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Alzheimer's Disease

Lilly’s Gamma Secretase Inhibitor for Alzheimer’s: Worse Than Nothing

Well, well, well. We finally have solid clinical data from a large trial of a gamma-secretase inhibitor for Alzheimer’s disease. And it doesn’t work.
Background, for those outside the field: a hallmark of Alzheimer’s is the appearance of plaques in the brain. These are insoluble clumps of a protein called amyloid-beta, surrounded by dead and dying neurons. This amyloid is split off (for some reason) from the middle of a larger precursor protein (APP), and there are two enzymes that make the cuts to release it: gamma-secretase and beta-secretase. Shutting down one or both of those has long been seen as the most direct route to keeping amyloid from accumulating, and compounds that do this have been sought for at least twenty years now.
Now this is interesting. The road to secretase inhibition data in the clinic has been a long one, to say the very least – I worked in this field myself in the early 1990s, when we were still guessing at the enzymes involved. I would not like to even guess about the man-hours that have been spent along the way. Gamma-secretase has been a beast of a target. One nasty surprise along the way was the discovery that it also processes Notch, which is a developmental signaling pathway that you’d really rather avoid, but people have persevered, and pushed compounds into the clinic.
(As an aside, I’d have to say that beta-secretase has been even harder. There are an awful lot of structures out there billed as beta-secretase (BACE) inhibitors – and so they are, in your choice of labware. Despite huge efforts, it’s been extremely hard to make an inhibitor with a reasonable chance of getting into the brain and being a drug. The only one I know of is CTS21166, from CoMentis, about which news has been rather scarce recently).
Myriad had taken a sort-of kind-of gamma-secretase inhibitor (Flurizan) into the clinic, and failed dismally. But Eli Lilly’s semagacestat (LY450139) has long been the most advanced pure gamma-secretase inhibitor. It inhibits the enzyme directly, and had shown dose-dependent lowering of amyloid formation in humans, which is all you can ask. There were side effects noted from Notch, mostly in the GI tract, but the profile was still good enough to go on into Phase III two years ago. And now we have the results.
Nothing. Worse than nothing – they saw real declines in cognitive function compared to the placebo group. It’s not getting as much play in the news this morning, but it also appears – insult to injury – that the drug was associated with a greater risk of skin cancer. Update: a commenter points out that this risk was known). Lilly has halted any development, and told all the study centers to stop dosing immediately. All the patients who received it will be monitored to see how they do over the next few months.
This is about as bad a result as could possibly be obtained, and I think it really has to torpedo the idea of gamma secretase as a drug target. Unless someone comes up with a very compelling and intricate argument to explain these results, I don’t see how anyone can risk going down this particular road again. What must they be thinking today over at Bristol-Myers Squibb, where they’ve been developing a direct competitor, BMS708163? And how about the other drug candidates behind them?
And what does this say about the amyloid hypothesis itself? Nothing good. This is the crucial period for the whole idea, with several different approaches finally yielding late-stage clinical data. And it’s starting to look as if the whole idea may have been just a terrible diversion.

41 comments on “Lilly’s Gamma Secretase Inhibitor for Alzheimer’s: Worse Than Nothing”

  1. Anonymous says:

    This result means nothing as the compound is not brain penetrant. Lilly was depending on the “central sink” hypothesis where inhibiting gamma in the periphery would reduce levels in the brain. Problem is that this has not been confirmed in animal models, and CSF Abeta reductions were not seen in the clinic. Makes one wonder why Lilly took it into the clinic! Someone got a huge bonus?

  2. Got_QSAR? says:

    Sad to say, but I think this is the nail in the coffin for the entire beta amyloid theory. Any investor willing to continue to pump money into either beta secretase or gamma secretase inhibition is pissing their money down the drain. Unfortunate to say the least. Time to move on.

