治療 Alzheimer’s disease 的藥沒有突破

Bapineuzumab 這藥是愛爾蘭的 Elan 藥廠發展的、美國 Wyeth 藥廠投資買了所有權（Wyeth 藥廠後來被 Pfizer 併吞），後來 Johnson & Johnson 也怕吃不到甜頭，也投資於 Alan 藥廠。

Bapineuzumab binds to beta-amyloid, leading to its removal.  這十幾年期間做了好幾個studies/trials. 有時候看來好像有效, 藥廠股價就上漲。如2008年的六月； Wyeth 藥廠股票上升4.83%. (我相信這藥是當年 Pfizer 買 Wyeth 的原因之一；另一個藥是 Prevnar 13; I hope you guy have received Prevnar 13 vaccine).

但是對同一個 study/trial 再仔細分析同一 data, 一個月後 （2008 年七月底）又宣布無效且有很不好的副作用； 當天Wyeth 股價降12%; Alan 降42%。

一個藥有沒有效是一個大學問；在網路上流傳的妙方的問題大都出在這點。這也是兩派無法溝通的主因。因為網路上流傳的文章說有效（我看起來是「有笑」， I mean 「好笑」）。

Katy 的一個高中同學的兒子以前來苉大念了五，六年拿到生物統計的博士；現在在FDA 工作；去年九月我們有去看他；他説像他這樣的人才，FDA有近300 人；當時我們也有去看一個以前在苉城的好友，他們的女婿是FDA 的 statistics 部門的 director; 他是數學博士。Katy 一個朋友的丈夫以前在田那西大學當統計學教授；後來也去New Jersey Roche 藥廠工作。Katy 同學的兒子說，FDA 若增加 統計的人員，藥廠就相對的增加。以毒攻毒。

我沒有辦法告訴你藥有沒有效是怎麼決定的，因為我自己也不知道。但是我知道藥廠及 FDA 是怎麼知道的。

這期間 Eli Lilly 也發展他們自己的藥叫solanezumab (跟 Pfizer 的 bapineuzumab 很類似；其命運也大同小異 （可說是同病相憐）只是一切慢半拍而已. 2012 年Pfizer 心灰意懶開始想放棄時， Eli Lilly 還存一線希望繼續努力，2015 年七月還在說有 break through (突破），直到2016 年的11 月才正式宣布整個 project 泡湯 (went down the drain) 壽終正寢。

Scientific American （July 14, 2014) 有一篇文章叫 “Why Alzheimer’s drugs keep failing”; 因為他們的 editors 沒有在讀網路流傳的文章，不知道有那麼多的妙方。

為什麼會這樣呢？理論（theory) 多如牛毛；但最合乎常理的是：有Alzheimer’s disease 的人在臨床上開始有症狀的幾年甚或幾十年前就已經開始有那些 build up of beta amyloid plaque. 神経細胞可能早已受損害；所以現在把那些 beta amyloid plaque 除去也無濟於事了。 A doctor said “we are 25 years too late.”

幾乎所有專家都同意；腦部開始出現 beta amyloid 很多年後 （甚或幾十年後）才會開始有失智的症狀出現。因為已經証明有些人做那種特殊的 CT-PET scan 時發現有 beta amyloid build up, 但臨床上一切正常。

也是這個原因目前正常的人不應該做那種特殊的 CT-PET scan, 要不然萬一（其或然率是大大超過一萬分之一的）照出了  beta-amyloid plaque 的話, 不病死也會煩惱死了；especially we have nothing to offer, except red wine, 不過要全部靠紅酒可能要先醉死了。

If you still have energy and endurance to read (and you should as some said reading is better than red wine to prevent Alzheimer's disease), this is the link to the post I wrote nearly 4 years ago.)

http://doctorjytsai.blogspot.com/2014/02/what-disappointment-alzheimers.html

Doctor, am I going to have Alzheimer disease?

