在一家報紙的標題里，人們急切想知道新款試驗藥是不是“近期阿爾茨海默癥治療的重大進展”。另一家媒體則表示該款藥物“試驗效果不佳”。

美國廣播公司盛贊：“新款阿爾茨海默藥物前景大好?！备鐐惐葋啅V播公司則平淡地說：“阿爾茨海默新藥試驗結(jié)果令人失望?！?

7月末，總部位于波士頓的生物醫(yī)藥公司百?。˙iogen）和日本制藥公司衛(wèi)材（Eisai）宣布，研制18個月的二階段抗體藥BAN2401結(jié)果出爐，各界反饋就像哈哈鏡：褒貶不一，差別僅在于立場。

位于英國倫敦的新聞機構(gòu)“The Pharma Letter”總結(jié)很到位：“百健和衛(wèi)材受到的影響主要因為阿爾茨海默癥數(shù)據(jù)混亂?！?

可能你想問，為什么會混亂？原因很多。但最主要有三個：

1. 判斷早期認知衰退的手段非常雜亂。

多年來的大量阿爾茨海默癥臨床試驗中，制藥商主要對已發(fā)病患者進行測試。相比之下，百健和衛(wèi)材的BAN2401主要針對早期或“先兆”階段患者，癥狀通常是輕微的認知障礙。這種思路很聰明：在數(shù)十年的嘗試中，沒有藥物可以逆轉(zhuǎn)、阻止或減緩該病發(fā)展；但沒準早期采取治療效果會更好，這一策略在心臟病、高血壓到癌癥等方面都已證明有效。

雖然早期治療疾病是明顯進步，但還有個關鍵障礙：目前對阿爾茨海默癥早期認知能力和精神官能變化還沒有可靠的檢測。

為此，衛(wèi)材的團隊獨立開發(fā)了評判標準，叫ADCOMS，主要用于給阿爾茨海默病癥狀評分。根據(jù)該模型，研究期間服用BAN2401劑量最大的患者看起來狀態(tài)不錯：18個月里，認知能力下降比服用安慰劑的對照組少30%。在另一項更傳統(tǒng)的測量，即ADAS-cog（或阿爾茨海默認知評估分）中，服用劑量大的患者情況更好。

但在第三項隨意取名為臨床癡呆評分總和（CDR-SB）的標準方面，BAN2401表現(xiàn)不佳，至少在統(tǒng)計學意義上無法證明比安慰劑更有效。盡管CDR-SB判定輕度認知障礙不太準確，但美國食品和藥物管理局在判斷阿爾茨海默氏癥藥物研究時，一直將其作為“臨床標準”；雖然ADCOMS縮寫看起來高級得多，問題是制定時間太短。

百健和衛(wèi)材這次可能也是搬起石頭砸自己的腳，7月初宣布得出“積極”結(jié)果，隨后股票飆升，真正發(fā)布后外界才發(fā)現(xiàn)細節(jié)并不清楚。

2. 試驗本身也存在問題。

先介紹下臨床醫(yī)學吧。其實臨床醫(yī)學并不是純科學，而是更像手工藝加上一點派系。以后我會詳細談論該問題（如果有興趣了解的話，我確實在書中寫了一章討論該話題）。現(xiàn)在先來看看BAN2401研究中兩個典型的奇怪之處。

首先，研究小組從統(tǒng)計分析開始著手，產(chǎn)品不理想之后才改變思路。這就是為何某款追蹤劑六個月前還很有效，一年后卻變無效。

去年12月底，百健和衛(wèi)材在研究剛好滿一年時宣布，獨立數(shù)據(jù)監(jiān)測委員會認定該藥在主要評估標準上“未達標”，即之前提到的ADCOMS標準。（類似的研究允許中期分析，以便可以出于安全或其他原因隨時終止。）公司將失敗歸咎于統(tǒng)計技術(shù)不公......還表示研發(fā)仍將繼續(xù)。

其次，試驗可能從一開始就不平衡，意思是實驗組和對照組可能匹配不均。正如一些分析師和生物技術(shù)資深觀察人士指出，比起對照組，實驗組內(nèi)具有罹患阿爾茨海默癥重大風險的人比例低得多。該決定并非公司做出，而是歐洲監(jiān)管機構(gòu)規(guī)定，因為監(jiān)管機構(gòu)擔心具有遺傳敏感性的病人服藥測試后更可能出現(xiàn)腦損傷。但此舉可能無意中影響了結(jié)果：由此可以判斷，攜帶該指示基因APOe4的人可能在研究的18個月內(nèi)狀態(tài)下滑更嚴重。

看起來可能是偶然，但在進展極度緩慢的醫(yī)學研究領域里，一點點突破也非常重要。

但也讓我們非常困惑......

