A provocative critique of Banner's 4/4 RCT

[SusanJ]

Another interesting take on BACE inhibitors.

These BACE trial failures have not been attributed to a particular reason and may therefore stem, in part, from an incomplete understanding of BACE1's role in the healthy brain.

To address this knowledge gap, Rudolph Tanzi, Se Hoon Choi, and colleagues investigated whether BACE1 is involved in adult hippocampal neurogenesis -- a process that may be responsible for the brain's ability to repair itself. Their study revealed that although mice which do not express BACE1 increase their production of neural stem cells, fewer of these cells reach maturity and could potentially compromise brain function in AD patients treated with a BACE inhibitor. The research suggests that partial, rather than complete, BACE inhibition may represent an alternative strategy for reducing AD pathology while maintaining adult neurogenesis.

Why BACE inhibitors may be failing Alzheimer's trials

[Julie G]

Really interesting, Susan. I suspect the abeta story is full of shades of gray. Abeta seems to be a "good guy" until it reaches a certain tipping point. My guess is that the ultimate goal will be to identify and address root causes that generate abeta before accumulation becomes prohibitive. Eye opening Significance Statement from Tanzi:

The present findings not only demonstrate that BACE1 regulates AHN, but also raise a note of caution that therapeutic inhibition of its enzymatic activity might have potential to produce a pool of adult-generated undifferentiated cells in the hippocampus. Our data strongly suggest that the complete loss of BACE1 activity dysregulates AHN in the adult mouse hippocampus. Alternatively, partial inhibition of BACE1 activity, e.g. in BACE1± mice, may mirror a more suitable therapeutic approach that would not impact AHN or NPC differentiation, for when BACE1 inhibition is being pursued as an effective means of lowering Aβ levels in AD.

[Fiver]

Thanks for the interesting information!

Maybe it is a lack of coffee this morning, but this is discouraging. I hope it is ok to gripe a bit...while the caffiene kicks in.

Oh, I wish this worked. Inhibiting the enzyme that makes AB42, the stuff of plaques, really ought to help with cognition. Sure, maybe it needs to be done earlier, in someone's 30s or 40s. OK. And maybe it is by itself not sufficient. But it really ought to work as part of a holistic treatment plan.

The seemingly positive BioGen results....I don't know if they are going to pan out. Like everyone else I'll be paying attention.

In the abstract above the warning against a total inhibition of BACE1 seems something to worry about later, frankly. Do we have medications that inhibit 100% of BACE1 activity? Not that I know of. Any new medication would almost certainly reduce (but not 100% inhibit) the enzyme. Like statins don't 100% stop cholesterol synthesis - but a 50% reduction is pretty helpful to protect against CVD. SSRIs don;t 100% inhibit serotonin reuptake, but work for many. If there were side effects, some patients would cut back or stop the treatment. Like with any other medication. If BACE1 inhibitor have some benefits but made patients more susceptible to infection we could work with that, giving anti-viral medication for example. Or develop and require immunizations for herpes viruses likely to cause problems.

I don't have a full view of all that is going on with AD research but I can't help but think that the standard model for, and pace of, clinical trials doesn't match the scale of the problem. I'd rather not slow down research on account of the possible protective effects of AB amyloid. I haven't seen many convincing studies showing that E4 folks get less infections. And I don't see many E3/E3s in line to raise their amyloid levels to gain protection from infection.

I hope that the studies continue full ahead until we find out once and for all if BACE1 inhibitors are helpful. If a few are approved then patients will have to make their own best decisions and we'll learn more along the way.

OK....caffeine is working now. Back to work for me

[DaleBru]

I'm about to join the Generation 2 study, but the more I learn the more I wonder if I should. I hear more and more that hyperinsulinemia is likely to be the underlying cause, and that beta amyloid plaques are likely a defense mechanism of the brain, protective rather than harmful, effect rather than cause. So after 200 trials have "proven" that the Generation drugs are more likely to harm me, or at best be not helpful, how is it ethical for Novartis to continue? I found this paper from 2014 interesting: https://bmcneurol.biomedcentral.com/art ... 014-0169-0. Its conclusion: "At this juncture it is no longer unreasonable to suggest that further iterations of anti-Aβ therapies should be halted."

