專家建議FDA批准降低膽固醇新藥

An expert group recommended on Tuesday that the Food and Drug Administration approve a powerful new drug to protect against heart attacks. If approved, it would be the first in a major new class of medicines in a generation that significantly lower levels of cholesterol, the leading cause of heart disease.

週二，一批專家建議美國食品與藥品管理局（Food and Drug Administration，簡稱FDA）批准一種預防心肌梗死的強效新藥。如果獲得批准，該藥物將成爲一個新的重要藥物類別中，最近二三十年獲批的首例藥物。此類藥物能大幅降低膽固醇水平，而膽固醇是心臟病的主要誘因。

Dr. Joshua W. Knowles, a Stanford cardiologist, called the medicines “a triumph of the modern genetic revolution.”

斯坦福大學(Stanford)的心臟病學專家約書亞·W·諾爾斯(Joshua W. Knowles)博士稱，這些藥物是“現代基因革命的一次勝利”。

The idea for such drugs arose from genetic studies about a decade ago and has tantalized cardiologists ever since. Early results of clinical trials raised hopes that the therapies would be critical new additions to the treatment arsenal for those at risk of heart disease, the biggest killer of Americans.

研製這類藥物的想法來自於約10年前的基因研究成果，此後一直令心臟病學專家可望而不可即。初步的臨牀試驗結果帶來了希望，這些療法可能爲心臟病高危人羣的治療方法提供新的重要補充。心臟病是美國人的頭號殺手。

People who have taken them have seen their LDL cholesterol, the so-called bad cholesterol, plunge to remarkably low levels. But definitive evidence of the drugs’ effectiveness in reducing heart attacks and deaths will only come after large clinical trials are completed in 2017.

服用這些藥物的人已經發現體內的低密度脂蛋白(LDL)膽固醇顯著下降，LDL膽固醇也就是所謂的“壞膽固醇”。不過，這種藥物降低心梗和死亡風險的確鑿證據，要到2017年大規模臨牀試驗完成後纔可能出現。

The panel, in a 13 to 3 vote, recommended the approval of Sanofi and Regeneron Pharmaceuticals’ drug, alirocumab. On Wednesday, the committee will turn to Amgen’s drug, evolocumab. The F.D.A. usually follows the recommendations of its advisory panels, but not always. The agency says that if it approves the drugs based on their effects on cholesterol, the approval will not be rescinded even if trials now underway fail to show the drugs reduce the risk of heart attacks and deaths.

這個專家委員會以13比3的投票結果，建議批准賽諾菲(Sanofi)和瑞澤恩製藥公司(Regeneron Pharmaceuticals)的藥物alirocumab。週三，這個委員會將開始評估美國安進公司(Amgen)的藥物evolocumab。FDA通常會聽取諮詢委員會的建議，但也並非總是如此。該機構表示，如果根據它們降低膽固醇的效果而批准了這些藥物，那麼即使目前進行的試驗無法證明它們能降低心臟病和死亡風險，批准的決定也不會被撤銷。

Once a drug is approved doctors can prescribe it to patients other than those for whom it was intended, although insurers generally will not pay.

一旦某種藥物獲得批准，醫生就可以向該藥物目標人羣之外的其他患者開出該藥物的處方，不過保險公司一般不會買單。

The drugs are injected every two weeks or once a month, depending on the formulation. The companies are asking that they be approved for use in three groups: patients with high levels of LDL cholesterol who cannot lower it enough with statins, the mainstay drug for cholesterol lowering first introduced in the late 1980s; people at very high risk because they have already had a heart attack or have diabetes and cannot get their levels low enough with statins; and people with high levels of LDL who cannot tolerate statins. Doctors often aim for LDL levels of 70 for people at high risk.

這種藥物需要每兩週或每個月注射一次，取決於具體的處方。這些企業正在要求批准三種人使用該藥物：LDL膽固醇水平較高、且用他汀類藥物（主流的降膽固醇藥物，上世紀80年代末推出）無法充分降低其水平的患者；已經患有心梗或糖尿病、且無法用他汀類藥物充分降低膽固醇水平的高危人羣；LDL膽固醇水平較高且無法耐受他汀類藥物的的人羣。醫生通常認爲，LDL膽固醇水平達到70即爲高危人羣。

The problem for the expert group was to decide if there was enough evidence to approve the Sanofi drug without waiting for results from the large clinical trials. Those who voted no said drugs should not be approved until clinical trials establish their efficacy, and voiced the worry that people participating in the trials would drop out once the drugs were approved so they could be sure to get the medicine, not a placebo.

專家組面臨的問題是，在不等待大型臨牀試驗的結果的情況下，判斷目前是否有足夠的證據支持批准賽諾菲(Sanofi)。投反對票的人認爲，除非臨牀試驗證實了其功效，否則任何藥物都不應該被批准。他們還表達了這樣的擔憂，即一旦藥物被批准，參加臨牀試驗的人們就會退出試驗，因爲這樣他們就能夠確保自己服用的是藥物本身，而不是安慰劑。

“We need clinical outcomes,” said Dr. Peter Wilson of Emory University.

“我們需要臨牀結果，”埃默裏大學(Emory University)的皮特·威爾森(Peter Wilson)博士說。

Some on the panel felt comfortable recommending approval only for a narrow group of people with a genetic condition, heterozygousfamilial hypercholesterolemia, who cannot control their cholesterol with statins alone. Others favored allowing use of the drug by the much larger group of people at high risk of heart disease for whom statins are insufficient.

