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“From All This You’d Imagine, That There Must Be Something Learned. . .”

Eli Lilly’s phase III clinical trial of semagacestat, a gamma-secretase inhibitor, was a notable disaster. The drug did absolutely nothing at all for Alzheimer’s patients – in fact, if anything, it made them slightly worse. The amyloid hypothesis was not illuminated in any useful way by this work – in fact, if anything, the situation was more confused afterwards than it had been before, and that’s saying something. For its part, Lilly spent a great deal of time and money that (in retrospect) could have been more usefully employed doing almost anything else.
Here’s a paper that combs through the wreckage looking for what we can learn from all this. It’s not an easy task:

Semagacestat was one out of the many candidate drugs that advanced as a γ-secretase inhibitor blocking Aβ generation in cell cultures, animals, and finally human. Only relatively late in the studies did it become clear that the potential side effects caused by blocking Notch-signaling were severely limiting the clinical use of semagacestat. In fact, from a scientific point of view, it remains puzzling why the company decided to move forward toward phase III tests with a dose (maximal 140 mg/day) that in none of the phase II tests had shown any significant impact on Aβ levels in the cerebrospinal fluid (CSF) of humans. Looking back, it seems clear that such a phase III trial was unlikely to test the amyloid hypothesis, as elaborated below.

The author, Bart de Strooper of Leuven and University College (London) argues that the bad effects of the drug can likely be assigned to its effects on Notch signaling, and that the eventual once-a-day dosing schedule may well have exacerbated the problem. Even the peripheral side effects (skin trouble, nausea) could have been enough to decrease the cognitive test scores of an Alzheimer’s population. As for the drug’s effects in the brain, it had a short enough half-life that combining this with q.d. dosing meant that there were periods where no drug at all would be expected to remain in the CSF. This may have actually stimulated beta-amyloid production during those periods – in fact, de Strooper argues that Lilly may have chosen one of the worst possible dosing protocols for the drug.
And he goes on to point out just how little we know about gamma-secretase, both in the disease state and under normal conditions. He characterizes the entire Lilly trial as “premature”, given the state of the field, and believes that it has in fact set back research in this area, industrial and academic. The article is a brief for the defense, from someone who clearly believes that gamma-secretase as a target has been ill served. It’s hard to argue with him on that point, but at the same time, one reason it’s been so poorly characterized is that coming up with good therapeutic approaches has been very difficult. Finding a gamma-secretase inhibitor with good properties has really been a long haul. In the end, the main lesson from the trial seems to be that we can’t draw many lessons from the trial, which reminds me of what Hegel had to say about learning from history.
I’d be willing to bet that some of the people who are upset about semagacestat’s failure and what it’s done to the field were actually glad to see it go into the clinic at the time. Finally, we’d get some sort of data on this mechanism, even if this wasn’t the best way to look at it. Had to be better than nothing, right? Well, this experience was more proof that there are worse things than nothing. The gamma-secretase field would have been better off if had continued to travel hopefully, rather than arriving at the end of that trial.

21 comments on ““From All This You’d Imagine, That There Must Be Something Learned. . .””

  1. Quote says:

    Hegel? I think you meant Santayana.

  2. Hap says:

    No, I am assuming (because I had to look it up, not having read Hegel) that Dr. Lowe meant meant “The only thing we learn from history is that we learn nothing from history.” as the reference quotation.

  3. Derek Lowe says:

    Yeah, those two pretty much land on the same target. I’m glad to work either one of them into the same post as a Pete Townshend quote, though.

  4. Lane Simonian says:

    The funny thing about failure is that it almost always leaves some room for the hope of future success: wrong dose, not applied at the right time, did not enter the brain in high enough concentrations, the placebo group confounded the results, etc. In this case, the main blame is placed on the inhibition of Notch signalling, but this signalling via the neuroprotective phosphatidylinositol 3-kinase/Akt pathway is likely not operating by the time you apply a gamma secretase inhibitor anyway (either because of presenilin gene mutations or the nitration of phophatidylinositol 3-kinase).
    The driving factor behind Alzheimer’s disease is oxidative stress and as far as amyloid is concerned each step produces less oxidative stress than the step before it such that the c-terminal fragment of the amyloid precursor protein produces more oxidative stress than amyloid oligomers which produces more oxidative stress than amyloid plaques. So if you prevent the conversion of the c-terminal fragment of the amyloid precursor protein to amyloid oligomers by using a gamma secretase inhibitor you are making the disease worse.
    Early stage Alzheimer’s disease (although this may continue with Alzheimer’s patients with hallucinations).
    Peroxynitrites–caspase 3 activation–beta secretase–c-terminal fragment of amyloid precursor protein–g protein activation–peroxynitrites.
    Mid-stage Alzheimer’s disease
    Gamma secretase–amyloid oligomers–peroxynitrite scavenging (resulting in the production of nitrite anions)–copper and zinc accumulation–hydrogen peroxide and nitrite anions–peroxynitrites or direct nitration via reduction of nitrite anions by zinc and copper.
    Late-stage Alzheimer’s disease
    Nitration–amyloid plaques–nothing

  5. Anonymous says:

    It should be (and has been right from the start) quite obvious that enzymes such as beta and gamma secretase haven’t evolved by natural selection specifically to cause Alzheimer’s disease, but to perform some important biological function. And therefore it should also be quite obvious that blocking this enzyme is going to do something bad. But as is usual in AD drug development, where the potential prize is so big, blind hope and reckless gambling trump any kind of common sense.