  3. Derek Lowe says:

    Anonymous, see and for CNS reduction of A-beta in human subjects after treatment with the drug. The CNS penetration wasn’t great, but it does get in (about 8% – see

  4. Bobby says:

    1. Another potential victim here could be biomarker’s in AD — Lilly took this drug to Phase III based primarily on biomarker data and with very little clinical data. It was a big bet. Many AD developers are pinning hopes on biomarker data, but there still haven’t been any definitive studies linking biomarker data with clinical outcomes in AD.
    2. Merck/S-P have a BACE inhibitor from Ligand but they don’t appear to be conducting any studies.
    3. Several companies, including Lilly, presented data from BACE inhibitor’s at this year’s ICAD meeting.

  5. Check your facts says:

    This drug wasn’t a test of the “sink” hypothesis. This post by Derek distinctly says that semagacestat is a gamma secretase inhibitor. Which means it prevents A-beta from being formed through the clevage of APP by gamma secretase. So if you follow the logic, I would think that you’d expect to slow the accumulation of amyloid plaques. I don’t see anywhere where it says it removes A-beta.
    I don’t think this says anything about the amyloid theory yet. All we know from Lilly’s press releases was that it showed a worsening of symptoms vs. placebo. As far as I’ve seen, they have not released any info on A-beta levels.

  6. anon says:

    “. . .next week. Less depressing. I promise!”
    Hey Derek, 2.5 more days left to post something positive for the week. But then again, maybe failed drugs are indeed less depressing then losing jobs or massive layoffs.

  7. Got_QSAR? says:

    @Check your facts See Derek’s links above. Semagacestat’s has demonstrated in past studies it’s efficacy in lowering A-beta levels in human.

  8. Sili says:

    At least they’d only called it a hypothesis (just as with serotonin).
    I think I’m getting too jaded, when my first thought was “kudos to them for stopping the trial”. Why is it that my first assumption is that ‘Big Pharma’ will always try to bury bad news? I guess ‘The Other Side™’ is winning the narrative.

  9. LAM says:

    This is why proper phase 3 studies are done. It also points out issues with “biomarkers” that have not been taken full-circle for validation through thorough clinical scrutiny.
    Seems a lesson that is needed for many small startups & biotechs. Example from your sites attention, Derek, is pointedly seen with the “wise and successful” people from places like Sirtris, who take up too much press coverage & news these days. They don’t understand the complexities and actual risks associated with trying to take NCEs all the way to possible new, approved drug entities. And, unfortunately, neither do some of these people’s apparent supporters within large Pharma.
    It’s sad, but we all of us in some way associated with the industry find ourselves on the slipperly downward slope from small molecule’s hay days.

  10. Betsy says:

    It would seem that the skin cancer occurrences were not completely unexpected:
    This is bad news for Elan, too, no?

  11. john says:

    ever think chemists are in trouble because we just keep making molecules to put in model systems which in most cases don’t tell us anything about diseases we’re going after?

  12. CRH says:

    @#6 anon:
    “”. . .next week. Less depressing. I promise!”
    Hey Derek, 2.5 more days left to post something positive for the week. But then again, maybe failed drugs are indeed less depressing then losing jobs or massive layoffs.”
    Hopefully you don’t think failed drugs are less depressing – you believe failed drugs won’t lead to MORE layoffs?
    The only positive news is the successful completion of a clinical study and drug launch. Anything less is fodder for “restructuring”.

  13. E. D. Thorsett says:

    As one who spent a good many career years working on the beta/gamma-secretases, many of those years in collaboration with Lilly which led to the clinical candidate, I find myself disappointed in the Lilly trial results. However, as I have watched the biology of the secretase story become ever more complicated I cannot be surprised by the outcome. Rather than being a spike in the heart of the secretase approach to AD therapy, I believe it is more a death knell for the concept of a “magic bullet” for such a complex disease. I do suppose that there are many companies discussing today the future of their own programs in the secretase area and wondering where to go or what to do next.

