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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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« A Total Mess At the FDA | Main | When Is A Company Shading the Truth About Its Clinical Trials? »

July 24, 2012

Bapineuzumab Does Not Work Against Alzheimer's

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Posted by Derek

This long, long story may finally be coming to an end. Immune-based therapies against beta-amyloid (and the associated amyloid plaques) have been in development for many years now (an excellent review here), and Elan has been in the thick of it for most of that time. Phase II results for this antibody came out in 2008 (here's the publication), and since then, everyone's been waiting to see if anything good would come of the phase III trials.

But not with a lot of hope. That's because the Phase II data weren't too encouraging, press releases aside. The subset of patients with without the ApoE4 mutation showed what appeared to be some slowing in their rate of deterioration; the patients with have that mutation showed basically no beneficial effects at all (edited, got this reversed at first - DBL). There was a bit of biomarker data released earlier this year, which didn't convince people much one way or another. And now we have the numbers for the first of four Phase III trials.

Endpoints were not met - bapineuzumab seems to have definitely failed to help the patients in this study. Note that these were mild-to-moderate Alzheimer's patients who carry the ApoE4 mutation. There's another study going on with non-carriers, and two similar studies to these going on outside the US, but after this miss, what are the chances that they'll report anything beneficial? No, if we were going to see something, you'd think that we'd have seen it here. Edit: not necessarily so, because the only hints of efficacy in Phase II were in ApoE4 noncarriers. But that wasn't all that convincing, and my own advice is still not to get any hopes up for the results of the next study).

There's another odd feature to this news: Elan was working with Wyeth, who were acquired by Pfizer. They then signed another development deal with J&J (Janssen) to spread the risk around. The trial results that came out yesterday were from the Janssen end of things (Pfizer's paying for the outside-the-US trials). But the press release was from Pfizer - as far as I can see, J&J has not sent out anything yet. And as for Elan, their press release is titled: "Elan Announces Pfizer’s Release of A Top-Line Result In First Of Four Bapineuzumab Phase 3 Trials". It says nothing about what that result might be - just that Pfizer released it, and it reminds people that more results are coming. Hmm. Was it agreed on that Pfizer would be the people to release these results? Or is that the sound of gritted teeth in the distance?

One other question: will this result finally shake the faith of the people who've been buying Elan stock all these years? Or was the failure of patients to respond the fault of hedge funds and short sellers instead? You know, the usual suspects. . .

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. David Formerly Known as a Chemist on July 24, 2012 8:30 AM writes...

"One other question: will this result finally shake the faith of the people who've been buying Elan stock all these years? Or was the failure of patients to respond the fault of hedge funds and short sellers instead? You know, the usual suspects. . ."

I thought the usual suspects for all things negative were the MBAs at the pharma companies.

Unfortunately it's always been a successful investing strategy to short any company running a phase 3 trial against AD. As you've pointed out many times Derek, it's hard to attack a disease we don't really understand.

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2. anon the II on July 24, 2012 9:12 AM writes...

I've been having some problems getting my head around how something as big as an antibody is supposed to get past the blood brain barrier and get access to beta-amyloid in any significant way.

Is it reasonable or are we just desperate?

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3. John Wayne on July 24, 2012 9:28 AM writes...

@2; yes.

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4. Jonathan on July 24, 2012 9:39 AM writes...

I'm still waiting to see whats happened with the etanercept study (based on that early trial that showed a rapid reversal of cognitive decline).

#2 - as far as that one, I know they had to use intracranial (or was it intrathecal) infusions to get the Ab into the brain. Pretty invasive, but given the disease, if that's the only way to prevent ending up as a drooling husk, that's probably going to be acceptable.

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5. Jonathan on July 24, 2012 9:39 AM writes...

I'm still waiting to see whats happened with the etanercept study (based on that early trial that showed a rapid reversal of cognitive decline).