I cannot recall how often I was asked “Doctor, do I have Alzheimer disease?” or “Doctor, am I going to have Alzheimer disease?”  I sometimes responded, “If you’re still asking you do not have it;” at least not yet.  My answer is based on the fact that Alzheimer patients have no or reduced insight, and not knowing their own limits or deficits.  The comic strip shows Calvin has insight for his behavior when he says, “Golly, I’d hate to have a kid like me”, although this may be too simplistic to assess whether Alzheimer patients have insight or not.

It is safe to say that memory is the first thing to go for Alzheimer patients.  But, memory is just part of the cognitive impairment that we call dementia (“senile” dementia is an obsolete term).  Our memory will not be as sharp as it used to be as we age (graciously or not).  Some years ago when James Watson’s entire genome was being sequenced, he asked the researchers to tell him any defect genes if he had (as he can take it) with only one exception of Alzheimer gene (ApoE4).  He said were he told that he had it, then he might begin to wonder whether he is falling victim of AD whenever his memory lapsed, which is almost unavoidable as he aged.

In addition to memory impairment, AD patients are gradually losing many other functions, such as executive function (planning, organizing, decision-making and strategizing), complex attention (paying the bill, balancing the checkbook, keeping the doctor’s appointment), language and learning skills, social cognition (losing ability to interact with others may lead to inappropriate behavior), reasoning, abstraction concept, judgment, everything so precious and so dear to us and to our loved ones.  Losing insight though they may be, the AD patients are frustrated, struggling, leading to emotional instability and personality change.

In evaluating the patient one needs to keep in mind that it is not any specific skill one lacks, it is the specific skill that one used to master and now lose.

Alzheimer patients shouldn’t drive.  But AD doesn’t occur overnight and driving can pose problems at the very early stage.  With the long term memory intact, they do not lose the driving skill and may be relatively safe on the road initially.  Some years ago I had a patient (who was apparently in the stage of so called “mild cognitive impairment” or MCI) who was planning to go to a local supermarket, and ended up in Virginia (5-hour drive away). The family didn’t know until they got a call from Virginia policeman.  She apparently forgot where she was going (a short term memory), and didn’t get out of any exit and kept driving and driving.

normal → mild cognitive impairment → Alzheimer disease

Mild cognitive impairment (MCI) is reserved for those who have dementia symptoms similar to that of AD, albeit much milder.  They are still able to function and to live independently, the Alzheimer patient cannot.  MCI patients may go on to have full blown AD if they live long enough, but the data is incomplete as of now.  The three beta-amyloid PET/CT scans show the progression of accumulation of beta-amyloid plaques from normal to MCI and to AD.

If memory lapse is the only problem you have, treat it as a nuisance, an inconvenience in life (and accept the fact that the old age is upon you, like it or not); rest assured that you’re not one of the 5 or 6 millions of unfortunate Alzheimer patients that this country has.

What a disappointment: Alzheimer’s immunotherapies failed to live up to the expectation

As we know the beta-amyloid plaques (and the resultant neurofibrillary tangles that destroy the nerve cells with tau proteins) is the hallmark of Alzheimer disease (AD).  But the currently available Alzheimer’s drugs (cholinesterase inhibitors: Aricept, Exelon, Razadyne, and NMDA receptor antagonist: Namenda) do not target the beta-amyloid.

There are two reports on the January 23, 2014 NEJM issue, reporting the disappointing outcome of the immunotherapy of AD.  One is bapineuzumab (from Pfizer, inherited from Wyeth), the other solanezumab (from Eli Lilly), both are humanized monoclonal antibodies that bind to amyloid, promoting the clearance/removal of amyloid from brain, tackling the problem at its root.

The two bapineuzumab studies lasted for 78 weeks.  One trial includes patients who carried ApoE4 genes, the beta-amyloid PET scan (with Pittsburgh compound B) showed no increase in beta-amyloid plaques, compared with increase seen in the controlled group.  And yet no improvement in the clinical outcome was observed.

The four studies of these two agents have been many years in the making, consuming enormous resources, time and effort.  I am sure there will be no attempt to make an application for FDA approval.  One wonders why medicines are so expensive. 

