研發“沉默殺手”剋星

Big pharma thinks it has spotted its next big opportunity — an untreatable silent killer that affects millions of people.

大型製藥企業認爲，它們發現了下一個重大機會——一個影響數以百萬計的人、無法被治癒的沉默殺手。

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.

近幾個月，艾爾健(Allergan)、吉利德(Gilead)和諾華(Novartis)加起來斥資數十億美元收購一類藥物或者獲得其許可。這類藥物針對的是一種很少有人聽說過的肝臟疾病——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.

根據投行伯恩斯坦(Bernstein)的數據，這種晚期脂肪肝病會導致肝臟瘢痕和炎症，據信在美國有逾1600萬人罹患這種疾病。

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.

在最嚴重的病例中，這種疾病會導致致命的肝硬化，還會提高患者患上肝癌或者心臟疾病的機率。美國疾病控制預防中心(CDC)認爲，每年約有2萬人死於與酒精中毒無關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.

製藥商正在押注，由於世界範圍內肥胖症的流行，未來數年罹患非酒精性脂肪性肝炎的人將出現戲劇性上升（此病更多見於超重人羣）。一些分析師預測，治療該病的藥品的全球市場將達到每年350億美元的峯值。

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.

目前還沒有獲批的對症藥物，但藥企正在對25種實驗化合物進行人體試驗，有4種藥物或是正在進行Ⅲ期臨牀試驗，或是即將進入這一最終試驗階段。

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.

艾爾健是大型製藥企業中的先行者。該公司去年11月斥資17億美元收購舊金山生物科技公司Tobira。Tobira的主要藥物Cenicriviroc將在今年晚些時候進入三期試驗，預計最早將在2019年出結果。

Allergan recently acquired another smaller Nash-focused drugmaker, Arkana, for $50m.

艾爾健最近斥資5000萬美元收購了另一家聚焦於非酒精性脂肪性肝炎藥物的規模更小的製藥公司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現在已經取代了丙型肝炎，成爲肝硬化和肝癌的主因，”艾爾健首席研發官戴維?尼科爾森(David Nicholson)博士表示，“而眼下還沒有對症的藥物。”

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.

吉利德也進入了這一領域，該公司最近支出至多12億美元收購Nimbus，同時大舉投資於內部研發工作。總部位於美國西海岸的這家生物科技公司已經在丙肝（另一種潛在致命的肝臟疾病）藥物上取得了重大成功。

Several other well-known pharmaceutical groups, including Novo Nordisk and Shire are working on Nash drugs at an earlier stage of development.

諾和諾德(Novo Nordisk)和Shire等其他幾家知名藥企對非酒精性脂肪性肝炎藥物的研發還處於較早階段。

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，目前在該領域取得最大進展的兩家公司並非大型藥企：紐約生物科技集團Intercept Therapeutics，及其法國競爭對手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.

上週Intercept的股價飆漲13%，此前該公司宣佈重新設計了其藥物奧貝膽酸(obeticholic acid)的臨牀試驗最終階段，使其研發更容易成功。

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.

在與美國食品藥品監督管理局(FDA)討論後，Intercept表示，試驗必須顯示該藥能夠治療非酒精性脂肪性肝炎，或者改善“肝纖維化”（肝臟瘢痕的醫學名詞）症狀。此前，該公司需要證明該藥同時具備這兩種療效。

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還表示，一旦招募到750名患者，而非1400名，就可以開始分析數據。此前招募參加試驗的患者耗時超出了該公司的預期。

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.

這些變更反映出美國食品藥品監督管理局監管者的靈活性，他們希望在患者數量快速上升之前，鼓勵製藥商研發出針對這種目前無法治癒的病症的藥物。

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在招募參加試驗的患者方面進展緩慢，表明研發非酒精性脂肪性肝炎藥物的製藥商面臨的最大障礙之一：該疾病很難診斷。

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.

絕大多數人並未意識到他們患上了這種“沉默”的疾病，即使在這種疾病進展到晚期，患者的症狀也只有黃疸、疲勞和體重減輕。

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升高，或者在超聲波掃描中發現異常，醫生們有時會懷疑患者罹患這種疾病。

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.

但唯一的確診方法是進行肝活檢——一種需要麻醉的侵入性複雜操作。在極少數病例中，活檢可能導致需要進行輸血或外科手術的出血。

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.

很多病人不願接受活檢，這不僅給招募參加臨牀試驗的患者帶來了困難，也意味着在現實世界中難以說服人們接受檢測，以確診他們是否患有該病。

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.

製藥商希望開發出利用生物線索（即“生物標記物”）的非侵入性檢測方法來診斷這種疾病，從而不再需要活檢。

“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.

“我們確信將會實現重大突破，讓醫生更容易診斷這種疾病，然後充分利用這些正在研發中的藥物，”艾爾健的尼科爾森博士說。

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.

選項之一是進行簡單的呼吸檢測，即將開始對該病藥物進行人體試驗的倫敦生物科技公司Tiz Pharma的首席醫療官伊蘭?亞龍(Ilan Yaron)說，“美國食品藥品監督管理局目前還不認可這些檢測方法，但將來會認可的。”

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，就算製藥商找到了一種可靠的非侵入性診斷方法，也無法保證該病患者會競相開始服藥。

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.

這種疾病發展緩慢，很多患者會死於別的原因；考慮到症狀較少，對於在自己感覺良好的時候需要終生服用一種藥物，人們可能抱有戒心。

“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.”

“我懷疑大多數人是否真的需要這個，”伯恩斯坦分析師龍尼?加爾(Ronny Gal)表示，“你實際上是在試圖讓一大羣人永久性地接受慢性治療，而他們的疾病很可能最終不會發展到最嚴重的程度。”

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.

加爾預測，除去那些病情最嚴重的患者，經費緊張的醫療保健系統可能會拒絕支付這種藥物的藥費。在美國，這些患者的數量大約爲150萬。

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”.

出於這種原因，他認爲，該病的市場將比華爾街其他許多分析師預測的小得多。對於他所稱的這種“中度疾病”，他預計銷售額峯值將達到80億美元。

“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.

“如果你統計一下所有晚期非酒精性脂肪性肝炎患者人數，然後問一問有多少人在有生之年會病重，這個數字實際上可能非常小，”他說。