  14. Got_QSAR says:

    Hey Derek- In light of the latest Lilly disaster, I think one of your previous comments on beta-amyloid is spot-on. Maybe this is why Lilly saw “declines in cognitive function”.
    “But that approach (and many others) presume that beta-amyloid is a cause of the disease. Perhaps it isn’t. Maybe it’s the body’s attempt at a solution”

  15. sgcox says:

    But the genetical basis of Early-onset Alzheimer is still there and still points on the amyloid and presenilin. It just can not be one cruel coincidence with no relation to sporadic disease. Or can it ??

  16. Carl Lumma says:

    It’s not just bad for the A-beta hypothesis, it’s potentially bad for the N-APP hypothesis too.

  17. Imaging guy says:

    Dear Derek,
    The third reference in your comment is a dead link.
    Could you post the correct link? I am interested in the method used to measure the amount of CNS penetration.

  18. gippgig says:

    The automatic link doesn’t work but the address is correct. Just type it in manually.

  19. Hap says:

    I keep waiting for the news to get less depressing, and it keeps disappointing me.

  20. Skeptic says:

    CNS is turning into the figurative ‘Little Bighorn’ for Med chems. 8% clinical success rate for CNS and the highest costs. Thats a massacre folks. Whats not already in China for CNS research is surely on the way.

  21. Skepticism says:

    Hmmm…me thinks all the doom and gloom might not be warranted just yet. This was a dog of a compound – only modestly active @ the target, unselective, and barely penetrant. Derek’s detail-free links aside, the compound DID NOT LOWER CSF ABeta through phase II, even at mg/kg doses that worked pre-clinically (see Drugs of the Future 2009, 34(8): 613-617). IF LLY really did see CSF ABeta lowering in phase III (and I hope they measured this directly rather than via the radiography hocus-pocus cited in the above reference), I suspect they had to push the dose well into the point at which off-target liabilities were engaged. Cognitive declines aren’t that surprising either – could just be progression of AD coupled with the “drug’s effect on some 20 other proteins” (Siemers,Eric R.; NYTimes; Aug. 17th 2010).

  22. Eka-silicon says:

    The patent cliff at Lilly just got a lot closer, with a much, much further way to fall….

  23. Evorich says:

    Maybe you could review the Armagen article in today’s Nature to add a bit of the promised positivity into the mix!

  24. Mark says:

    Here is the story I heard, and it actually SUPPORTS the beta-amyloid theory.
    The Lilly compound had tox issues that were evident when dosed twice per day. In order to avoid those, the Phase III trial only dosed once per day. The theory was inhibiting beta secretase for only 1/2 a day was better than nothing.
    Apparently this was wrong. After the drug was cleared, they actually saw a rapid INCREASE in beta secretase activity, that is, above baseline. Basically a rebound effect.

  25. E. D. Thorsett says:

    @#24: I assume that you mean gamma-secretase not beta. Regarding your last statement about a “rebound effect,” similar effects have been observed in cell assays for gamma-secretase inhibition as well as in in-vivo experiments using transgenic mouse models. At very low concentrations, gamma-secretase inhibitors appear to actually stimulate the production of A-beta peptide.

  26. Anonymous says:

    The thing about surprising results is that sometimes you can learn from them.
    #14, QSAR:
    >> Maybe it’s the body’s attempt at a solution
    That ran through my head as well. Just for example, if main cause of the problem were too much of the precursor (APP), then inhibiting its breakdown could be _expected_ to be counterproductive. I’m sure there are also other possible ways that the whole amyloid thing could be part of, or a byproduct of, the body’s (less than perfect) solution to some (as-yet) unidentified primary problem.
    Of course, I’m just a layman (albeit, a layman who is old enough to remember when people started getting scared that aluminum cooking pans might be causing Alzheimer’s), so I’m probably screwing up the details. But I can’t help but think that the basic idea here (that the problem we see is a side-effect of some attempted solution to some other problem) might be well worth exploring.