[NF52]

I'm about to join the Generation 2 study, but the more I learn the more I wonder if I should. I hear more and more that hyperinsulinemia is likely to be the underlying cause, and that beta amyloid plaques are likely a defense mechanism of the brain, protective rather than harmful, effect rather than cause. So after 200 trials have "proven" that the Generation drugs are more likely to harm me, or at best be not helpful, how is it ethical for Novartis to continue? I found this paper from 2014 interesting: https://bmcneurol.biomedcentral.com/art ... 014-0169-0. Its conclusion: "At this juncture it is no longer unreasonable to suggest that further iterations of anti-Aβ therapies should be halted."

Hi DaleBru,

You are wisely cautious in deciding whether to join the Generations 2 drug trial, which is a five-year Phase 2/3 study testing a 15mg and 50mg dose of CNP520, a BACE-1 inhibitor, against a placebo, in healthy people with one or two copies of ApoE 4. As someone at the 17-month mark of taking either 50 mg of CNP520 or a placebo in the Generations 1 trial, I also read quite a bit before I signed up.

I'm not sure that it's completely accurate to say that "200 trials have 'proven' that the Generation drugs are more likely to harm me, or at least not be helpful." There may have been 200 trials in people diagnosed with Alzheimer's using a number of different anti-amyloid drugs. But BACE-1 inhibitors have not been studied in humans that long.

CNP520 as a BACE-1 drug isn't attacking amyloid-beta plaques; it is given "upstream" to prevent too much amyloid beta from forming. Importantly, it is given to people before they are diagnosed with MCI or dementia. It reduces the formation of three different types of amyloid beta (the pathological form of the amyloid protein) by about 62% in people taking a 10mg dose and by about 82% in people taking a 35 mg. dose (and about the same in the 50 mg dose, I think).

It isn't the same as earlier drugs that targeted BACE 1 and BACE 2 together, or even the same as other BACE-1 trials that were recently stopped. It does not seek to totally prevent amyloid beta from forming, any more than drugs to lower blood pressure seek to get blood pressure to life-threatening low levels. In fact, Generations 2 is targeting 2 different doses is that, if effective, could be safely given to people for a long time to prevent the accumulation of amyloid beta plaques, not to prevent all amyloid.

Here's a quote from a colleague of Rudy Tanzi at Harvard, and co-author of one of the papers suggesting that some amyloid is helpful. Notice the final sentence--I read that as support for the Generations approach.

"Neurodegeneration in Alzheimer's disease has been thought to be caused by the abnormal behavior of A-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients' brains," says Robert Moir, MD, of the Genetics and Aging Research Unit in the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), co-corresponding author of the paper... "Amyloid-based therapies aimed at dialing down but not wiping out beta-amyloid in the brain might be a better strategy."

{Emphasis added.} https://www.sciencedaily.com/releases/2 ... 161351.htm

You may be interested in this report by Novartis of the results of the earlier trial of CNP520 at 3 doses against a placebo. They were VERY thorough in having people track any symptom, from hiccups to feeling cold. Only one person had a "serious adverse effect"--and ankle fracture. Generally, the only symptom I've heard of as reported somewhat frequently is a minor rash on some people.
https://www.novctrd.com/CtrdWeb/display ... ltid=15947

Below is a link to the ongoing National Institute of Health website page for the Generations Trial, which is funded by the NIH with $33 million, an amount that suggests that the stringent NIH advisory committees thought the earlier trials showed promise of both safety and efficacy. The attached link has several tabs with various info; this one opens to paper published as part of the grant to date.

NIH Research Portfolio Online Reporting Tool

[Julie G]

As someone at the 17-month mark of taking 50 mg of CNP520 in the Generations 1 trial, I also read quite a bit before I signed up.

NF52, you KNOW you’re taking the drug as opposed to the placebo? Is this not a blinded study?

[NF52]

Sorry about that!! It is a doubly-blinded study. Neither I nor the staff at the site know what I am taking. They simply refer to taking the “study drug”, which is labeled as “CNP520 50mg/placebo” on the prescription label.
Per the consent forms, I have a 62% chance of being on CNP520 and a 32% chance of being on the placebo.