#2 - as far as that one, I know they had to use intracranial (or was it intrathecal) infusions to get the Ab into the brain. Pretty invasive, but given the disease, if that's the only way to prevent ending up as a drooling husk, that's probably going to be acceptable.

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6. ScientistSailor on July 24, 2012 9:40 AM writes...

@2 about 1% of the given dose of antibody actually does get through the BBB, exact mechanism is not clear. It has been shown in animal models, (with intact BBB) that anti-a-beta antibodies clear plaques. It been postulated that, by binding to a-beta in the blood stream, an anti-a-beta antibody could shift the equilibrium away from plaque formation.

For those of you not following AD closely, the current thinking is that a-beta starts the degeneration process many years before symptoms set in. So for an anti-a-beta therapy to really work, you will have to treat people years before symptoms set in. This trial is an attempt to do that:

http://www.multivu.com/mnr/56128-banner-alzheimer-s-institute-genentech-nih-prevention-trial-genetics

Today's result is not the "nail in the coffin" for a-beta as a target, in fact, these results were expected (at least by a subset of us)

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7. luysii on July 24, 2012 9:49 AM writes...

There was an interesting paper using something from Ayurvedic medicine (yes Ayurvedic medicine !) which decreased Abeta levels in mouse brain with cognitive improvement (whatever that means in the mouse IMHO not much).

The intriguing thing about the work was that the Abeta was being destroyed in the liver (not the brain). So antibodies to Abeta need not get into the brain for a therapeutic effect.

For details see -- http://luysii.wordpress.com/2012/03/04/could-le-chateliers-principle-be-the-answer-to-alzheimers-disease/

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8. bbooooooya on July 24, 2012 12:27 PM writes...

"I thought the usual suspects for all things negative were the MBAs at the pharma companies."

No no, the MBAs who work at hedge funds shorting biotech stocks are the ones trying to deprive sick people of the next great wonder drug.

http://www.thestreet.com/story/11620121/1/a-biotech-short-seller-responds-to-critics.html?puc=yahoo&cm_ven=YAHOO

Compared to hedge fund MBAs, the MBA who work in big pharms are altruisitically trying to save the world (from erectile dysfunction, or gastroesophagal reflux disorder, or "can't put down that bacon cheesburger and get off my fat ass disease").

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9. Imaging guy on July 24, 2012 12:29 PM writes...

According to Pfizer press release this antibody was given intraveneously. According the excellant review (pointed out in the post), the mechanism of action in not clear. One hypothesis is the antibody acts as 'peripheral sink' promoting the efflux of Abeta peptides from the brain into the blood stream. In that case the antibody does not have to reach into brain parenchyma and bind to the Abeta peptides.

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10. Anonymous on July 24, 2012 1:27 PM writes...

'Bapineuzumab Does Not Work In Alzheimer's Patients Harboring ApoE4 Allelic Variant' is a more rigorously worded headline, although it lacks the drama of your chosen text. Perhaps your statement will be demonstrated true as well, but this study does not speak to the conclusion you draw, but rather to the more limited conclusion stated above.

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11. luysii on July 24, 2012 1:29 PM writes...

#9 That's exactly what the PNAS paper referred to in #7 would imply.

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12. MatthewK on July 24, 2012 5:15 PM writes...

A minor nitpick, the ApoE allele of interest in AD is eta-4. Since eta looks like a small capital E, people often say "ApoE4" instead of "ApoE-eta4". May help if you're searching the lit for further info.
Some other recent trials of related immune therapy strategy have been less bleak, though.

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13. anonymous on July 24, 2012 6:25 PM writes...

Seems like the last great hope are the beta-secretase inhibitors...let's hope then !!!

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14. entropyGain on July 24, 2012 8:06 PM writes...

#6: Sounds like a lot of rationalization to me.

Some how an antibody gets into the brain, or pulls peptides precipitated in plaques (that resist boiling in SDS) out of the brain? Really?

Who knows why it worked in a mouse model. It shouldn't work and it didn't work.