  6. Lane Simonian says:

    For those skeet shooters out there let me throw up some more things for you to try to topple from the sky.
    People with gout are at 24 percent less risk for developing Alzheimer’s disease. Uric acid is a peroxynitrite scavenger.
    People with autism sometimes have amyloid plaques in their brains (due to high levels of homocysteine and low levels of glutathione), but rarely develop Alzheimer’s disease. Individuals with autism have troubles breaking down polyphenols. Polyphenols are peroxynitrite scavengers.
    People with Down syndrome by the age of 40 have considerable plaques and tangles in the brains (due to high levels of myo-inositol) but only about 50 percent go to develop Alzheimer’s disease. Individuals with Down syndrome have high levels of hydrogen sulfide in their brains. Hydrogen sulfide is a peroxynitrite scavenger.
    Children exposed to high levels of air pollution sometimes have plaques and tangles in their brain but when fed cocoa saw improvements in cognitive function. Cocoa is a peroxynitrite scavenger.
    If oxidative stress is intense but not yet prolonged it is possible to have plaques and tangles without having Alzheimer’s disease or with sufficient antioxidants even after prolonged oxidative stress it is possible to have plaques and tangles without having Alzheimer’s disease.
    All the clinical trials that have partially reversed Alzheimer’s disease have involved peroxynitrite scavengers:
    Rosemary essential oil via aromatherapy (eugenol)
    Lemon balm extract (rosmarinic acid, caffeic acid, p-coumaric acid)
    Sage extract (diosmetin)
    Rice bran and Angelica archangelica (ferulic acid)
    Panax ginseng (ferulic acid, syringic acid, p-coumaric acid, vanillic acid, and maltol).
    Once Alzheimer’s disease is seen as caused by oxidative stress and not by amyloid and tau tangles, the pathway towards its effective treatment is wide open.
    O.K. fire away.

  7. Anonymous says:

    @7: “People with Down syndrome by the age of 40 have considerable plaques and tangles in the brains (due to high levels of myo-inositol) but only about 50 percent go to develop Alzheimer’s disease.”
    That’s definetely wrong. They almost all develop Alzheimer’s if they don’t die from heart failure early enough. At the age of 60-65 the incidence is roughly 75-85%, depending on source.

  8. Lane Simonian says:

    I have seen different figures, too. Here is just one:
    The relationship between Down syndrome and Alzheimer’s disease is complex. Studies have shown that by the age of 40, almost all people with Down syndrome have evidence of the brain changes characteristic of Alzheimer’s disease. This does not mean that everyone with Down syndrome will develop symptoms of the dementia of Alzheimer’s disease…
    Although the brain changes associated with Alzheimer’s disease are seen in people with Down syndrome by around 40 years, onset of the disease is not inevitable. Current research studies suggest that only about 50 percent of people with Down syndrome will develop clinical symptoms of Alzheimer’s disease by the age of 60 years, and the average age of diagnosis in people with Down syndrome is reported to be at around 55 years.
    My larger point is that though it comes at a high cost, hydrogen sulfide–a peroxynitrite scavenger–is likely the reason why not all people with Down syndrome go on to develop Alzheimer’s disease even though they have the supposed pathological markers of the disease (amyloid and tau tangles).
    Here is a supporting finding. 70 percent of people with mild cognitive impairment who have high levels of myo-inositol in the hippocampus go on to develop Alzheimer’s disease.
    Myo-Inositol, N-Acetylaspartate Are Sensitive Biomarkers for Conversion From MCI to Alzheimer’s Disease

  9. Anonymous says:

    LS: the king of ctrl+c and ctrl+v

  10. Anonymous says:

    @5
    You said, “it should also be quite obvious that blocking this enzyme [beta and gamma secretases] is going to do something bad”.
    Gamma secretase knockout mice are nonviable; however, to the contrary, beta secretase knockouts are healthy (see PMID 11406613).

