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Alzheimer's Disease

Another Alzheimer’s Antibody Goes Down

The clinical failure rate for disease-modifying Alzheimer’s therapies remains perfect, unfortunately: a flat 100%. The latest news is from Roche. Their in-licensed amyloid-targeting antibody (gantenerumab, from MorphoSys) came up empty on an interim trial analysis. Other trials are apparently continuing, but with what hopes?
Roche’s rationale seems to be that these other trials are targeting milder and/or earlier forms of Alzheimer’s. And it’s true that if an antibody approach is going to show something, those are probably the patients where it will. (There are a number of such trials going on now). But the odds are very long. And the situation is complicated by companies wanting to get something, anything, out of these extremely expensive drug development efforts – and by many scientists who have committed their research careers to the amyloid hypothesis. Add in the terribly slow clinical readouts in any Alzheimer’s trial and the large and desperate market for anything that works, and you have a tough landscape indeed.

26 comments on “Another Alzheimer’s Antibody Goes Down”

  1. steve says:

    I’m not an Alzheimer’s researcher but my immunology background makes me think that the issue might be clearance. Antibodies against amyloid are likely to work by targeting amyloid for clearance by macrophages (microglia in the CNS). What if the problem with Alzheimer’s isn’t the amyloid itself but a compromised clearance mechanism? If the microglia are compromised then tagging amyloid with antibody isn’t going to help. Has anyone looked at whether the microglia in Alzheimer’s are functioning properly?

  2. luysii says:

    God knows, we could use a few fresh approaches to Alzheimer’s disease. Two recent papers imply that Alzheimer’s disease could be a problem in physics rather than chemistry.
    First: the extracellular deposits could block the increase in flow of CSF through the brain which occurs during sleep (at least in the mouse).
    Second: the pattern of roughness of the environment can be sensed by neurons. (Amazing that someone thought to look). Too much roughness (e.g. the size of the plaques) can kill neurons in culture.
    For details —

  3. Anonymous says:

    I’ve seen the bifunctional Genentech story presented a few times this year . They target the transferrin receptor to cross the BBB, then BACE for therapeutic effect. Assuming BACE is a legitimate player in the disease pathology. it will be interesting to see how these targeting antibodies will go. They’ve been into simians and I assume humans are next. $$$

  4. Anon says:

    I’ve seen the bifunctional Genentech story presented a few times this year . They target the transferrin receptor to cross the BBB, then BACE for therapeutic effect. Assuming BACE is a legitimate player in the disease pathology. it will be interesting to see how these targeting antibodies will go. They’ve been into simians and I assume humans are next. $$$

  5. Anon says:

    @1 Did you know there is the ‘transporter hypothesis’ of AD that P-gp can extrude Abeta out of the brain (via BBB) and that those with AD have lower P-gp expression, meaning Abeta is not cleared adequately, leading to plaque formation.
    There is direct evidence for the transport of Abeta (125I labeled), but no proof that the transporters are actually decreased in patients with AD.

  6. Lane Simonian says:

    #1 I just found this last night.
    Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology
    Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the [amyloid] deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation…However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood.
    Here is one explanation for why microglia lose their function in Alzheimer’s disease.
    J Neurochem. 1999 May;72(5):1948-58.
    Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia.
    Peroxynitrite inhibited the activity of isolated KGDHC [alpha-ketoglutarate dehydrogenase], nitrated tyrosine residues of all three KGDHC subunits, and reduced immunoreactivity to antibodies against two KGDHC components. Thus, our data suggest that inhibition of the mitochondrial respiratory chain diminishes aerobic energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vulnerable to NO. and peroxynitrite that result from microglial activation. Thus, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.
    Thus you have the curious case of peroxynitrites activating microglia that produce more peroxynitrtes that then inactivate microglia. So if amyloid is somehow toxic it cannot be removed by dysfunctional microglia.
    Regarding BACE1 it is activated by caspase-3 and peroxynitrites cause capsase-3 activation. A BACE1 inhibitor may be too far down the line to effectively treat Alzheimer’s disease (not to mention the side effects).
    I have been in contact with researchers working on peroxynitrite scavengers for the treatment of Alzheimer’s disease. I cannot do the experiments myself. But certain peroxynitrite scavengers have already improve cognition and/or behavior in people with Alzheimer’s disease in small-scale human clinical trials. It does not seem to difficult to start assaying plants to identify their chemical composition and to start seeing which compounds most effectively treat Alzheimer’s disease.

