美国国家公共电台 NPR--FDA seems poised to approve a new drug for ALS, but does it work?

FDA seems poised¹ to approve a new drug for ALS, but does it work?

Transcript²

The Food and Drug Administration is likely to approve a controversial new drug for ALS by the end of the month.

But it's still not clear whether the drug, called AMX0035, truly helps people with ALS, a rare and fatal neurological disorder³ that eventually leaves a person unable to walk, talk, swallow and breathe.

In March, the FDA's Peripheral⁴ and Central Nervous System Drugs Advisory⁵ Committee concluded that a study of 137 ALS patients did not provide "substantial evidence" that AMX0035 was effective.

Then in September, after prodding⁶ from FDA officials and an email campaign by patients and their families, the same committee reconvened, and this time recommended approving the drug.

The FDA, which usually follows advisory committee recommendations, has indicated it will make a decision by Sept. 29.

An approval is more likely now that it would have been decades ago, says Holly⁷ Fernandez Lynch, an assistant professor of medical ethics⁸ and health policy at the University of Pennsylvania.

"The trajectory⁹ at FDA has been increased willingness to accept weaker evidence," she says.

Two old products, one new drug

AMX0035 is a combination of two existing products. One is a dietary supplement called taurursodiol, which can be purchased online.The other is a prescription¹⁰ drug called sodium¹¹ phenylbutyrate, which is used to treat a rare type of metabolic¹² disorder.

The combination is meant to slow down ALS, which gradually destroys cells in the brain and spinal¹³ cord that control voluntary muscle movement.

AMX0035 was developed by Amylyx— a company based in Cambridge, Mass. that was founded in 2013 by two graduates of Brown University.

Amylyx sought FDA approval of its drug based on a single study of 137 patients with ALS. The results suggested that AMX0035 could extend patients' lives by several months.

But at a public meeting in March, most experts on the FDA's advisory committee said they were unconvinced by the study, called Centaur¹⁴.

"There are many features of Centaur that limit its persuasiveness," said Dr. G. Caleb Alexander, an epidemiologist at Johns Hopkins University.

"The applicant¹⁵ hasn't provided robust¹⁶ evidence," said Dr. Bryan Traynor, a neurologist at the National Institute on Aging.

"The data isn't as strong as we would hope," said Dr. Liana Apostolova, an Alzheimer's expert at Indiana University.

The study was "problematic," said Dr. Kenneth H. Fischbeck, a neurogenetics researcher at the National Institutes of Health.

It "did not meet the threshold," said Dr. Thomas J. Montine, a pathologist at Stanford University.

"This study, on its own, doesn't establish that this drug is effective in the treatment of ALS," said Dr. Robert C. Alexander, chief scientific officer of the Alzheimer's Prevention Initiative, led by the Banner Alzheimer's Institute.

All six of those committee members voted no, when asked whether the evidence showed the drug was effective. Four other committee members voted yes.

Advice to the advisors¹⁷

Typically, that kind of response would have been the end of it, at least until Amylyx was ready to present data from a much larger study, which is already underway.

But after the March meeting, ALS patients and family members took to the Internet.

"There were thousands of emails that went to the [FDA] commissioner's office," says Neil Thakur, chief mission officer at the ALS Association, which helped fund the Amylyx study. "There were over 1,100 comments that went to the advisory committee themselves, and also there was a sustained effort from ALS clinical scientific leaders."

The small clinical trial does have flaws, Thakur said, but the advisory committee should have been willing to overlook those when it first reviewed the evidence in the spring.

"They were asking to hold that drug to the same standard they would hold any drug for any disease that wasn't fatal and had lots of effective treatments," he says.

Sponsor Message

Right now, ALS patients are offered variants¹⁸ of just two drugs: edaravone and riluzole. And even with these drug treatments, they typically die within two to five years after a diagnosis¹⁹.

From no to yes

The email campaign by ALS patients seemed to have an effect on some FDA officials.

Early this month, the agency took the unusual step of reconvening its advisory committee to reconsider the Amylyx drug. And this time, the FDA encouraged committee members to take a different perspective, Thakur says.

"This committee, it was clear that they were being asked to make a decision taking into account the available treatments and the needs of the ALS community," he says.

The committee also received some additional data on patients in the Amylyx study, and data from a study of Alzheimer's patients who took AMX0035.