  11. luysii says:

    This is reminiscent of what I used to hear in Cambridge back in the 60’s — “the problem with socialism is that it’s never been really tried.”
    But the evidence for some relationship to abeta and gamma secretase is SO tantalizing. The best is —
    [ Nature vol. 388 pp. 38 – 39, 96 – 99 ’12 ] The quick and dirty is that a mutation has been found in the amyloid precursor protein which PROTECTS against Alzheimer’s disease. The authors sequenced the APP gene of 1,795 Icelanders, just to look for low frequency variants. A mutation was found 1 amino acid away from the site cleaved by beta secretase (it changes amino acid #673 from alanine to threonine (written A673T). When the protein is cleaved this becomes amino acid #2 of the Abeta peptide.
    The mutation is far from common — around 1/200 in Scandinavian populations, and even lower in a more heterogeneous North American population.
    Then they looked at two groups of people — those with and those without Alzheimer’s disease. 5 times fewer people with Alzheimer’s disease 1/1000 had the mutation than those without, so the mutation in some way is associated with protection against the disease.
    What’s going on? A study in isolated cells shows that the mutation is associated with a 40% reduction in the formation of Abeta peptide from APP. This makes sense. A different variant at this position (alanine to valine) INCREASES Abeta formation, and is associated with Alzheimer’s. So this is excellent evidence that APP and Abeta are involved in Alzheimer’s disease.
    The news gets better and better, the (rare) variant increased the odds of reaching 85% by 50%. Then they studied people over 85 living in nursing homes. 41 carriers of A673T had better cognitive function that 3,673 non carriers.
    So this gives a lot of hope to the decrease Abeta and slow down or prevent Alzheimer’s disease hypothesis and therapies aiming to do
    so. Whether or not doing this in people who’ve already begun to decline from Alzheimer’s dis

  12. Anonymous says:

    @10: It should also be quite obvious that “viable mice” does not equal normal healthy humans without any behavioural deficits or other side effects. 😉

  13. Ann O Mouse says:

    “There is a fifth dimension beyond that which is known to man. It is a dimension as vast as space and as timeless as infinity. It is the middle ground between light and shadow, between science and superstition, and it lies between the pit of man’s fears and the summit of his knowledge. This is the dimension of imagination. It is an area which we call the Twilight Zone.”
    Definitely opened some kind of portal with this post, @Derek. Good that you stepped back from the brink and didn’t get sucked in.

  14. Anonymous says:

    Feared clicking on this as I knew Lane would be flying in with multiple walls of text in a matter of minutes.

  15. Lane Simonian says:

    There’s nothing to fear except more trials that produce more failures.
    I will focus on the most substantive comment and that is from luysii.
    Amyloid precursor protein mutations and c-terminal fragments of the amyloid precursor protein contribute to neuronal cell death even in the absence of the development of amyloid oligomers and plaques. And beneficial mutations partially protect against cell death by preventing the formation of the c-terminal fragment of the amyloid precursor protein.
    J Neurochem. 2014 Jul;130(2):291-300.
    A mutation protective against Alzheimer’s disease renders amyloid β precursor protein incapable of mediating neurotoxicity.
    Hashimoto Y1, Matsuoka M.
    http://www.ncbi.nlm.nih.gov/pubmed/24646423
    To a lesser extent, beta secretase inhibitors also limit the neurotoxicity of amyloid beta precursors. But to date these secretase inhibitors have produced dangerous side effects.
    The key to neurotoxicity throughout Alzheimer’s disease is peroxynitrite:
    J Neurochem. 2001 Jul;78(1):109-20.
    C-terminal fragment of amyloid precursor protein induces astrocytosis.
    Bach JH1, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.
    Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity.
    Behav Brain Res. 2007 Jun 18;180(2):139-45. Epub 2007 Mar 12.
    A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).
    Alkam T1, Nitta A, Mizoguchi H, Itoh A, Nabeshima T.
    For those who don’t like multiple lines of text, don’t like cutting and pasting, don’t like research unless the person does the experiment himself or herself, I can put it simply.
    Peroxynitrites are the cause of Alzheimer’s disease not oligomers, plaques, or tangles.
    The best peroxynitrite scavengers not only stop the progression of the disease, they partially reverse it.
    Read the studies again and try to provide a well-reasoned argument as to why I am wrong.

  16. Anonymous says:

    @Lane: You’re dead wrong simply because of your attitude and approach to science: Cherry picking papers and data to fit your pet hypothesis, and banging on and on about it rather than doing any new experiments, is tantamount to post hoc data analysis. It’s biased, it’s based on your beliefs rather than due scientific process, and it’s wrong. Wrong, wrong, wrong!

  17. Anonymous says:

    PS. And I wish Derek had the balls to write a blog post explaining why your attitude and approach to science is dead wrong, even though your hypothesis about peroxynitrites *might* be correct.

