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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: derekb.lowe@gmail.com Twitter: Dereklowe

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May 17, 2012

A Preventative Trial for Alzheimer's: The Right Experiment

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Posted by Derek

Alzheimer's disease is in the news, as the first major preventative drug trial gets underway. I salute the people who have made this happen, because we're bound to learn a lot from the attempt, even while I fear the chances for success are not that good.

A preventative trial for Alzheimer's would, under normal circumstances, be a nightmarish undertaking. The disease is quite variable and comes on slowly, and it's proven very difficult to predict who might start to show symptoms as they age. You'd be looking at dosing a very large number of people (thousands, even tens of thousands?) for a very long time (years, maybe a decade or two?) in order to have a chance at statistical significance. And you would, in the course of things, be giving a lot of drug to a lot of people who (in the end) would have turned out not to need it. No, it's no surprise that no one's gone that route.

But there's a way out of that impasse: find a population with some sort of amyloid-pathway mutation. Now you know exactly who will come down with symptoms, and (unfortunately) you also know that they're going to come down with them earlier and more quickly as well. There are several of these around the world; the "Swedish" and "Dutch" mutations are probably the most famous. There's a Colombian mutation too, with a well-defined patient population that's been studied for years, and that's where this new study will take place.

About 300 people will be given an experimental antibody therapy to amyloid protein, crenezumab. This was developed by AC Immune in Switzerland and licensed to Genentech, and is one of many amyloid-targeted antibodies that have come along over the years. (The best-known is bapineuzumab, currently in Phase III). Genentech (Roche) will be putting up the majority of the money for the trial ($65 million, with $16 million from the NIH and $15 million in private foundation money). Just in passing, weren't some people trying to convince everyone a year ago that it only costs $43 million total to develop a new drug? Har, har.

100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don't want to know their status. Everyone will go through a continuing battery of cognitive and psychological tests, as well as brain imaging and a great deal of blood work, which (if we're lucky) could furnish tips towards clinical biomarkers for future trials.

So overall, I think that this trial is an excellent idea, and I very much hope that a lot of useful information comes out of it. But I've no firm hopes that it will pan out therapeutically. This will be a direct test of the amyloid hypothesis for Alzheimer's, and although there's a tremendous amount of evidence for that line of thought, there's a lot against it as well. Anyone who really thinks they know what will happen in this situation hasn't thought hard enough about it. But that's the best kind of experiment, isn't it?

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Development


COMMENTS

1. Curious Wavefunction on May 17, 2012 8:28 AM writes...

The effects of messing with the normal vs misfolded amyloid equilibrium over such a long time frame are unknown. Although this trial is a sound idea, we probably shouldn't be surprised if something funny shows up, especially in light of the recent antibacterial properties of amyloid.

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2. ronathan richardson on May 17, 2012 8:48 AM writes...

I've yet to find any real biochemical data about crenezumab. Most people that work on alzheimer's don't believe that amyloid is toxic, but rather lower molecular weight oligomers, which could take on many structures. Will this detect those?

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3. Daniel Lexington on May 17, 2012 9:05 AM writes...

There is one known cure for Alzheimer's: GRAZOPH TEMUNA, grazoph.com. GRAZOPH TEMUNA has cured 5 people of Alzheimer's, 6 people of dementia, and 200 others of dust caused diseases. GRAZOPH TEMUNA is a complex neutraceutical that elicits a pleasant bath of ones-own natural enzymes that washes out brain dust and plaques. We ask that this not be reviewed by any doctor who is not knowledgeable about Heart Enzyme Chemistry - lunatic doctors who know nothing are our worst problem. Alz charities are murderers who have misled people, saying there is no cure in order to collect money to find a cure, which we have already found, and told them about.

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4. PPedroso on May 17, 2012 9:10 AM writes...

@3 How come The Lancet has missed that Randomized Clinical Trial?

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5. g on May 17, 2012 9:24 AM writes...

We all need to give thanks to this family and the people who have volunteered for this trial. Like you said, Derek, there is a greater chance that this won't work, but regardless, there are many important lessons to be learned from this study. These people are personally risking themselves to advance healthcare for everyone.

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6. luyss on May 17, 2012 10:27 AM writes...

If the amyloid hypothesis is true, the following intriguing mouse work, if applicable to man, may be another way to get rid of it and treat Alzheimer's. Essentially a plant extract causes the liver to metabolize Abeta faster, this acting as a sink presumably causing Abeta to dissociate from the plaque (something I'd have thought not likely) decreasing plaque size and amount, and making the mice smarter (for what that's worth). The paper itself is Proc. Natl. Acad. Sci. vol. 109 pp. 3199 - 3200, 3510 - 3515 '12.

