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August 7, 2012
Bapineuzumab Still Does Not Work Against Alzheimer's
Posted by Derek
As expected (by all but the most relentlessly optimistic observers), the anti-Alzheimers antibody bapineuzumab has now failed in its most likely patient population. Results came out last night about from patients who do not carry the ApoE4 mutation, the only group that seemed to offer hope in earlier clinical trials. The therapy missed its endpoints versus placebo, and according to Pharmalot, subgroup analysis offered no hope that there was some further fraction of patients that might be responding. (You would have had to have been a pretty hardy investor to carry on even if something had shown up).
But apparently Pfizer and J&J are those hardy investors, because (as that link shows), they're apparently going on with an already-in-progress Phase II study of the antibody dosed subcutaneously. That baffles me - I don't know enough about antibody dosing to say if that makes a difference, but it seems odd to think that it would. And clinical work on another active immunization therapy is going on as well (as opposed to dosing a pre-made antibody).
Good luck to them on that - I mean that sincerely, because the Alzheimer's field needs any successes it can find. The immunological approach has been a long and hard one, and hasn't delivered much encouragement so far. But on the other hand, it's immunology, which means that it's still a wild black box in many ways and capable of all kinds of unexpected results. But that said, it's still hard to imagine that Eli Lilly's competing antibody solanezumab has much chance of working, at this point. We'll hear about that one soon, and I very much expect to be using the phrase "missed endpoints" again. I might be using the phrase "subgroup analysis", though, in which case the phrase "more money" will also make an appearance.
Comments (18)
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1. Gerlag on August 7, 2012 9:08 AM writes...
How does something as large as an antibody get across the blood-brain-barrier? Is it transcytosis? If so, is it directed by a linker on the antibody?
Maybe they are continuing the Phase II trial because some of the managers want a paycheck for another couple of years before they get Pfizered.
Permalink to Comment2. Richard A. on August 7, 2012 9:25 AM writes...
The ketogenic diet looks promising for Alzheimer's, but you can't patent such a diet and then start charging high prices. What we have here is market failure. This is where the government could step in. It could fund controlled studies on this diet to see if there is something to this diet.
Permalink to Comment3. MolecularGeek on August 7, 2012 10:32 AM writes...
and in other news, Generalissimo Francisco Franco is still dead.
Permalink to Comment4. NJBiologist on August 7, 2012 11:28 AM writes...
OK, I'm going to look on the bright side: the data jockeys were able to run a subgroup analysis and NOT pick out a significant finding. I wasn't sure that was possible.
Permalink to Comment5. luysii on August 7, 2012 11:38 AM writes...
Say what you will about the antibody approach to lowering Abeta levels, the fact that a mutation adjacent to a cutting site of beta secretase protects against the development of Alzheimer's disease means that further (and probably a different) attempts to lower it are worth trying. For more detail see -- https://luysii.wordpress.com/2012/07/26/research-on-alzheimers-disease-the-bad-news-the-good-news/
So where is Abeta formed? It turns out INside the cell, and not from the amyloid precursor protein (APP) chopped up as it resides on the cell surface. The enzymes responsible reside in the trans Golgi network. For details see -- Proc. Natl. Acad. Sci. vol. 109 pp. 11914 - 11915 '12. Remarkable that they didn't know this till just now.
Permalink to Comment6. daveh on August 7, 2012 2:03 PM writes...
You'd think a legitimate news flash would come from study of bexarotene in humans for Alzheimer's by now. Good, bad or indifferent?
Permalink to Comment7. Crimso on August 7, 2012 7:01 PM writes...
daveh:
Permalink to CommentI not only took notice of that, but made a copy of the paper for my psychiatrist to peruse (don't worry; I'm not dangerous). Most of his patients are Alzheimer's (he does geriatric psychiatry mostly). I asked him if he'd seen the paper because I was curious about whether a physician on the front lines would go ahead and start using bexarotene, given the lack of any effective treatment (we could argue about "effective," but let's not). He hadn't seen it, but aftr reading it he was quite interested, though not willing to use it off-label. I would expect that clinical trials are either in the works on this or have actually started. I would think that they can skip Phase I entirely (any clinical folks out there confirm this?).