I didn’t mean to imply to DaleBru that I knew I was on CNP520 with no side effects; merely that I am familiar with the study protocol and aims.

I’ve edited my earlier post to indicate that I am on either the drug of the placebo.

[Julie G]

No worries, NF52. Your comment just made me question the study design...

[DaleBru]

I really appreciate your reply, @NF52. I always read your posts on this forum carefully.
But I'm still not following the logic (not just yours but Generation's). To wildly oversimplify, I'll use an analogy that beta amyloid plaque is a scab on the brain. 200 prior studies tried to pick it off or dissolve it, which didn't help AD. Now the Generation study is trying to prevent formation of the scab. I don't see why that might be helpful.

[NF52]

...To wildly oversimplify, I'll use an analogy that beta amyloid plaque is a scab on the brain. 200 prior studies tried to pick it off or dissolve it, which didn't help AD. Now the Generation study is trying to prevent formation of the scab. I don't see why that might be helpful.

Having waited 6 weeks since foot surgery to have almost all the ugly scabs disappear, I'm probably a fan of getting rid of scabs, although I admit they are a poor proxy for my ability to walk on two feet!

But your point is well-taken, and I think decisions on clinical trials come down to deeply personal risk/benefit calculations. Or how many MRIs we are willing to endure! For me, the evidence is suggestive that ApoE 4 (or 4/4 in my case) may be an over-active remnant of a helpful anti-parasite, anti-infection fighter from our earliest genetic history, with an inept response to amyloid not found in people with ApoE 3/3.

So here's just two more links that amyloid "scabs" may be interfering with synapses. Not the only way to get Alzheimer's by any means. But one that presents unique dangers to people with ApoE 4/4 who may produce too much amyloid beta mis-folded proteins, and lack the infrastructure to clear it.

This 2013 Stanford study suggests that even before plaques form, amyloid beta may be harmful to some individuals genetically at risk of AD, but not those who don't share that risk:

Beta-amyloid begins life as a solitary molecule but tends to bunch up — initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer’s. The study showed for the first time that in this clustered form, beta-amyloid can bind strongly to a receptor on nerve cells, setting in motion an intercellular process that erodes their synapses with other nerve cells.
Synapses are the connections between nerve cells. They are essential to storing memories, processing thoughts and emotions, and planning and ordering how we move our bodies.

Scientists reveal how beta-amyloid may cause Alzheimer's

And the quote below (apologies for the length) is from a November 2017 article in Neuron with a title that got my attention:
ApoE4 Accelerates Early Seeding of Amyloid Pathology

Emerging findings indicate that Aβ begins to deposit in the brains of dementia patients decades before the onset of clinical symptoms (Bateman et al., 2012, Perrin et al., 2009). Identification of a 20- to 30-year interval between amyloid positivity and dementia implies that there is window of opportunity to intervene as prevention strategies for AD (Jansen et al., 2015)...Identifying the factors that promote amyloid seeding should help to understand the mechanism underlying the onset of AD and suggest strategies for early intervention.

...Aβ deposition as senile plaques is more abundant in APOE4 carriers than in non-carriers (Kok et al., 2009). APOE4 gene dose is associated with fibrillar Aβ burden, suggesting that apoE4 might promote Aβ aggregation (Morris et al., 2010, Reiman et al., 2009). Although studies indicate that apoE4 enhances the accumulation and deposition of Aβ in the brain, the critical period when apoE4 has the strongest effects on amyloid pathology remains unclear.

We have developed innovative mouse models, allowing human apoE3 or apoE4 to be expressed specifically in astrocytes in an inducible fashion during different stages of amyloid plaque development. We revealed a crucial pathogenic role of apoE4 in the seeding of amyloids in vivo. Together, our study provides crucial evidence that apoE4 facilitates amyloid development during the early stage, gaining biological insights into apoE-targeted therapies to suppress amyloid pathogenesis to treat AD.

{Emphasis added.}

Then again, meet-ups in Indianapolis sound like another very effective intervention strategy! If only I didn't live 9 hours away--not to mention the small problem of no driving after foot surgery!