研发“沉默杀手”克星

Big pharma thinks it has spotted its next big opportunity — an untreatable silent killer that affects millions of people.大型制药企业指出，它们找到了下一个根本性机会——一个影响数以百万计的人、无法被医治的绝望刺客。In recent months, large drugmakers including Allergan, Gilead and Novartis have collectively spent billions of dollars acquiring or licensing medicines designed to treat a liver disease that few people have heard of — non-alcoholic steatohepatitis, or Nash.近几个月，艾尔健(Allergan)、吉利德(Gilead)和诺华(Novartis)特一起耗资数十亿美元并购一类药物或者取得其许可。这类药物针对的是一种很少有人听闻过的肝脏疾病——非酒精性脂肪性肝炎(Nash)。

This advanced form of fatty liver disease causes scarring and inflammation of the liver and is thought to affect more than 16m people in the US, according to Bernstein, the investment bank.根据投行伯恩斯坦(Bernstein)的数据，这种晚期脂肪肝病会造成肝脏瘢痕和炎症，据信在美国有逾1600万人患有这种疾病。In the most serious cases, the illness causes fatal cirrhosis, while also increasing a person’s chances of developing liver cancer or heart disease. The US Centers for Disease Control believes there are roughly 20,000 fatalities each year from chronic liver disease or cirrhosis that are not related to alcoholism.在最相当严重的病例中，这种疾病不会造成可怕的肝硬化，还不会提升患者患上肝癌或者心脏疾病的几率。美国疾病掌控防治中心(CDC)指出，每年大约有2万人病死与酒精中毒牵涉到的慢性肝病或者肝硬化。

Drugmakers are betting that the number of people with Nash — which is more common in overweight people — will rise dramatically in the coming years because of the worldwide obesity epidemic. Some analysts are predicting the global market for Nash medicines will be worth as much as $35bn a year at its peak.制药商正在押注，由于世界范围内肥胖症的风行，未来数年患有非酒精性脂肪性肝炎的人将经常出现戏剧性下降（此病更加常见于超载人群）。一些分析师预测，化疗该病的药品的全球市场将超过每年350亿美元的峰值。There are no approved drugs to treat the condition but pharmaceutical groups are studying more than 25 experimental compounds in humans, with four medicines either being studied in phase III clinical trials, or about to enter this final stage of testing.目前还没获批的对症药物，但药企正在对25种实验化合物展开人体试验，有4种药物或是正在展开Ⅲ期临床试验，或是将要转入这一最后试验阶段。Of the large drugmakers, Allergan is furthest ahead, having spent $1.7bn to acquire Tobira, a San Francisco biotech group, in November last year. Tobira’s main medicine, Cenicriviroc, will enter phase three trials later this year with results expected as early as 2019.艾尔健是大型制药企业中的先行者。

该公司去年11月耗资17亿美元并购旧金山生物科技公司Tobira。Tobira的主要药物Cenicriviroc将在今年晚些时候转入三期试验，预计最先将在2019年出有结果。Allergan recently acquired another smaller Nash-focused drugmaker, Arkana, for $50m.艾尔健最近耗资5000万美元并购了另一家探讨于非酒精性脂肪性肝炎药物的规模更加小的制药公司Arkana。“Nash is now the leading cause of liver cirrhosis and cancer, having taken over from hepatitis C,” says Dr David Nicholson, Allergan’s chief research and development officer. “And at the moment, there’s nothing out there to treat it.”“非酒精性脂肪性肝炎现在早已代替了丙型肝炎，沦为肝硬化和肝癌的主因，”艾尔健首席研发官戴维?尼科尔森(David Nicholson)博士回应，“而眼下还没对症的药物。

”Gilead has entered the field too, recently acquiring Nimbus for up to $1.2bn, while also investing heavily in its internal research efforts. The West Coast-based biotech company has already had huge success with its treatments for hepatitis C, another potentially fatal liver disease.吉利德也转入了这一领域，该公司最近开支最少12亿美元并购Nimbus，同时乘机投资于内部研发工作。总部坐落于美国西海岸的这家生物科技公司早已在丙肝（另一种潜在可怕的肝脏疾病）药物上获得了根本性顺利。Several other well-known pharmaceutical groups, including Novo Nordisk and Shire are working on Nash drugs at an earlier stage of development.诺和诺德(Novo Nordisk)和Shire等其他几家著名药企对非酒精性脂肪性肝炎药物的研发还正处于较早于阶段。

However, the two companies that are most advanced do not come from the ranks of big pharma: Intercept Therapeutics, a New York-based biotech group, and GenFit, its French rival.然而，目前在该领域获得仅次于进展的两家公司并非大型药企：纽约生物科技集团Intercept Therapeutics，及其法国竞争对手GenFit。Shares in Intercept jumped 13 per cent last week after the company said it had redesigned a late-stage clinical trial of its drug, obeticholic acid, in a way that would make it easier for the study to succeed.上周Intercept的股价上涨13%，此前该公司宣告新的设计了其药物奥贝胆酸(obeticholic acid)的临床试验最后阶段，使其研发更容易顺利。Following discussions with the US Food and Drug Administration, Intercept said the trial must now show that the drug can either resolve Nash or improve “fibrosis” — the medical term for liver scarring. Previously, the company would have had to prove the medicine could do both.在与美国食品药品监督管理局(FDA)辩论后，Intercept回应，试验必需表明该药需要化疗非酒精性脂肪性肝炎，或者提高“肝纤维化”（肝脏瘢痕的医学名词）症状。