  7. Anonymous says:

    Trying to solve systems biology problems with targeted approaches….haven’t we learned this is a futile strategy already?

  8. bhip says:

    Well, that was fast. Always nice to hear from you, Lane. When I was in graduate school, there was a professor (loony, but a tenured loony) who invariably asked invited speakers about the role of zinc and atrial natriuretic factor in whatever biology they were discussing. It got to the point where we warned the speakers ahead of time- it just seemed to be the compassionate thing to do…

  9. Lane Simonian says:

    Or alternatively (just for the sake of argument), peroxynitrites may actually be linked to most of the aspects of Alzheimer’s disease. If it were just me, I would accept the loony moniker, but there are actually reputable scientists working on this approach to Alzheimer’s disease. They are no more loony than those claiming that amyloid is the cause of Alzheimer’s disease and in the end they may very well be right (they have already experienced more success).

  10. Anonymous says:

    I would be surprised if the antibody have worked.

  11. Anonymous says:

    @6 and 10:
    I worked on AD for a few years, a decade ago. Eventually devised my own novel hypothesis of the causes and pathways leading to neuronal death… for which I found a good amount of supporting information in the literature, enough to get my PI excited in any case.
    However, the main learning that I derived from this experience is that the sheer amount of work that has gone into AD and the gigantic trove of data generated almost guarantees that ANY new theory for AD, no matter how ludicrous, is bound to have “some” validation data already available in the literature. Which makes sense given the massive changes taking place in the brains of AD patients over the years.
    I am not trying to dismiss your comments and hypotheses but just wanted to point out to the larger readership of this blog that anyone (including myself) can come up with a novel, half baked AD hypothesis with a bit of data behind it.
    Which might also be why the B-amyloid hypothesis has not yet gone away despite all of the clinical failures focused on it… No widely accepted, credible alternative has emerged yet.
    So yes, we need novel hypotheses but let’s be very careful about vetting these before investing in them.

  12. Marvis says:

    How do people know when an earlier form of AD exists? Isn’t it hard to diagnose even more progressed AD? The testing of any AD hypothesis requires quality disease and control groups…can such groups be identified for trials?

  13. Eric says:

    It’s disappointing to see another clinical failure in AD, but it’s not particularly surprising given the past history. Any one care to predict the odds of clinical success for the BACE inhibitors? I’d like to think there is a chance, but I’m not optimistic.

  14. Lane Simonian says:

    @10: Good find, as well.

  15. Anonymous says:

    I wonder why on earth anyone expects antibodies to work anyway, given that they can’t even get into the brain. Never mind the fact that all evidence indicates that soluble oligomers of amyloid are the primary toxic species, while the insoluble amyloid plaques are relatively benign.

  16. TX raven says:

    “… the sheer amount of work that has gone into AD and the gigantic trove of data generated almost guarantees that ANY new theory for AD, no matter how ludicrous, is bound to have “some” validation data already available in the literature.”
    Can you say the same thing about finding evidence to disprove any theory for AD?

  17. bank says:

    What is new about this study is that gantenerumab was targeted to amyloid fibrils and not the single peptide. So this is potentially a blow for the Abeta oligomer hypothesis.
    Abeta oligomers are much more toxic to neurons in culture than single Abeta molecules, and form more readily from Abeta42 than Abeta40, so it has been proposed that they, and not free Abeta peptides, are the etiological agent in Alzheimer’s disease. Gantenerumab efficiently prevented Abeta oligomer toxicity in cultured neurons and stimulated clearance of Abeta in organotypic cultures. So, it had been hoped that specifically targeting Abeta oligomers would overcome the limitations of the previous immunotherapy approaches, which targeted single species of Abeta.
    It is unclear why the trial was stopped, but it doesn’t appear to be due to any adverse effect of the antibody.
    Another nail in the coffin for Abeta???