  27. srp says:

    Well, presumably it hasn’t escaped people in the field that targeting the thing that shows up when there’s damage might be like trying to eliminate fire engines because they tend to appear wherever houses are burning down. Biology types seem very aware of complexity and feedback loops. It’s just that people were HOPING that the simple correlation-implies-causality story were true because that would give the shortest intellectual distance to a treatment. It’s not even irrational in decision-theory terms.

  28. sgcox says:

    Confusing: presenilin inhibitors (including Lilly compound) are in multiple clinical trials as anticancer agents. But this trial shows increased risk of cancer !?

  29. Mike says:

    I have to jump in here. One of the central problems is that the AD field believes that all amyloid plaques are the same: they are not. Ones that form from leaky vessels, so-called diffuse plaques, do not lead to gliosis (inflammation), and are not associated with cognitive impairment. I suspect that pre-clinical data shows a reduction of this plaque type; but so what. However the so-called, dense-cored plaques, originate from dying neurons, are associated with cognitive impairment and inflammation. You cannot rescue a dead neuron! But, preventing intracellular accumulation before the neuron degenerates can be possible. Perhaps the pathological aspects of too much amyloid are at the blood-brain barrier, but that’s another aspect of the AD pathology not fully embraced YET.

  30. Diana says:

    Ok, so maybe it is or maybe it isn’t beta or gamma secretase. What about glutaminyl cyclase?

  31. RedHotChillyPeppers says:

    Probably, this guy is not very far of the real thing:
    Med Hypotheses. 2011 Nov 29.
    Are γ-secretase and its associated Alzheimer disease γ problems?
    Rodríguez-Manotas M et al
    Following his paper, one can understand why presenilin is not the final point of the Alzheimer disease. It could be the great memory chipset (inside of gamma secretase complex).
    In the next years, we look the Alzheimer disease over the amiloid hypothesis, and we understand the real thing as a more complex dinamic system that only a cluster of clusters of “toxic” proteins.

  32. Rolling Stones says:

    It can not be as simple as: “amyloid-β being the central part of the AD mechanism”.
    The inhibitors and modulators of the secretases should work as using cyanide to inhibit the respiratory chain at mitochondria to avoid the production of CO2 that is accumulated in excess in patients with chronic obstructive pulmonary disease. How about the normal role of the enzymes that we are trying to inhibit, in order to decrease the Aβ production?

  33. Rolling Stones says:

    It can not be as simple as: “amyloid-beta² being the central part of the AD mechanism”.
    The inhibitors and modulators of the secretases should work as using cyanide to inhibit the respiratory chain at mitochondria to avoid the production of CO2 that is accumulated in excess in patients with chronic obstructive pulmonary disease. How about the normal role of the enzymes that we are trying to inhibit, in order to decrease the Abeta production?

  34. Todd Lanzoni says:

    Somebody essentially help to make seriously posts I would state. This is the very first time I frequented your web page and thus far? I amazed with the research you made to make this particular publish extraordinary. Excellent job!

  35. Until they start realizing that Alzheimer’s and other dementia’s are a result of poor glucose uptake in the brain and that coconut oil can really help and reverse it in some cases, the drug manufacturers will continue to waste their money on useless drugs that end up harming the elderly.

  36. pat says:

    i see the drug has now been successful in hair cell regeneration for hearing loss. See recent work by Harvard.

  37. DS says:

    The harvard study injected in directly into mouse cochleas. I think you would need more CNS penetration to be successful as a cure for hair cell growth. Also still the risk for skin and gi cancers with notch inhibitors

  38. Romana Rogel says:

    Hi Karlie. Good of you to think of the people IN the demos. SOmething I did not mention is that one must use good judgment in who to use in Demos. The guy with the markers-Chris- I know very well. He was in a class last semester and we have gotten to know each other well enough that I knew he could take it. I only use men for that one as it is better and always pick someone i know can take it. So good observation (and yup i factor that in).Interesting you noticed i did not move up the aisles as much. 50 minutes into class i had the same conscious thought as well- :hmmm i have been down in front a lot” again to change it up. ALWAYS moving sometimes is as bad as ALWAYS staying put.