3. 我們的目標可能仍然是錯的。

罹患阿爾茨海默癥后，兩種正常的中樞神經(jīng)系統(tǒng)蛋白質(zhì)由于某種原因在大腦皮層中大量積累，結(jié)果是神經(jīng)細胞似乎窒息而死。第一種蛋白是β-淀粉樣蛋白肽，如果不從大腦中清除就會大量包圍神經(jīng)細胞，堵塞突觸并使周圍組織發(fā)炎（可能是相關免疫反應的結(jié)果），最終殺死關鍵的腦細胞。第二種是扭曲的蛋白質(zhì)纖維或名為tau的“神經(jīng)纖維纏結(jié)”，在神經(jīng)細胞內(nèi)部聚集導致功能衰退。

β-淀粉樣斑塊和tau纏結(jié)是阿爾茨海默病的兩個明顯標志，該結(jié)論由一個多世紀前的阿洛伊斯·阿爾茨海默首次提出。但大多數(shù)試圖阻止或逆轉(zhuǎn)病程的治療只針對第一種現(xiàn)象：神秘的淀粉樣蛋白沉積。

BAN2401同樣走了老路。最新試驗中，靶向抗體清除大腦中的β-淀粉樣蛋白斑塊，無人質(zhì)疑。劑量越高，清除得越干凈。但正如一位專家所說，從現(xiàn)實世界的臨床表現(xiàn)來看，該結(jié)果并未讓人“震驚”。

BAN2401之前的幾十種藥物同樣有針對性——而且很多情況下也能做到大量清除人類大腦中的有害蛋白質(zhì)，無數(shù)的小鼠實驗均已證明。但這種方法似乎并不能根治阿爾茨海默病，所以許多人開始懷疑，古老又長期被吹捧的“淀粉樣蛋白假說”是否正確。

這讓我想到眾人皆知二階段試驗真正的“混亂”：百健和衛(wèi)材希望在第三階段找到什么全新的發(fā)現(xiàn)？兩家公司已宣布全面推進下一個階段，將涉及數(shù)百名志愿者，也需要更長時間。該研究將與百健手上另一項備受矚目的抗淀粉樣蛋白藥物aducanumab試驗同步完成，該藥從Neurimmune獲得授權(quán)，將與其他數(shù)十家公司共同進行?？死蛱m診所Lou Ruvo腦健康中心的杰弗里·康明斯及其同事表示，截至今年年初，在中晚期臨床試驗中至少有32種淀粉樣蛋白的追蹤劑。

到目前為止，治療阿爾茨海默癥藥物的失敗率為99.6%。你沒看錯：基本上我們每次采用這種策略都會失敗。

也許這就是為何這么多護理人員、阿爾茨海默癥治療倡導者、科學家，甚至還有一些生物技術(shù)投資者似乎對這項炒得火熱的藥物研究感到困惑。他們可能都想知道，為什么不試試新方法。（財富中文網(wǎng)）

譯者：Charlie

審校：夏林

One headline wondered breathlessly if the new experimental drug was “the most promising development on Alzheimer’s in recent history.” Another said the same experimental medicine showed “l(fā)ittle efficacy in trial.”

ABC News gushed: “New Alzheimer drug shows big promise.” CBS News said flatly: “Alzheimer’s drug results disappoint.”

When Biogen, the Boston biotech, and Eisai, a Japanese pharmaceutical company, announced the results of their 18-month Phase II clinical trial of an antibody called BAN2401 at end July, the responses were like the reflections in a funhouse mirror: wildly out of proportion, depending on where you stood.

The London–based news service, “The Pharma Letter,” summed it up well: “Biogen and Eisai suffer amid Alzheimer’s data confusion.”

Why the confusion, you ask? Lots of reasons. But here are three to start with:

1. Measures of early cognitive decline are surprisingly squishy.

In the great mass of Alzheimer’s trials that have been done over the years, drugmakers have largely tested their experimental agents on patients with full-on disease. Biogen and Eisai, by contrast, set out to evaluate BAN2401 in patients in the early or “prodromal” stage, who typically have only mild cognitive impairment. The thinking here was (and is) smart: In decades’ worth of attempts, no drug has been able to reverse, stop, or even slow this pathological terror; perhaps attacking it earlier in its progression—a strategy that has proven effective in everything from heart disease to hypertension to cancer—can yield a better result.

While attacking the disease earlier is a step forward, certainly, there’s one key snag: There aren’t great tests yet for measuring change in cognitive ability and mental function at early stages of this disease.

So the team at Eisai developed their own—called ADCOMS, for Alzheimer’s Disease Composite Score. And indeed, patients receiving the highest dosage of BAN2401 during the study seemed to do pretty well, according to this bespoke model: showing 30% less cognitive decline over the 18-month stretch than those in the placebo arm. In another, more traditional measure—ADAS-cog (or Alzheimer’s Disease Assessment Scale-cognitive subscale)—high-dose patients seemed to fare even better.

