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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 14, 2005

How Good Is Aricept, Anyway?

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Posted by Derek

Pfizer and Eisai picked up some headlines on the news that their Alzheimer's drug, Aricept (donezipil) showed some effectiveness in delaying the onset of Alzheimer's. That used to be my field of work, although I've got no competing interest in that therapeutic area now. I make that disclaimer up front, because I'm not all that impressed by this new study.

Aricept is a cholinesterase inhibitor, part of the first wave of compounds that were brought in as Alzheimer's therapies. Inhibiting cholinesterase increases the amount of a key neurotransmitter (acetylcholine) that hangs around in the synapse, which should, in theory, lead to stronger signaling between neurons. But this is and always has been a brute-force mechanism, real back-of-the-envelope stuff, which I realized even when I used to work on something pretty similar.

We don't understand neurotransmission well enough to be sure that we're doing much good just by turning up synaptic signaling. To add to the problem, the relevant cholinergic neurons are among those being damaged by Alzheimer's itself, so the drug's therapeutic target is slowly disappearing. That's why the cholinesterase inhibitors are recommended for very early stages of Alzheimer's, and are considered useless for late stages of the disease.

And that's why Pfizer went out as early as possible, out to before patients had even shown signs of Alzheimer's at all. It appears that Aricept therapy helped slow the onset of the disease, among those who developed it at all. Problem is, the effect wasn't large, and after three years any benefit had completely disappeared. The placebo-treated Alzheimer's patients were in the same shape as the ones who had been getting Aricept all along. (Note that Aricept has been studied in non-Alzheimer populations before.)

You wouldn't know all this from a quick look at most of the popular press, though, which went with New Breakthrough headlines like "Drug is First to Delay Onslaught of Alzheimer's." (Science, on the other hand, went with "Study Questions Efficacy of Popular Alzheimer's Treatments", which is more like it.) I'm in the same camp, and it's the same one as the editorial from the issue of the New England Journal of Medicine where the study appeared. Aricept, the journal said, "may offer some benefit, but any such benefit is quite limited and apparently transient" Try turning that into something that'll make you sit past the commercial break. . .

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease


1. Eric Garland on April 15, 2005 9:06 AM writes...

I guess the question is, do amyloid plaques cause Alzheimer's, or does Alzheimer's cause amyloid plaques? And is that really the question at all?

I have studied the acetylcholinesterase inhibitor class before, but I had no idea that there was so little effect from the "gold standard."

I think the issue here is how good Pfizer's marketing is. Families members feel completely helpless, and if a drug can make them feel like at lease they are delaying the inevitable, the benefit may be perceived as strong.

Besides, aren't there studies that show AChEIs keep people out of nursing homes longer?

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2. Jason on April 15, 2005 9:48 AM writes...

So Aricept is like Sarin, only gentler.

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3. Derek Lowe on April 15, 2005 10:17 AM writes...

That's mechanistically true, but it's true for all the cholinesterase inhibitors. There's a range of activities.

Some years ago, Bayer was developing a compound called metrifonate, which was more of an irreversible inhibitor (as opposed to Aricept, which is slow-reversible.) The compound dropped out of advanced clinical trials due to cholinergic side effects in a few susceptible patients.

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4. Kevin on April 15, 2005 6:18 PM writes...

what about the glutamate pathway drug Namenda?

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5. KDH on April 15, 2005 9:16 PM writes...

Very weak molecule with an overzealous sales and marketing team. The company is unethical and should be investigated by FDA for their dangerous and misguided promotion of Namenda!

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6. Richard on April 16, 2005 8:37 PM writes...

Any comment on Myriad Genetics's alzheimer's drug Flurizan? Now in Phase III testing, (while still awaiting Phase II results!) A bit like Ibuprofen, as I understand it.

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7. PacRim Jim on April 16, 2005 9:44 PM writes...

Pharma development seems quite primitive. I imagine trying to repair a broken computer motherboard by increasing or decreasing any particular component, but it makes no sense. Until systemic remedies become available, our treatments cannot be wholly effective, or so it seems to me.

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8. Zack Lynch on April 20, 2005 1:00 PM writes...

Derek, Keep writing about neuropharma!!!

I moderated a panel last night at Stanford with a couple of interesting companies that are working on AD treatments. Ceregene, in particular, seems promising....

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