Demand Soars For Fruit Used In Bird-Flu Drug
Taking a lunchtime break from examining his fields, a flushed Chen Jinning tips a tumbler at fellow farmers and bellows: "To bajiao," the Chinese word for star anise, the coin-sized fruit used in everything from Asian soup to French alcoholic drinks.
Farmers at the table offer toasts to prosperity, to traditional agricultural methods, even to Swiss pharmaceutical giant Roche Holding AG, splattering foamy beer onto the plastic tablecloth.
It didn't take much alcohol to make Mr. Chen and his friends giddy. Just 10 days ago, these farmers faced such low prices for star anise, some didn't bother to harvest their crops. Now, interest in the eight-pointed star anise has soared following disclosures earlier this month that its seed pod forms the genesis for oseltamivir, the generic name for Roche's drug Tamiflu. The drug is considered one of the possible defenses against an outbreak of human-to-human avian flu.
Wholesale prices for the fruit, which is chiefly grown in southern China, have jumped 40% to about 0.7 yuan (about eight U.S. cents) per kilogram -- or 18 U.S. cents per pound -- in little over a week. Prices for the acid extracted from star anise and used directly in the drug's manufacture has jumped tenfold to $600 per kilogram over the past month.
Star anise, used in an avian-flu drug, is sold at a Chinese spice market.
The heightened interest follows the recent outbreak of avian flu in poultry, which has spread from Asia to Europe. While cases of humans contracting the disease are relatively few, doctors fear the disease could mutate into a highly infectious strain against which humans have little resistance.
Many governments don't stock enough supplies of Tamiflu to deal with such a scenario and are pressuring Roche to increase production. Companies rushing to replicate Tamiflu are flocking to China seeking one of the main ingredients in star anise -- a chemical compound called shikimic acid that the fruit contains in abundant supply. The acid forms the basic building block for making Tamiflu.
While Roche has developed at least one other way of producing shikimic acid that doesn't require the use of star anise, extracting it from the plant remains a key way to make the drug, experts say. John Frost, a chemistry professor at Michigan State University who licensed to Roche the technology for creating shikimic acid through fermentation in a laboratory, calls extraction of the acid from star anise "a marvelous process. This high concentration in one product isn't common."
Until now, few star anise farmers knew their produce played such an important role in high-tech pharmacology, although the fruit has been used in traditional Chinese cold medicine for thousands of years. "We thought of it mostly as a cooking spice," says Mr. Chen, a farmer for about 18 years. Thanks to the recent publicity, the 43-year-old is fielding calls from buyers as far away as Switzerland and France. "It's like I am dealing with a whole new product," he says.
Star anise, which is tough-skinned and green in color, grows on leafy trees that take between six to 10 years to bear fruit. Aside from some fertilization treatments, the crops are relatively easy to tend until harvest, from August through September -- when the trees produce their fragrant fruit. Workers are paid about $3 a day to scramble up the misty hills to pluck the pods. The harvest is blanched in huge wood-fired vats and dried.
Supplies are high this year. China's Star Anise Association says it currently has some 10 to 20 million kilograms of dried star anise in stock, although it is unclear exactly how much of this is best suited for the chemical process specific to Tamiflu.
Nevertheless, Roche's competitors who are copying Tamiflu say they have difficulty securing enough shikimic acid from suppliers in China. In the past month, demand for shikimic acid "has gone through the roof," says Y.K. Hamid, chief executive of Mumbai, India-based Cipla Ltd., which is making a generic equivalent of Tamiflu. Cipla has secured between 200 to 300 kilograms of shikimic acid, enough for some 300,000 doses, from a Chinese supplier, according to a person familiar with the matter.
With little demand for the acid until recently, there are few companies doing the extraction. Many are small firms clustered around the central Chinese city of Xian which mostly extract the acid for use in anti-inflammatory medication.
Wang Hanping, a sales representative at Tianyuan Biological Co., which now makes hundreds of kilograms of shikimic acid monthly using star anise, says the chemical was previously "just a minor product." Now, production capacity is booked until the end of the year and the company can't handle new orders, Mr. Wang says. Farmers say wholesale prices are still relatively low. "This isn't the way to get rich," laments Mr. Chen.
A number of Roche's competitors say the acid is in short supply because the Swiss company has cornered as much as 90% of the supply. People familiar with the matter say Roche's main Chinese supplier is Beijing Gingko Group, which has six factories across China. Beijing Gingko declined to comment.
In an email response, a Roche spokesman said that the company buys "a large portion of the anise available in order to produce shikimic acid." However, Roche said it is not 90% of the star anise cultivated.
When Tamiflu was invented in 1996, the drug used the more costly quinic acid taken from the bark of the chinchona tree. Scientists who created the drug at Foster City, Calif.-based Gilead Sciences Inc. subsequently sold the rights to Roche.
Roche pharmacist Martin Karpf improved the original manufacturing process by substituting shikimic acid. People familiar with the matter say Dr. Karpf's work shortened the Tamiflu production process to about 10 steps from 16, and it enabled the company to forge ahead of rivals such as GlaxoSmithKline, which produces a rival drug called Relenza.
Some scientists say it is ironic that an ingredient for a drug to fight bird flu is found in south China, the same region where the disease is believed to have originated. "I guess God made it that way," jokes Chao Yu-sheng, director of biotechnology at Taiwan's National Health Research Institutes, which is working with ScinoPharm Taiwan Ltd. to roll out a generic version of Tamiflu in the next three to five months using shikimic acid derived from star anise. "There's always a yin and a yang."