  39. Lane Simonian says:

    Hidden in this failure is likely one of the keys to understanding Alzheimer’s disease. Presenilins the catalytic subunit of gammma secretase activate the neuroprotective phosphatidylinositol 3 kinase/Akt pathway. Inhibition of gamma secretase or presenilin gene mutations disrupt the functioning of this pathway and thus contribute to the progression of Alzheimer’s disease.
    Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.
    One of the ways in which the PI3/Akt protects the brain is by limiting the formation of peroxynitrites.
    Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.
    Peroxynitrites induce the beta secretase cleavage of the amyloid precursor protein.
    These novel NO-mediated regulatory mechanisms likely protect BACE1 from being further oxidized by excessive oxidative stress, as from H2O2 and peroxynitrite which are known to upregulate BACE1 and activate the enzyme, resulting in excessive cleavage of APP and Aβ generation; they likely represent the crucial house-keeping mechanism for BACE1 expression/activation under physiological conditions.
    By contrast, the gamma secretase is regulated by the release of intracellular calcium.
    However, it is the link between γ-secretase cleavage and intracellular Ca2+ stores which is the most intriguing aspect. Cheung et al. [50] found that PS mutant-induced enhancement of Aβ secretion can be abolished by IP3 receptor knockout, indicating that γ-secretase activity is controlled downstream of PS by IP3. How this finding relates to the hypothesis that PS is the catalytic subunit of the γ-secretase needs to be explored further.
    It is possible to have the gamma secretase cut without first having the beta secretase cut. The former leads to the production of amyloid oligomers and plaques. The latter is caused by peroxynitrites which is very likely the true cause of Alzheimer’s disease. Thus, it is possible to have amyloid oligomers and plaques in ones brain without having Alzheimer’s disease.

  40. Lane Simonian says:

    Following on the study cited by #31, inhibition of the gamma secretase increases the production of the c-terminal fragment of the amyloid precursor protein, which in and of itself causes the death of neurons.
    Early on the c-terminal fragment of the amyloid precursor protein increases activation of g protein-coupled receptors which in turn increases the formation of the neurotoxic oxidant peroxynitrite.

  41. Lane Simonian says:

    Here is the best explanation for why gamma secretase inhibitors make things worse.
    J Neurochem. 2004 Aug;90(4):800-6.
    Presenilin-directed inhibitors of gamma-secretase trigger caspase 3 activation in presenilin-expressing and presenilin-deficient cells.
    Alves da Costa C1, Ayral E, Hernandez JF, St George-Hyslop P, Checler F.
    Here we demonstrate that three distinct presenilin-directed gamma-secretase inhibitors as well as JLK compounds indirectly potentiate caspase 3 activity, the effector caspase of the apoptotic cascade. Thus, inhibitors were shown to drastically stimulate caspase 3 activity in wild-type mice blastocyst-derived and fibroblast cells.
    Peroxynitrites stimulate caspase activity which leads to the beta secretase cut in the amyloid precursor protein producing the c-terminal fragment. The c-terminal fragment leads to further peroxynitrite formation and caspase activity via g-proteins.
    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. These suggest that CT-APP may participate in Alzheimer’s pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.
    The gamma secretase partially interrupts this process by converting c-terminal fragments into amyloid oligomers. C-terminal fragments produce more peroxynitrites than amyloid oligomers than amyloid plaques.
    A beta secretase inhibitor may slow down this process by slowing down the production of peroxynitrites but not stopping the production of peroxynitrites. Therefore beta secretase inhibitors are a better option than gamma secretase inhibitors early on but not as good an option as peroxynitrite scavengers.

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