When the committee held its second public meeting on the drug, they were offered guidance from Dr. Billy Dunn, who directs the FDA's Office of Neuroscience. He urged them to consider the plight²⁰ of patients with ALS, and suggested his agency was open to approving the drug.

"For these serious diseases, like ALS and so many other neurological diseases, the maximum degree of regulatory flexibility²¹ is operational," he said.

The FDA even revised its question to the committee. Instead of asking whether the drug was effective, they asked simply whether it should be approved.

After listening — instead of six no votes, seven of nine committee members decided²² to vote yes.

Echos of Aduhelm?

The process leading to the yes vote was "fishy," says Fernandez Lynch, the bioethicist at UPenn.

"The very cynical²³ version of this is that there was some kind of goal of manipulating the advisory committee to vote in a different way," she says.

"They were swayed by this concern that they might be making the wrong judgment²⁴ if they recommended FDA not to approve this product," she says. "But nobody, as far as I heard, said this drug meets the substantial evidence standard."

The substantial evidence standard was also in question when the FDA was considering the controversial Alzheimer's drug Aduhelm. The FDA approved that drug last year despite an overwhelming vote from the advisory committee that the standard had not been met.

If AMX0035 is approved, that could send troubling message to pharmaceutical²⁵ companies, Lynch says.

"The message to companies is that you don't have to show that your drug works," she says. "You have to do the bare minimum to show that it might work."

1 poised   

a.摆好姿势不动的

参考例句：

• The hawk poised in mid-air ready to swoop. 老鹰在半空中盘旋，准备俯冲。
• Tina was tense, her hand poised over the telephone. 蒂娜心情紧张，手悬在电话机上。

2 transcript   

n.抄本，誊本，副本，肄业证书

参考例句：

• A transcript of the tapes was presented as evidence in court.一份录音带的文字本作为证据被呈交法庭。
• They wouldn't let me have a transcript of the interview.他们拒绝给我一份采访的文字整理稿。

3 disorder   

n.紊乱，混乱；骚动，骚乱；疾病，失调

参考例句：

• When returning back,he discovered the room to be in disorder.回家后，他发现屋子里乱七八糟。
• It contained a vast number of letters in great disorder.里面七零八落地装着许多信件。

4 peripheral   

adj.周边的，外围的

参考例句：

• We dealt with the peripheral aspects of a cost reduction program.我们谈到了降低成本计划的一些外围问题。
• The hotel provides the clerk the service and the peripheral traveling consultation.旅舍提供票务服务和周边旅游咨询。

5 advisory   

adj.劝告的，忠告的，顾问的，提供咨询

参考例句：

• I have worked in an advisory capacity with many hospitals.我曾在多家医院做过顾问工作。
• He was appointed to the advisory committee last month.他上个月获任命为顾问委员会委员。

6 prodding   

v.刺，戳( prod的现在分词 )；刺激；促使；（用手指或尖物）戳

参考例句：

• He needed no prodding. 他不用督促。
• The boy is prodding the animal with a needle. 那男孩正用一根针刺那动物。 来自《现代英汉综合大词典》

7 holly   

n.[植]冬青属灌木

参考例句：

• I recently acquired some wood from a holly tree.最近我从一棵冬青树上弄了些木料。
• People often decorate their houses with holly at Christmas.人们总是在圣诞节时用冬青来装饰房屋。

8 ethics   

n.伦理学；伦理观，道德标准

参考例句：

• The ethics of his profession don't permit him to do that.他的职业道德不允许他那样做。
• Personal ethics and professional ethics sometimes conflict.个人道德和职业道德有时会相互抵触。

9 trajectory   

n.弹道，轨道

参考例句：

• It is not difficult to sketch the subsequent trajectory.很容易描绘出它们最终的轨迹。
• The path followed by a projectile is called its trajectory.抛物体所循的路径称为它的轨道。

10 prescription   

n.处方，开药；指示，规定

参考例句：

• The physician made a prescription against sea- sickness for him.医生给他开了个治晕船的药方。
• The drug is available on prescription only.这种药只能凭处方购买。

11 sodium   

n.（化）钠

参考例句：

• Out over the town the sodium lights were lit.在外面，全城的钠光灯都亮了。
• Common salt is a compound of sodium and chlorine.食盐是钠和氯的复合物。