  18. Anonymous says:

    I am with #16.
    Who on earth first get this idea of using AB in a brain chronic disease ?
    And why everybody follow it like lemmings wasting $$$ billions?

  19. Anonymous says:

    I have to agree with 12, having read pretty much ALL the literature on AZ, my only conclusion was nobody has a clue. And this was before the whole ABeta hypothesis started to look shaky.
    Recently, I read the book ‘ghost map’ about how John Snow discovered the cause of cholera. What I didn’t know was at the time was there were LOADS of competing theories and everyone had their own ideas and proof of what the cause was. It went so far as developing a sewage system to remove ‘bad odours’ that actually caused cholera epidemics in other parts of London.
    I think we need to find the equivalent of the broad street pump for AZ because until then what are we really doing?

  20. Pipeline Reader says:

    Considering the results reported above, I wonder if Roche is going to remove this video from their YouTube Channel:

  21. ANon says:

    @13: one way to go about this is to identify families of people carrying one of the autosomal dominant AD-causing mutations, which tend to have very high penetrance and predictable ages of onset, and give them the drug years before they’re predicted to start showing symptoms. Whether these people have the same disease as sporadic AD is anyone’s guess.

  22. Anonymous says:

    It’s disappointing to see another clinical trial failure in AD, but even more disappointing to see another post from Lane.

  23. Anonymous says:

    “Which might also be why the B-amyloid hypothesis has not yet gone away despite all of the clinical failures focused on it… No widely accepted, credible alternative has emerged yet.”
    Great comment. So true, but a very sad replacement for scientific method.

  24. anon says:

    Has this blog made any mention of the impressive
    Alzheimer results from Biogen? Their antibody did so well in a phase 1 trial that they intend to go directly into a phase 3. The phase 1 trial moved amyloid and cognitive endpoints significantly within 54 weeks in mild AD patients.
    Is not this some cheerful news for the season?

  25. Lane Simonian says:

    All outlying hypothesis are initially considered half-baked, loony, ludicrous, and the work of “crazy” people. That, however, does not make them wrong. And this is especially true when they explain the existing phenomena better than the established hypothesis.
    First how do peroxynitrites lead to the features of Alzheimer’s disease:
    Peroxynitrites–caspase 3 activation–beta secretase-c terminal fragment of amyloid precursor protein–g protein activation–peroxynitrites.
    Peroxynitrites–cytochrome c release, intracellular calcium release–gamma secretase–amyloid oligomers.
    Amyloid oligomers–increased hydrogen peroxide–peroxynitrites (nitrite anions–a product of peroxynitrite scavenging–combine with hydrogen peroxide to reform peroxynitrites)–nitration–amyloid plaques and/or reduction of nitrite anions to nitrite by transition metals–nitration–amyloid plaques.
    Peroxynitrites–inhibition of the phosphatidylinositol 3-kinase/Akt pathway–GSK 3 activation–hyperphosphorylation (and nitration) of tau proteins–and sometimes neurofibrillary tangles.
    You can have cell death without neurofibrillary tangles, you can have the release of intracellular calcium and amyloid plaques without much formation of peroxynitrites, and you can have the formation of peroxynitrites without much release of nitracellular calcium (heparin and caffeine are to compounds which inhibit intracellular calcium release). So you can have plaques and/or neurofibrillary tangles without having Alzheimer’s disease. And you can have Alzheimer’s disease without plaques and tangles.
    Antibodies against plaques and tangles have all failed because they do not attack the root cause of the disease. Inhibiting beta secretase may help delay the progression of the disease not primarily because they are inhibiting the formation of amyloid oligomers but because they are limiting peroxynitrite formation.
    A hundred percent of peroxynitrite scavengers have inhibited Alzheimer’s disease in vitro, but only the most powerful peroxynitrite scavengers (or combinations of scavengers) have partially reversed Alzheimer’s disease in human beings.
    So for those amyloidist and tauist out there, Bah Humbug, but happy holidays, nevertheless.

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