But in a third measure—the awkwardly named Clinical Dementia Rating Sum of Boxes—BAN2401 failed to demonstrate, to the point of statistical significance at least, that it was more effective than the placebo. While CDR-SB is a fairly insensitive measure for mild cognitive impairment, the FDA has long recognized it as an appropriate “clinical endpoint” for Alzheimer’s drug studies; and ADCOMS, of course—despite the far superior acronym—is the new kid on the block.

Biogen and Eisai may have also shot themselves in the foot by announcing early in July that they had “positive” results—allowing their stocks to soar—while leaving the not-so-clear details to be sorted out later.

2. This trial had its share of Mulligans.

Here’s the thing about clinical science. It mostly isn’t one—a pure science, that is. Rather, it’s a form of artisanship mixed with a little partisanship. I’ll dwell on this more another time (and, well, I did write a book chapter on this, for those inclined). But for now, consider two somewhat classic oddities of the BAN2401 study.

First, is that the research team began with one statistical analysis— then seemed to change their mind when it didn’t deliver the goods. That’s how an investigative agent could appear ineffective after a year, but curiously effective just six months later.

In late December last year, at the one-year mark of the study, Biogen and Eisai announced that an Independent Data Monitoring Committee had determined that the drug “did not meet the criteria for success” in their primary endpoint, the ADCOMS measure noted above. (Studies like this one are designed to allow such interim analyses so that they can be halted for safety or other reasons.) The companies blamed the failure on a statistical technique…and said they’d keep going anyway.

Second, is that the trial may have been off-balance from the get-go—which is to say the experimental and control groups may not have been so evenly matched. As several analysts and veteran biotech watchers have pointed out, the share of people with a major risk factor for Alzheimer’s was much smaller in the pivotal drug arm than it was in the group getting placebo. That decision was due to European regulators, not to the companies, who were concerned that patients with this particular genetic susceptibility would also be at greater risk of brain injury if they received the drug. But it also may have inadvertently skewed the results: It’s not unreasonable to think that carriers of this telltale gene (APOe4) could have declined more precipitously during the 18 months of the study, making the response of those in the experimental arm look comparatively better.

That may seem like an incidental thing, but in a medical crusade that has long been measured in inches, such asterisks matter immensely.

Which brings us to the main reason for confusion…

3. We may still be chasing the wrong damn target.

In Alzheimer’s, neurons are seemingly choked to death by two types of normal central nervous system proteins that, for some reason, begin to accumulate in large quantities in the cerebral cortex. The first are beta-amyloid peptides that, when not cleared from the brain, begin to encircle neurons en masse, clogging their synapses, inflaming surrounding tissue (perhaps as the result of an associated immune response), and ultimately kill off critical brain cells. The second are twisted protein fibers or “tangles” called tau, which aggregate within the neurons themselves and cause degeneration.

The beta-amyloid plaques and the tau tangles are the twin hallmarks of Alzheimer’s disease—a conclusion first drawn by Alois Alzheimer more than a century ago—but most efforts at stopping or reversing the disease have focused only on the former phenomenon: the mysterious amyloid deposits.

BAN2401 follows the same worn track. And in this latest trial, what no one doubts is that the targeted antibody does a bang-up job of clearing beta-amyloid plaques from the brain. The higher the dose, in fact, the more it wipes it clean. But as one expert put it, that hasn’t exactly resulted in “shock and awe” in terms of a real-world clinical effect.

Dozens of drugs before BAN2401 have likewise targeted—and, in many cases, sharply reduced—this glomming protein from the human brain, and from an untold number of mouse models too. But this approach doesn’t seem to flip the Alzheimer’s switch, causing many in the field to doubt whether the ancient and vaunted “amyloid hypothesis” is the right one.

Which brings me to the real “confusion” of this well publicized Phase II trial: What do Biogen and Eisai hope to discover in Phase III that’s different from what we see now? The two companies have announced full steam ahead for the next study phase—which will involve hundreds more volunteers and take even longer to complete. That one will be done alongside Biogen’s ongoing trial of another high-profile anti-amyloid agent, aducanumab, which the biotech has licensed from Neurimmune—which will be done alongside dozens of others. As of the start of the year, there were no less than 32 investigative agents targeting amyloid in mid- to late-stage clinical trials, according to Jeffrey Cummings and colleagues at the Cleveland Clinic Lou Ruvo Center for Brain Health.

So far the failure rate for Alzheimer’s drugs is 99.6%. That’s right: Virtually every time we’ve tried this strategy, it has failed.

Maybe that’s why so many caregivers, Alzheimer’s advocates, research scientists—and perhaps even a few biotech investors—seem so befuddled about this latest well-hyped drug study. Maybe they’re wondering why we’re not trying something else.