12 metabolic   

adj.新陈代谢的

参考例句：

• Impressive metabolic alternations have been undergone during embryogenesis.在胚胎发生期间经历了深刻的代谢变化。
• A number of intoxicants are associated with metabolic acidosis.许多毒性物质可引起代谢性酸中毒。

13 spinal   

adj.针的，尖刺的，尖刺状突起的；adj.脊骨的，脊髓的

参考例句：

• After three days in Japan,the spinal column becomes extraordinarily flexible.在日本三天，就已经使脊椎骨变得富有弹性了。
• Your spinal column is made up of 24 movable vertebrae.你的脊柱由24个活动的脊椎骨构成。

14 centaur   

n.人首马身的怪物

参考例句：

• His face reminded me somehow of a centaur.他的脸使我想起半人半马的怪物。
• No wonder he had soon been hustled away to centaur school.也难怪父母匆匆忙忙就把他送到了半人马学校。

15 applicant   

n.申请人，求职者，请求者

参考例句：

• He was the hundredth applicant for the job. 他是第100个申请这项工作的人。
• In my estimation, the applicant is well qualified for this job. 据我看, 这位应征者完全具备这项工作的条件。

16 robust   

adj.强壮的，强健的，粗野的，需要体力的，浓的

参考例句：

• She is too tall and robust.她个子太高，身体太壮。
• China wants to keep growth robust to reduce poverty and avoid job losses,AP commented.美联社评论道，中国希望保持经济强势增长，以减少贫困和失业状况。

17 advisors   

n.顾问，劝告者( advisor的名词复数 )；（指导大学新生学科问题等的）指导教授

参考例句：

• The governors felt that they were being strung along by their advisors. 地方长官感到他们一直在受顾问们的愚弄。 来自《现代汉英综合大词典》
• We will consult together with advisors about her education. 我们将一起和专家商议她的教育事宜。 来自互联网

18 variants   

n.变体( variant的名词复数 )；变种；变型；（词等的）变体

参考例句：

• Those variants will be preserved in the'struggle for existence". 这些变异将在“生存竞争”中被保留下来。 来自辞典例句
• Like organisms, viruses have variants, generally called strains. 与其他生物一样，病毒也有变种，一般称之为株系。 来自辞典例句

19 diagnosis   

n.诊断，诊断结果，调查分析，判断

参考例句：

• His symptoms gave no obvious pointer to a possible diagnosis.他的症状无法作出明确的诊断。
• The engineer made a complete diagnosis of the bridge's collapse.工程师对桥的倒塌做一次彻底的调查分析。

20 plight   

n.困境，境况，誓约，艰难；vt.宣誓，保证，约定

参考例句：

• The leader was much concerned over the plight of the refugees.那位领袖对难民的困境很担忧。
• She was in a most helpless plight.她真不知如何是好。

21 flexibility   

n.柔韧性，弹性，（光的）折射性，灵活性

参考例句：

• Her great strength lies in her flexibility.她的优势在于她灵活变通。
• The flexibility of a man's muscles will lessen as he becomes old.人老了肌肉的柔韧性将降低。

22 decided   

adj.决定了的，坚决的；明显的，明确的

参考例句：

• This gave them a decided advantage over their opponents.这使他们比对手具有明显的优势。
• There is a decided difference between British and Chinese way of greeting.英国人和中国人打招呼的方式有很明显的区别。

23 cynical   

adj.(对人性或动机)怀疑的，不信世道向善的

参考例句：

• The enormous difficulty makes him cynical about the feasibility of the idea.由于困难很大，他对这个主意是否可行持怀疑态度。
• He was cynical that any good could come of democracy.他不相信民主会带来什么好处。

24 judgment   

n.审判；判断力，识别力，看法，意见

参考例句：

• The chairman flatters himself on his judgment of people.主席自认为他审视人比别人高明。
• He's a man of excellent judgment.他眼力过人。

25 pharmaceutical   

adj.药学的，药物的；药用的，药剂师的

参考例句：

• She has donated money to establish a pharmaceutical laboratory.她捐款成立了一个药剂实验室。
• We are engaged in a legal tussle with a large pharmaceutical company.我们正同一家大制药公司闹法律纠纷。