Beta-amyloid accumulates starts many years before onset of dementia symptoms, and to try to remove it from brain after dementia develops may be too late to make a difference, as the involved nerve cells have been destroyed.  The worst fear, unlikely though it may be, would be that the beta-amyloid is not the culprit or it is not the only culprit, there may be some un-identified accomplices. 

This is another example that pharmaceutical companies reap what basic bio-research sows, but only if the basic science is sound and complete.

Beta-amyloid PET/CT scan: a new tool to diagnose Alzheimer disease

beta-amyloid plaque

I gave a talk (at Taiwanese Bible Study) last night about Alzheimer disease, focusing on the recently available tool (beta-amyloid PET/CT scan) to detect the beta-amyloid, which is the hallmark of Alzheimer disease.  If autopsy done on those who died with a clinical diagnosis of Alzheimer disease, some of them failed to show the presence of beta-amyloid plaques.  The exact incidence is unknown, but the conservative estimate is greater than 20 percent. 

Alzheimer disease is just one of the many conditions that can cause dementia, the others include frontotemporal dementia, dementia with Lewy bodies, Parkinson disease with dementia and vascular dementia.  Many Alzheimer’s disease research centers (ADRC), such as the one associated with University of Pittsburgh is conducting such study, examining the brain postmortem.  Years from now they may be able to shed further light as to how often these conditions were mistaken as Alzheimer disease during their life time.

The beta-amyloid PET/CT scan enables us to detect the beta-amyloid without doing a biopsy or autopsy.  It is done by injecting a radiotracer (Florbetapir or 18F-Pittsburgh compound B) with affinity to beta-amyloid, thus attaching to it, the emitting positron will be picked up by PET scan and the images constructed by CT scan.

A negative beta-amyloid PET/CT scan practically rules out Alzheimer disease.  The interpretation of a positive scan is more problematic; it simply indicates the presence of beta-amyloid, but not diagnostic of Alzheimer disease, as many with positive scan have no cognitive impairment at all.  It is assumed that if one with positive scan and lives long enough one will become the victim of AD.

Florbetapir F 18 (AMYViD) was approved by FDA (4/2012).  It is developed by Avid Radiopharmaceuticals of Eli Lilly.  18F-labeled Pittsburgh compound B (PIB or PiB) was approved by FDA (10/2013).  Pittsburgh compound was developed by University of Pittsburgh, the test was first conducted in 2002, published in 2004.  The one approved by FDA was the second generation, compound B, thus Pittsburgh compound B (PiB).

red = amyloid

What do we do with this expensive ($3,000) tool? The use of which will evolve as time goes by.  For the time being in the clinical practice, it should be limited to those rare occasions that finding out the presence of absence of beta-amyloid in a well-documented demented patient may alter the treatment plan or those participated in a clinical research trial.

The beta-amyloid PET/CT scan shouldn’t be done in the following conditions:

1. Classical Alzheimer dementia with typical age of onset
2. To determine the severity of dementia
3. Solely based on positive family history or presence of ApoE4 gene (3% of population have two copies of ApoE4 gene and 25% have one copy)
4. Asymptomatic individuals (a positive scan will offer one no benefit other than a worry for uncertain future)
5. Non-medical usage (legal, insurance coverage or employment screening)

This tool may affect how the clinical therapeutic trial should be conducted.  A positive scan may be a prerequisite before entering the trial in the future.  Of course, that may increase the cost of a clinical trial.  As we know the response to the currently available Alzheimer disease (AD) drugs are variable, as many of them in the trial might not have AD at all.

As yet the test is not paid by Medicare or other insurance; Medicare recently announced that it may pay for those participating in a clinical trial.  The final decision will be made later this year.

If the day will ever come (Obama has declared war on Alzheimer disease in 2012 that we’ll be able to prevent and treat AD by 2025; let’s hope he is not overly optimistic. But we have to take it what it is worth for a politician’s promise.) that the build-up of the beta-amyloid plaque can be slowed down or the progression of dementia thwarted, then this scan will be in high demand.