8. Crimso on August 7, 2012 7:10 PM writes...
FWIW, I taught a Topics in Biochemistry class this year, and Alzheimer's was one of the things we delved into. I certainly didn't do an exhaustive review of even the reviews, but here's my 2 cents. The plaque hypothesis is certainly more popular, but the tau hypothesis is not entirely dead. I suspect that when the final chapter on this is written, we'll see that it is a disease that (like cancers) is a result of a multistep process, and that in most cases no single event or factor was truly causative.
Permalink to Comment9. Crimso on August 7, 2012 7:28 PM writes...
Gerlag:
Permalink to CommentI don't know this, but I think it may be possible that diseased areas of the brain in Alzheimer's could possibly have a compromised BBB. I'll shut up now.
10. matt on August 7, 2012 7:57 PM writes...
The more I read about the underlying biology, the more I am amazed a Phase III trial was undertaken, especially given the lackluster results in Phase II.
I agree with most of the points in this article.
Once again, it's a failure of management. "Taking shots on goal" is foolish when you have been placed blind-folded, spun around, on a field you aren't sure is a soccer pitch. The proper thing is to investigate around, and support some basic research to help direct those shots.
I think pharma is paying the price for overconfidence from past successes. Two dangerous things have happened in the past. First, some took utterly blind shots and got lucky. Not in AD, but in other fields where the first blind guesses turned out to be useful. Now, it seems, pharma has wasted its money taking blind shots and feels like the hard, slow work of uncovering the underlying biology is too expensive. And second, others took blind shots and MISSED and still made good money. (That would be all the existing drugs in the AD field.) So managers are thinking, hey, ineffective may still be good enough.
Does pharma completely and utterly depend on NIH and disease foundations for basic research? Why are Phase IIIs being used to test basic research hypotheses? It seems barely sane to start building drug candidates before there was even an approved diagnostic to measure "pre-mortem" the substance you have decided to remove. I suppose now we have PiB, but was that around for AN1792?
Permalink to Comment11. imatter on August 7, 2012 9:31 PM writes...
The bexarotene case is complicated--I hope they can work out the patent issues with the compound---everyone involved should work together. Upside is that there's gonna be a surge of me-too derivatives out there based on bexarotene--curcumin anyone?
Permalink to Comment12. vasili on August 8, 2012 12:11 AM writes...
#10 : it is a question of risk/benefit ratio , it is close to one but both numbers would be huge
Permalink to Comment13. vasili on August 8, 2012 12:12 AM writes...
#10 : it is a question of risk/benefit ratio , it is close to one but both numbers would be huge
Permalink to Comment14. anchor on August 8, 2012 6:12 AM writes...
@ Matt....for both Pfizer and JJ, it was one "hail Mary," pass worth undertaking knowing well that they have a depleting pipeline. In other words, Vasili got it correct.
Permalink to Comment15. Matthew Herper on August 8, 2012 7:33 AM writes...
At least one thought on the sub-q dosing was that if the amyloid theory proves true but one needs to move upstream in disease, the next study of bapi would be in patients with some kind of pre-Alzheimer's condition.
Permalink to Comment16. Jonathan on August 8, 2012 7:56 AM writes...
#8 - there's been some interesting work done on the inflammation hypothesis too, including some intriguing findings with etanercept, very curious to see if they pan out in phase II.
Permalink to Comment17. hibob on August 8, 2012 6:08 PM writes...
@15: "the next study of bapi would be in patients with some kind of pre-Alzheimer's condition."
Turning 65?
Permalink to Comment18. daveh on August 9, 2012 7:03 AM writes...
Speak of the devil:
http://www.medpagetoday.com/Geriatrics/AlzheimersDisease/34110
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