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An Alzheimer’s Compound Runs Into Big Trouble

Another interesting approach to Alzheimer’s therapy has just taken a severe jolt in the clinic. Elan and Transition Therapeutics were investigating ELEND005, also known as AZD-103, which was targeted at breaking down amyloid fibrils and allowing the protein to be cleared from the brain.
Unfortunately, the two highest-dose patient groups experienced a much greater number of severe events – including nine deaths, which is about as severe as things get – and those doses have been dropped from the study. I’m actually rather surprised that the trial is going on at all, but the safety data for the lowest dose (250mg twice daily) appear to justify continuing. The higher doses were 1g and 2g b.i.d., and the fact that they were going up that high makes me think that the chances of success at the lowest dose may not be very good.
So what is this drug? Oddly enough, it’s one of the inositols, the scyllo isomer. Several animal studies had shown improvements with this compound, and there were promising results for Parkinson’s as well. At the same time, scyllo-inositol has been implicated as a marker of CNS pathology when it’s found naturally, so it’s clearly hard to say just what’s going on. As it always is with the brain. . .

18 comments on “An Alzheimer’s Compound Runs Into Big Trouble”

  1. retread says:

    Scyllo — what a name ! Looking at the structure, shows it to be quite similar to glucose in that all the functional groups attached to the ring can get into the equatorial position. Perhaps that’s why “Nature” (whatever that is) chose (if Nature can be said to choose) glucose as the hexose of choice for metabolism, glycogen, cellulose etc. etc. There is also an L hexose where all the groups can get equatorial but I’ve forgotten what it’s called.

  2. A. Nonimus says:

    Not to nitpick, but the inositols, while vaguely similar to hexoses, are not sugars, but rather hexahydroxycyclohexanes. Myo-inositol is perhaps the best known as it is a constituent of the inositol phospholipids, and also found in multiple phosphorylated forms. Fascinating area, and I wasn’t aware of the Alzheimer’s trials. Thanks for the note, Derek!

  3. anchor says:

    The death of 9 people is too serious to be ignored. What contributed to their death? From the time the results were generated in rodents and then to clinical trials, I thought every one rushed to rake it in. Along with the death of patients, I bet ya ELEND005 is also dead!
    Moral- Haste makes waste!

  4. philip says:

    I wonder how it was supposed to work. Recently, while preparing a little talk on the blood-brain barrier, I came across an interesting method of getting cancer drugs into the brain. A large bolus injection of manitol into the blood stream will make the blood brain barrier (BBB) leaky. Co-injection with an oncolytic agent will allow some of the drug to get past the BBB and into the brain to do its work.
    Does this stuff just make the BBB leaky so that the bad stuff just leaks out rather than form those nasty plaques? Manitol doesn’t look a lot different from inositol. Just a guess. Doesn’t bode well for the low dose.

  5. cynical1 says:

    Anyone know what’s going on with the perispinal administration of etanercept (anti-TNF antibody)to alzheimers patients that was reported to literally work miracles in minutes? I read the paper in the J. Neuroinflammation earlier this year. (Tobinick E, Gross H: Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 2008, 5(2):3) It was pretty incredible.

  6. Old Timer says:

    Unlike most of your posts, I am way ahead of you on this one. The lovely structure of AZD-103 combined with the clearance of the drug in early trials is what led me to invest in this company a few years back. Although this stock produced “paper” gains greater than any holding of my life, I am currently down – significantly. I hope the lower dose comes through 🙂

  7. Cellbio says:

    cynucal1, your name serves you well for your question. The doctor whose work you reference makes a “business” out of TNF inhibition and his work is not to be trusted. Previously, he claimed enbrel utility in back pain, filed patents, then ran ads in local papers for novel patented technique. For an office visit fee, then procedure fee that came out of pocket (about $1000), he’d inject enbrel into your spine.
    Now he is on to to AD and the miracle of immediate benefit. Total scam artist, IMO.

  8. Skeptik says:

    Yes, you are correct, there was a lot of skepticism. But it turns out that TNF inhibition for sciatica and back pain appears to work (look up TNF and sciatica at And there is an awful lot of new information about TNF and Alzheimer’s. A lot of new things in science are ridiculed. There was a time when everyone thought the earth was flat! Looks like TNF inhibition is actually useful for a lot of things.