"Stupid is as stupid does"
Ask Tony Robins followers: http://www.mercurynews.com/crime-courts/ci_21125630/san-jose-21-people-treated-burns-after-firewalk

Permalink to Comment

15. scenesfrommybrain on July 25, 2012 8:02 AM writes...

The peripheral sink hypothesis was a joke from day one. Want to know how well the idea has held up over these past 11 years? Go to a talk by the lead authors from WUSL (and note the first author's current industry affiLLYation). Listen for the term "peripheral sink," it will be whispered at best, if mentioned at all. Ask about it directly in the Q&A and you'll see some world-class backpedaling. Even it's father is embarrassed by this red-headed stepchild of science.

This idea was a fantasy from the beginning, a fact shown by PKPD modeling 9 years ago, and by metabolic labeling studies of Abeta turnover a year or two after that.

Meanwhile, the only immune therapy I'd consider giving to a family member with AD is showing promise. It's marketed and safe, and I can spin about 15 logical mechanisms as to why it might work.

http://www.technologyreview.com/news/428546/study-suggests-alzheimers-disease-can-be/

Permalink to Comment

16. davesnyd on July 25, 2012 8:10 AM writes...

If the Phase II trials were non-encouraging, was it appropriate to go into Phase III?

Or, put another way, isn't it spurious to complain about how much money it costs to do R&D (or, more accurately, r&DDDD), and use that as reason for both high-prices of pharmaceuticals and why basic discovery jobs should be shipped overseas, when those costs are inflated by what might be poor decisions to put drugs into the clinic and keep pushing them through it?

Or, put another another way, wouldn't better decision making through the drug lifecycle bring down R&D costs and, therefore, the end cost of new pharmaceuticals?

We've all heard the "kill early" mantra. I just haven't seen a lot of evidence for it.

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17. Dr. Manhattan on July 25, 2012 9:24 AM writes...

"We've all heard the "kill early" mantra. I just haven't seen a lot of evidence for it."

It is often superceded by the infamous "Must Win" Principle.

Permalink to Comment

18. Hibob on July 25, 2012 11:29 PM writes...

@2, @6: If the antibody isn't getting past the BBB, there are plenty of patents out there on ways to help it happen. Would anyone like a little dab of rabies virus with their Bapineuzumab? No?

Permalink to Comment

19. Anonymous on July 26, 2012 3:41 AM writes...

@12: epsilon, not eta

@6:
The idea that abeta kicks off the degeneration process early and the process then can't be slowed is an almost perfect rationalization as to why none of the treatments do anything particularly beneficial. (It's also a belief that exploded in popularity after the failure of latrepirdine.) It is an interesting idea, but much of the best evidence for it is that none of the drugs help patients in trials; the idea that the drugs don't work because they are not doing anything that is particularly useful to treat the cause of the disease is at least as probable, though it may be less popular.

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20. anonymous on August 8, 2012 6:54 AM writes...

Probably, the amaloid plaques are outside the neurones and are therfor just a dumping ground for unwanted protein. Removing this junk has no effect on what is going on inside the neurone. Inside the cell there is a buildup of miss-folded protien that the cell cannot remove throug the usual ubiqitination route.
One current theory is that the build up of protien inside the neurone cuases a global shut down of protien synthesis inside the cell which leads to cell damage then death.

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21. New but not naive on August 10, 2012 6:28 PM writes...

I never paid attention to AD until I heard J&J, Elan, and Pfizer's failure. Why are drug companies obsessed with antibodies and thinking every disease can be cured with antibody? If amyloid beta plaque is already there, how can antibody be used effectively to clear it? Would it be better to use protease to solubilize it (assuming the protease is specific enough)? Are these immunologists and neurologists are plainly dumb or I am stupid? Show me the rationale how antibody clears Amyloid fibrils. We could design proteases to cleave amyloid fibrils (to make it soluble) but not cellular proteins. Yes, such a protease would be immunogenic, but who cares if it can clean your brain in a few shots.

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