此前，该公司必须证明该药同时不具备这两种疗效。Intercept also said it would be able to analyse the data once it had enrolled 750 patients, rather than 1,400, after the process of recruiting patients to the trial took longer than the company had originally expected.Intercept还回应，一旦召募到750名患者，而非1400名，就可以开始分析数据。此前召募参与试验的患者耗时远超过了该公司的预期。The changes reflect the flexibility of regulators at the FDA, who want to encourage drugmakers to invest in researching medicines for the untreatable condition before the number of sufferers increases rapidly.这些更改体现出有美国食品药品监督管理局监管者的灵活性，他们期望在患者数量较慢下降之前，希望制药商研发出有针对这种目前无法医治的病症的药物。

However, the sluggish recruitment to Intercept’s trial is indicative of one of the biggest hurdles facing Nash drugmakers: the disease is very difficult to diagnose.然而，Intercept在召募参与试验的患者方面进展较慢，指出研发非酒精性脂肪性肝炎药物的制药商面对的仅次于障碍之一：该疾病很难临床。The vast majority of people do not realise they have the “silent” disease, which only causes symptoms such as jaundice, fatigue and weight loss in the very late stages.绝大多数人未意识到他们患上了这种“绝望”的疾病，即使在这种疾病进展到晚期，患者的症状也只有黄疸、疲惫和体重减轻。

Doctors sometimes suspect a patient has Nash when they have elevated liver enzymes in their blood or when they spot abnormalities during ultrasound scans.如果患者血液中的肝酶水平增高，或者在超声波扫瞄中发现异常，医生们有时不会猜测患者患有这种疾病。But the only surefire way of diagnosing the disease is to carry out a liver biopsy — a complex, invasive procedure that requires an anaesthetic. In rare cases, the biopsy can cause bleeding that requires a transfusion or surgery.但唯一的发病方法是展开肝前列腺——一种必须麻醉的侵入性简单操作者。

在极少数病例中，前列腺有可能造成必须展开器官移植或外科手术的发炎。Many patients are reluctant to undergo the procedure, which poses a difficulty not just for recruiting them to clinical trials, but also convincing people in the real world to get tested for the condition.很多病人不愿拒绝接受前列腺，这不仅给召募参与临床试验的患者带给了艰难，也意味著在现实世界中无法劝说人们拒绝接受检测，以发病他们否患上该病。Drugmakers are hoping that less invasive tests will be developed that use biological clues or “biomarkers” to diagnose the disease without the need for a biopsy.制药商期望研发出有利用生物线索（即“生物标记物”）的非侵入性检测方法来临床这种疾病，从而仍然必须前列腺。

“We really believe that there will be big breakthroughs that will make it much easier for physicians to diagnose the disease and subsequently to utilise the drugs in development,” says Dr Nicholson.“我们相信将不会构建重大突破，让医生更容易临床这种疾病，然后充分利用这些正在研发中的药物，”艾尔健的尼科尔森博士说道。One option is a simple breath test, according to Dr Ilan Yaron, chief medical officer of Tiz Pharma, a London-based biotech group that is about to start testing its Nash drug in humans. “The FDA does not recognise these tests yet, but it will in time,” he says.选项之一是展开非常简单的排便检测，将要开始对该病药物展开人体试验的伦敦生物科技公司Tiz Pharma的首席医疗官伊兰?亚龙(Ilan Yaron)说道，“美国食品药品监督管理局目前还不接纳这些检测方法，但将来不会接纳的。”However, even if drugmakers find a reliable, non-invasive way of diagnosing the disease, there is no guarantee that Nash sufferers will rush to start taking their medicines.然而，就算制药商寻找了一种可信的非侵入性临床方法，也无法确保该病患者不会竞相开始服药。

The disease progresses slowly and many sufferers will die of something else; given the lack of symptoms, people could be wary of taking a drug for life when they feel perfectly well.这种疾病发展缓慢，很多患者不会病死别的原因；考虑到症状较较少，对于在自己感觉良好的时候必须终生服用一种药物，人们有可能抱着有戒心。“I’m sceptical as to whether this is actually needed for most people,” says Ronny Gal, analyst at Bernstein. “You’re essentially trying to put into chronic treatment forever a broad population that will probably never develop the most serious form of the disease.”“我猜测大多数人否知道必须这个，”伯恩斯坦分析师龙尼?加尔(Ronny Gal)回应，“你实质上是在企图让一大群人永久性地拒绝接受慢性化疗，而他们的疾病很有可能最后会发展到最相当严重的程度。”Cash-strapped healthcare systems could resist paying for the drug in all but the sickest patients, predicts Mr Gal. These number approximately 1.5m in the US.加尔预测，除去那些病情最相当严重的患者，经费紧张的医疗保健系统可能会拒绝接受缴纳这种药物的药费。在美国，这些患者的数量约为150万。

For that reason, he believes the market for Nash drugs will be much smaller than many others on Wall Street are expecting, and is pencilling in peak sales of $8bn for what he describes as a “midsize condition”.出于这种原因，他指出，该病的市场将比华尔街其他许多分析师预测的大得多。对于他称之为的这种“中度疾病”，他预计销售额峰值将超过80亿美元。

“If you take all the people with advanced Nash and ask how many people will end up becoming seriously ill in their lifetimes, the number could actually be very small,” he says.“如果你统计资料一下所有晚期非酒精性脂肪性肝炎患者人数，然后问一问有多少人在有生之年不会病重，这个数字实质上有可能十分小，”他说道。

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