  9. partial agonist says:

    Old timer, I know that beauty is in the eye of the beholder, but this hardly looks like a beautiful drug-like structure to me.
    It looks like a compound that would promiscuously bind to highly polar hydrogen-bond rich areas of proteins, and also something that wouldn’t necessarily get passively transported very well at all.
    If it were an HTS hit, I would certainly want to move on down the list. Am I the only one that thinks this way?

  10. sgcox says:

    Just curios if the extra deaths are cancer related.
    Not sure if how solid is this link but looks interesting:
    Apparently we are doomed either way.
    merry Christmas everyone.

  11. Cellbio says:

    Yes, TNF inhibition is broadly useful. But a scam artist is still a scam artist. There is an effect noting upon TNF administration regarding pain, first noted in controlled RA trials, no doubt, but off label use of enbrel for pain, promoted in popular press, inappropriately highlighting a UCLA address to imply an association, was all designed for the personal profit of the doc, not for the appropriate manner of pain relief. This is not flat earth thinking, but outrage at scandlous behavior of a snake oil salesman.

  12. retread says:

    Enbrel is a genetically engineered fusion protein, consisting of two identical chains of the recombinant extracellular human tumor necrosis factor receptor p75 monomer fused with the constant domain of human immunoglobulin G1. Does anyone seriously think administration of Enbrel adjacent to the spinal canal will allow it to get into the brain. the site of Alzheimer pathology (which may be several FEET away).
    Sad. I dealt with sort of malarkey as a physician, trying (with little success) to dissuade desperate patients whom I couldn’t help (ALS, MS) from trying stuff like this. One of the worst was the use of snake venom (yes snake venom) for ALS.

  13. Chris K says:

    CEO of Elan commented the day of the news release that they had seen desired levels of the drug in the CSF at the lowest dose. This probably played into their decision to stop the higher doses until they see the results of the trial.

  14. Chemiluminescence says:

    Patients who have progressed to “moderate Alzheimer’s disease” may not be expected to live much longer than the duration of this study. How did the researchers control for that possibility? Is it out of the ordinary for nine out of the roughly three hundred and fifty test subjects to have died anyway?

  15. Cellbio says:

    Snake venom, and especially scorpion venom, has some wicked potent channel inhibitors, along with really efficient proteases that ensure tissue penetration. Great way to incapacitate prey and allow for slow digestion. Some peptides working there way towards clinical trials, but poor selectivity points towards neurological tox, my guess anyway. Snakes are good, but not as good as med chemists. No regulatory agency driving natural selection of toxins.

  16. Rosalind says:

    “Does anyone seriously think administration of Enbrel adjacent to the spinal canal will allow it to get into the brain.”
    Actually…Yes, in the case of Alzheimer’s. But ONLY in the case of inflammatory-associated amyloid diseases. Apparently the disease progression itself makes the BBB porous enough to accept IgG penetration; see other biologics therapies for Alzheimer’s (e.g. bapineuzumab, Iscomatrix conjugates, Novartis’ anti-Abeta mAb) that are currently in clinical trials.
    In healthy people, yes, you are correct, the BBB is freakin’ nigh-impossible to get anything bigger than a peptide through, tissue penetration of biologics is a big problem generally speaking. During the Alzheimer’s process specifically though, the BBB turns into Swiss cheese along with the brain.

  17. retread says:

    Rosalind — Interesting. Clinically, one never sees contrast extravasation with the iodinated dyes on CT or with gadolinium contrast agents on MRI in patients with Alzheimer’s disease. So I’d like some pointers to the literature concerning the porosity of the BBB in Alzheimer’s disease (not animal models).

  18. Old Timer says:

    partial agonist: I guess I should have elaborated a bit 🙂 Your concerns are what I liked about the molecule. Relying on active transport and tight binding makes for an interesting new class and breaks some of the screening stereotypes out there. As for the promiscuity, the same argument could be made for the thousands of lipophilic compounds deemed acceptable for further development every year. Sure they could bind to albumin or what have you, but specificity can be attained in those instances without too much difficulty (relatively speaking, of course). Bottom line, I think your gut reaction would be more typical than atypical, but that’s why compelling PK makes this an unusual, and therefore interesting, candidate.

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