禽流感疫情让八角变成了抢手货
歇晌的时候，刚在自家田里忙过农活的陈金宁将一大杯酒推向他的一位乡亲，脸红脖子粗地嚷道："为八角干杯！"八角是八角茴香的中国名字，这种硬币大小的果实有多种用途，亚洲人用它做汤料，法国的酿酒业也要用到它。
把酒言欢的农人们在为他们的幸福干杯，在为他们的传统农业耕作方式干杯，甚至也在为瑞士的制药业巨头罗氏公司 (Roche Holding AG)干杯，酒杯里泛著泡沫的啤酒频频地溅落到桌上的塑料桌布上。
酒不醉人人自醉。就在10天前，这些八角的价格还低得可伶，让很多人甚至懒得收割。而眼下，自10月初有报导称八角是罗氏公司抗病毒药物达菲(Tamiflu)的重要原料后，抢购八角之风应时而起。达菲被普遍认为是可能抵御禽流感在人群之间传播的重要药物。
一周内，八角的批发价格猛涨40%，至每公斤人民币0.7元（合8美分），即每磅18美分。一个月间，从八角中提取的、可直接用于达菲生产的莽草酸价格翻了十倍，达到每公斤600美元。
最近禽流感在亚洲和欧洲的蔓延引起了全世界的广泛关注。虽然人类目前感染禽流感的病例寥寥无几，但医学界担心，这种病毒可能会发生变异，转化为人类难以抵抗的极具传染性的病毒。
很多国家政府尚未储备足够的达菲以供应急之需，它们正在向罗氏公司施加压力，要求其扩大产量。与此同时，寻求生产达菲仿制药的企业也蜂拥涌入中国采购八角，以期从八角中获取达菲的基础原料莽草酸。 专家表示，虽然罗氏公司已开发出至少一种其他办法生产莽草酸，但从八角提取该成分仍是生产达菲的主要途径。密歇根州立大学(Michigan State University)化学教授约翰o弗罗斯特(John Frost)将在实验室通过发酵生产莽草酸的这一技术授权给了罗氏，他表示，从八角中提取莽草酸简直是"不可思议"。它的含量之高绝不多见。
尽管中国传统医药界使用八角治疗感冒已有数千年历史，但直到最近，这些种植八角的农民才知道，八角还会在高科技制药行业有如此举足轻重的作用。"我们以为它主要用作烹饪调料，"从农18年之久的陈金宁说。最近的信息公布后，远自瑞士和法国的电话很快让陈金宁应接不暇。他说，他就好像在卖一种全新的产品一样。
八角属双子叶植物，叶革质、绿色，种植后6至10年开花结果。除适当施肥外，它种植起来相对容易，收割季通常在八至九月间。当地的收割工人每天收入3美元左右，攀上云雾缭绕的高山，采下八角果实，然后晾干保存。
今年的供给非常充足。中国八角协会表示，目前的干八角库存为1,000万至2,000万公斤，但目前尚不清楚有多少最适合用于达菲的生产。 然而，力争生产达菲仿制药的罗氏竞争对手们却表示，他们很难从中国的供应商处获得足够的莽草酸。一个月来，莽草酸的需求已经"冲破了屋顶，"印度公司Cipla Ltd.的首席执行长Y.K. Hamid说。该公司正在生产达菲的仿制药。据知情人士称，Cipla已经从中国供应商获得200至300公斤莽草酸，足够生产30万剂达菲仿制药。
由于以往莽草酸需求稀少，从事莽草酸提取的公司也屈指可数。它们主要是集中在西安市周围的一些小公司，提取的莽草酸多数用于生产消炎药。
天源生物(Tianyuan Biological Co.)的销售代表王汉平表示，以前，莽草酸只是一个次要产品。该公司每月从八角中提取数百公斤莽草酸。王汉平说，公司目前接到的订单已经排到了年底，眼下无法再处理新的订单。而农民们却表示，批发价仍然相对较低。陈金宁说，这还不能被作为致富之路。 罗氏的很多竞争对手称，莽草酸供给短缺是因为罗氏已经独占了90%的市场供应。据知情人士透露，罗氏在中国的主要供应商是北京绿色金可生物技术有限公司(Beijing Gingko Group)。金可生物的发言人拒绝发表评论。
罗氏发言人通过电子邮件对记者答复称，公司收购了大量八角以用于生产莽草酸。但罗氏表示，并没有囤积90%的八角产量。 1996年最初发明达菲时，其主要成分是从金鸡纳树树皮中提取的、较为昂贵的奎尼酸。位于加州的Gilead Sciences Inc.首先研制出该种药物，随后将专利权卖给了罗氏。
罗氏药剂师马丁o卡普夫(Martin Karpf)通过以莽草酸代替奎尼酸改善了最初的生产过程。知情人士称，卡普夫的成果使达菲的生产过程由16步缩短为10步，让罗氏抢在葛兰素史克(Glaxosmithkline)之前推出了此类药物。葛兰素史克生产达菲的竞争性药物瑞乐沙(Relenza)。
一些科学家称，具有讽刺意味的是，盛产八角的中国南方恰恰也正是中国禽流感的发源地。"我觉得老天就是这样安排的，"台湾国家卫生研究院(National Health Research Institutes)生物技术部负责人赵宇生开玩笑说。未来三至五个月卫生研究院将与台湾神隆股份有限公司(ScinoPharm Taiwan Ltd.)一道，使用从八角中提取的莽草酸开发达菲的仿制药。
