with other anti-viral approaches, or, those inappropriately receiving broad-spectrum antibiotics.

CURRENLTY AVAILABLE INFLUENZA ANTIVIRALS

There are four flu antiviral drugs approved for use in the United States, two Neuraminidases: oseltamivir (brand name Tamiflu®); zanamivir (brand name Relenza®); and two Adamantanes: amantadine (Symmetrel®, also generic); and rimantadine (Flumadine®, also generic). Despite these being the only approved options for seasonal variations of influenza, and despite extensive stockpiling by governments for pandemic influenza, there are growing concerns regarding effectiveness due to emergence of resistance and due to side effects.

Influenza Resistance to Adamantanes and Neuraminidases
There is increasing concern about influenza viruses' resistance to antiviral drugs. Since 2005, scientists have known that seasonal flu viruses have become widely resistant to the Adamantanes, with at least 90% of H3N2 strains and at least 15% of H1N1 strains no longer susceptible to the drugs. In view of the rapid increase of Adamantane resistance among circulating influenza A viruses worldwide, these medications are no longer recommended by the CDC for prevention or treatment. This leaves only oseltamivir and the less widely used zanamivir as treatment options, and as a result, this has led to oseltamivir being the most commonly used influenza antiviral in the world. However, like the Adamantanes, oseltamivir resistance is now growing among seasonal influenza strains. In January of 2009, the Centers for Disease Control and Prevention reported that that 86 of the 88 H1N1 surveillance samples tested in the U.S. were resistant to oseltamivir. Responding to the rapid emerging of resistance to oseltamivir in the U.S., Dr. Kent A. Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center in New York said: “It’s quite shocking.” “We’ve never lost an antimicrobial this fast. It blew me away.” (Jan 8, 2009, New York Times) Similar rates of resistance to oseltamivir have been found around the world. 100%, or close to 100%, of surveillance samples taken during the Southern Hemisphere 2008 flu season were found resistant to oseltamivir (South Africa, 225 of 225, New Caledonia, 7 of 7, New Zealand, 2 of 2, Senegal 10 of 10, Australia 47 of 59, and Uruguay 13 of 26). Even more alarming is the possibility of emerging Avian influenza resistance. On January 8, 2009, the World Health Organization (WHO) reported that those who had died from contracting the H5N1 virus strain in Egypt showed moderate resistance to oseltamivir. An article in the New England Journal of Medicine from 2005 demonstrated that two Vietnamese girls who were being treated for H5N1 developed resistance to oseltamivir while on therapy. They went on to die. The responsible mutation, H274Y, is the same one found in the current resistant H1N1 seasonal virus (about which the New York Times was reporting).

Targeting Host, Not Virus, May Reduce Emergence of Resistance
Both the Neuraminidase and Adamantane classes of marketed drugs target a component of the influenza virus itself. Virtually all drugs currently in development, such as peramivir (Biocryst), T-705 (Toyama/Fuji), and CS-8958 (Biota/Daiichi-Sankyo), do as well. This targeting drives selection pressure, such that as these viruses mutate, which they do rapidly as a matter of course, viruses preferentially emerge that are resistant to these anti-virals. As indicated by the emergence of influenza resistance in both of these cases, a new approach is required. Unlike current antiviral compounds and vaccines, Fludase® targets human host receptors, not virus components, and thus carries a reduced risk of drug resistance due to lack of selection pressure. Extensive, prolonged nonclinical studies have not shown the development of any meaningful resistance.

Neuropsychiatric Events Associated with Neuraminidases
Neuropsychiatric events have also been associated with the use of both oseltamivir and zanamivir. Such events may have lead to the death of children in Japan. While the cause of these events has not been fully established, in 2008, the Food and Drug Administration recommended that the makers of both oseltamivir and zanamivir add a “Neuropsychiatric Event” warning to both drugs’ labels.

VACCINES

Inactivated or attenuated live human influenza vaccines are in worldwide use, especially for high-risk groups. However, these vaccines must be modified yearly to maintain efficacy due to constant viral mutation. Each year it may take up to 8 months before the updated or modified influenza vaccine is ready for use against the annual influenza epidemic. Past pandemics have spread to most continents within 6 months and future pandemics are expected to spread much faster due to international airline travel. Compounding the problem, it is impossible to predict the exact immune signatures of a pandemic virus strain in advance. For this reason, though a pre-pandemic vaccine has been approved and others are in development, it is not possible to ensure that such a vaccine will be protective for the specific pandemic strain that emerges. Indeed, the WHO director for initiative in vaccine research has cited an inability to predict whether the next pandemic will be caused by H5, H2, H7, or H9 virus as the reason for not stockpiling the currently-approved pre-pandemic vaccine.