委員會的一些成員認爲，只可以批准存在基因缺陷的一小批患者服用這些藥物，即雜合子型家族性高膽固醇血癥患者。這類人無法單獨依靠他汀類藥物控制膽固醇。還有一些成員支持把藥物的適用範圍擴大到一個大得多的羣體，即他汀類藥物已經無法滿足其需求的心臟病高危人羣。

The group’s chairman, Dr. Robert J. Smith of Brown University, argued for broader availability of the drugs. He said he sees patients in his own practice with out of control cholesterol who are at very high risk because, for example, they have already had a heart attack. Two years is a long time for them to wait for clinical trial findings. “I am unwilling to subject patients to that wait,” Dr. Smith said.

委員會主席、布朗大學(Brown University)的羅伯特·J·史密斯(Robert J. Smith)博士呼籲在更大範圍內提供這種藥物。他說，自己在行醫過程中看到，一些膽固醇水平失控的患者處境十分危險，原因是他們可能已經患過心梗。爲了臨牀試驗結果再等待兩年對他們來說太漫長了。“我不願意讓病人就這麼等着，”史密斯博士說。

The companies and many independent cardiologists say they have reason to believe the drugs will perform as expected. Lowering LDL cholesterol has generally been found to protect against heart disease. And, they say, the drugs were designed to mimic mutations in a gene, PCSK9, that protects people from getting heart disease, even if they smoke or have high blood pressure.

這些企業和許多獨立心臟病學專家稱，他們有理由相信這些藥物會產生預期的效果。降低LDL膽固醇被普遍認爲能預防心臟病。此外，他們還說，這些藥物模仿了PCSK9基因突變，這種基因能防止人們罹患心臟病，哪怕他們吸菸或有高血壓。

But the drugs have caused trepidation among insurers and others who would have to pay the bills because the drugs are certain to be expensive — perhaps $10,000 a year — and millions of people are likely to qualify to take them if they are approved for the broader group. Sanofi estimates that 11 million Americans might qualify. Amgen puts the number at eight million.

不過，這些藥物已經引發了一些恐慌，比如必須爲它們買單的保險公司和其他人，以及該藥物獲准適用於更大羣體的話，上百萬名可能有資格服用這些藥物的患者。因爲這些藥物註定昂貴，也許每年要花1萬美元。賽諾菲估計，可能有1100萬美國人有資格接受該藥物。安進公司認爲這個數字是800萬。

So far, it looks like just about everyone who takes the new drugs responds. LDL cholesterol levels plunge by 40 to 65 percent, even if the starting level was achieved with a statin.

迄今爲止，似乎每一名使用了新藥的患者都見到了療效。LDL膽固醇水平下降了40%到65%，即使他們之前一直在服用他汀類藥物來控制膽固醇。

Safety studies so far have found the drugs seem to have no more side effects than a placebo but the large clinical trials are needed to get more substantial information.

目前的安全性研究表明，這些藥物的副作用似乎和安慰劑差不多，不過，在大型的臨牀實驗之後才能獲得更多實質性的信息。

Meanwhile, pharmaceutical companies see the tantalizing prospect of multibillion dollar blockbuster drugs, and are racing to get them to market as rapidly as possible. Sanofi bought an F.D.A.-backed voucher for $67.5 million that gave them an expedited review. The company says the F.D.A. agreed to decide whether to approve their drug by July 24. Amgen, which did not pay, expects an answer by Aug. 27, the company says. Pfizer also has a drug in this new class but it is further behind in development.

與此同時，製藥公司已經看到了價值數十億美元的重磅藥物的誘人前景，它們正在競相以最快的速度將其投放市場。賽諾菲以6750萬美元的價格購買了FDA的批文，可以獲得快速審覈。該公司表示，FDA同意在7月24日之前做出是否批准該藥物的決定。安進公司沒有花這筆錢，該公司表示，預計將在8月27日之前得到答案。輝瑞公司(Pfizer)也有一款這種類型的藥物，但研發進度要更慢。

Then there is the question of cost. The new drugs, like many new cancer drugs, are monoclonal antibodies, produced from living cells at great expense. The companies will not say what they plan to charge. But Dr. William Shrank, chief scientific officer at CVS Health, estimates they will cost $7,000 to $12,000 a year.

還有成本的問題。這些新藥就像許多新型抗癌藥物一樣，是單克隆抗體，它們是以高昂的成本用活體細胞製造的。這些公司不願透露藥品未來的定價。但CVS健康公司(CVS Health)的首席科學官威廉·史蘭克(William Shrank)估計，服用這種藥物一年將需要7000至1.2萬美元。

If drugs were restricted to those with dangerously high cholesterol levels who cannot get their LDL low enough with statins, the cost would be $16 billion, he estimated. If people who are intolerant to statins are included, that would add another $20 billion. If people with a history of heart disease are included, the bill for the drugs rises another $150 billion.

他估計，如果藥物僅限於那些膽固醇水平過高且無法利用他汀類藥物降低膽固醇水平的人，總成本將達到160億美元。如果包括無法耐受他汀類藥物的人，成本將增加200億美元。算上有心臟病史的人，成本將再升高1500億美元。

“Managed pharmacy care, indeed the health care system, has never seen a challenge like this to our resilience in absorbing costs,” Dr. Shrank wrote in Health Affairs.

史蘭克在健康事務(Health Affairs)網站上寫道：“保健藥學管理體系吸收成本的能力，實際上整個衛生體系吸收成本的能力，都沒有遇到過這樣的嚴峻挑戰。”