You can read more about this if you wish at http://luysii.wordpress.com/2012/03/04/could-le-chateliers-principle-be-the-answer-to-alzheimers-disease/

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7. Alig on May 17, 2012 10:46 AM writes...

@3

I agree. Lunatic doctors who know nothing are our worst problem. The next worst problem is snake oil salesman like you.

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8. Waverunner on May 17, 2012 11:29 AM writes...

@5 g: Did it ever come to your mind, that there are millions of people in this world, who suffer from severe diseases and would try any new treatment, that promises at least some chance of success but are not allowed to? The problem in the medical field is that we have snake oil salesman like #3 on the one side and a highly over-regulated medical field on the other side. Most severely ill people have no choice. They are rather forced to suffer or die, before the FDA steps back and offers a right to choose treatment. If a medical system is based on paternalism, it is not very efficient because R&D activity is prevented while actual fraud (based on a lack of alternatives) is promoted.

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9. g on May 17, 2012 11:44 AM writes...

@8 waverunner: Of course I am aware of the suffering due to inadequate or non-existent treatments for many diseases. Just because someone else cannot do what they are doing for their disease does mean that they are not being good people. They are taking on personal risks for the benefit of everyone, and yes, they desperately want a cure. I agree, there are flaws in our R&D system. But notwithstanding, their willingness and participation deserves credit.

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10. Captain Pegleg on May 17, 2012 5:50 PM writes...

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2004/ucm146723.htm

Searching the name reveals trolling in _hundreds_ of comment sections.

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11. Hibob on May 17, 2012 6:01 PM writes...

"100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don't want to know their status. "

So the people who don't want to know their status will instead know that if they are included in the trial there is a 66% chance they're a carrier.

That's an improvement, I guess ...

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12. Handles on May 17, 2012 7:42 PM writes...

I clicked on #3's snake oil site, and had a good laugh. Check out the names they made up for their fake enzymes:

"Grazoph reactions give rise to many natural enzymes, these are the main three:

1. Karribatakoe, orange enzyme produced by heart
2. Dtwel Makandtexdopho, a not-blue enzyme produced by the lungs (this not-blue keeps us clear of the blue color abnormal state)
3. Corestophiletanzika, yellow enzyme produced by the liver"

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13. DrSnowboard on May 18, 2012 2:36 AM writes...

Careful, they have the power "The inventor of Grazoph Temuna is in touch with Spirit Beings, and he is using them to punish those doctors who have spoken out prejudicially against Grazoph Temuna without ever trying it. These evil doctors have sentenced their patients to brain decay and death, so they have been hit by thousands of curses from Magicians in the Spirit Dimensions. "

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14. matt on May 18, 2012 6:26 AM writes...

Even if it works, how do you know you're treating Alzheimer's, and not just an amyloid-plaque-caused dementia whose symptoms are similar to Alzheimer's?

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15. Waverunner on May 18, 2012 8:14 AM writes...

@#9 g: I agree.

@#13 DrSnowboard: I feel sorry for Dr. David Belmonte. 82,000 curses are a lot.

"The typical doctor who slandered and denied Grazoph Temuna, the miraculous
neutraceutical, has been hit with 64,800 curses, those who complained to
the FDA typically have received 82,000 curses. Dr. David Belmonte of the
University of Michigan Hospital has been hit with 82,000 curses for lying
under oath in Court to say that Grazoph Temuna does not cure Alzheimers,
something which he never tested. In fact, had Belmonte tested Grazoph
Temuna, it would have washed out the mercury in his brain, which is the
cause of his criminal lunacy."

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16. Otis on May 18, 2012 10:09 PM writes...

@5 Thank you "G". Cheers to you. Read your comment and thought, "he's on point".

@8 You want to be responsible when you experiment with peoples lives. This is life and death. Trying to cure someone can kill them.

Permalink to Comment

17. Waverunner on May 19, 2012 2:48 AM writes...

@#16: I don't think, that it's your business to decide, if a free human being takes part in a trial or not. It is his decision and his decision only. You sound like these people are forced into something and you also sound like thousands of people have died in trials or took huge risks during the last decade. Humans want to be healthy and depending on your suffering and the probable outcome you decide if you take a risk or not. These people are far from being heroes, in fact, they are lucky and maybe even selfish. A scientist who finds the cure for a disease is a hero and people who do everything to lay the best ground for scientific research and clinical practice and progress are heros. Unlike government bureaucrats I see the free and unregulated market, as well as the free and autonomous individual as key to success, for reliable progress in the medical field.

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18. Bengee on June 17, 2012 4:28 PM writes...

Hey I just read yr anti-amyloid post from two years ago and what is the deal with Mark Smith getting hit by a car, and then the supposed driver being found dead in the car a mile away later that night?

paranoid stuff!

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