  18. Some idiot says:

    This stuff is so far out of my depth that I would be drowning even with a snorkel (and probably even with a scuba tank… (-; ) but I am glad to see that the debate is ferocious but amicable… As my father would say, this way it generates more light than heat….!
    (-:
    Please continue… I am learning….!
    (-:

  19. Lane Simonian says:

    #18 Thanks (this time I actually got the number right). Open debate is good; it makes you redefine and sometimes reconsider.
    #16-17 I actually agree with you: I am a very poor messenger for what may be the correct hypothesis for Alzheimer’s disease. And my attitude needs improvement as well (some of that is a hardened defense as to what I consider unfair criticisms by scientists over the years–what I saw as red herrings, false premises, ingrained assumptions, a sense that their method for finding the truth was better than mine). I am a historian not a scientist. My method is inductive not deductive. Historians read vast amounts of information to try to tell accurate stories. We don’t reach conclusions early on.
    I was three years into research on Alzheimer’s disease before I stumbled onto an obscure reference to peroxynitrites. My aunt and cousin were in the late stages of the disease and my mother was in the early stages of the disease. About a month later (in 2007) I found the article on how rosmarinic acid ameliorated memory loss in Alzheimer’s disease. So I started having my mother smell rosemary essential oil every morning (not knowing at the time that the key compound in rosemary essential oil is not rosmarinic acid but eugenol). After a month she asked why I had been giving this to her every day for a month and why I had moved an object on her shelf. We added other essential oils high in polyphenols later.
    Over time, my mother recognized her home again (sometimes even before we got to the driveway–she would say we are almost home), she stopped having delusions, and she was much more alert and aware. She smiled again and became much less withdrawn, more talkative, but only slightly more lucid. She continued to improve for five years before dying of heart failure.
    Once it appeared that peroxynitrites were the primary cause of Alzheimer’s disease, I began to work backwards: what were the causes of peroxynitrite formation and did these increase the risk for Alzheimer’s disease, how did they contribute to amyloid oligomers, plaques, hyperphosphorylated and nitrated tau, tau tangles, how did they relate to the beta and gamma secretases, what limited the formation of peroxynitrites and did this lower the risk for Alzheimer’s disease, how did peroxynitrites relate to other diseases and why did these disease have different outcomes from Alzheimer’s disease, and what were the outcomes of peroxynitrite scavengers in the treatment of Alzheimer’s disease (when the study came out in 2009 that aromatherapy with rosemary essential oil via aromatherapy improved cognition as related to personal orientation, I said yes this is what I have seen myself).
    So I bristle at comments regarding cherry picking and copying and pasting–it is much more than that. It is supporting a hypothesis that seems to explain all the observed phenomena. The approach is not “scientific” per se–so maybe the question is what are the differences between scientific and historical research and the advantages and disadvantages of each. For example, can you come to an understanding of a disease purely by reading the experiments that have been done, without ever having done an experiment yourself? And should a thorough literature search be done before doing the experiment in the first place?
    I will conclude with my two favorite quotes on Alzheimer’s disease. One is by the late Mark A. Smith who I would have liked to have met because he seemed to share my persistence and passive aggressive tendencies. The other by a non-scientific, inductive anonymous researcher.
    “I have received a lot of stick for my scientific talks where for over a decade I have challenged the amyloid hypothesis. I typically tell the audience that my views are controversial and that I would really appreciate someone pointing out the flaw in my logic or presenting evidence that shows that I am wrong. Neither has ever happened.”
    [Clinical trials with over-the-counter supplements have concentrated either on items which suppress
    inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s disease do little to slow the deterioration, but instead offer a mild temporary symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer’s disease is a nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau
    accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite
    scavengers, with reversals of Alzheimer’s disease in human clinical trials being repeatedly
    demonstrated. IMHO, the only thing which may be preventing the abolition of Alzheimer’s disease is the mental inertia of scientists, as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones. Common sense is anything but…]

  20. passionlessDrone says:

    @16: > You’re dead wrong simply because of your attitude and approach to science:
    I’m not convinced this is the case; I think we should applaud people who likely have no capability to actually run experiments still be interested in learning, but for the sake of argument, assuming that you are correct here, it would seem that she would have plenty of company considering this post was about people being so enamored with the amyloid hypothesis that even with non-existent results in phase II, lily went ahead with phase-III trials utilizing different methods. Considering the frequency with which this board bemoans the lack of scientific literacy in the general population, I’m not sure throwing insults at LS is appropriate.

  21. Ann O Mouse says:

    I completely agree with @20. While I think Lane Simonian’s hypothesis is overly simplistic, I don’t think it’s snake oil either. I commend him for diving head first into a field where he clearly has an interest beyond professional. More to the point, I think the entire debate in these comments has drifted into the twilight zone and away from the point of the original post and article, namely that poorly designed trials with poorly chosen compounds set back the field, even if the underlying hypothesis is correct. The failure of semagacestat simply does not address the amyloid hypothesis any more than drinking phenol would address the oxidative stress theory.

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