An Anonymous Coward writes:
Dr. Derek Lowe, from In the Pipeline, writes about another disappointing failure to treat Alzheimer's Disease:
Merck announced last night that the first Phase III trial of their beta-secretase (BACE) inhibitor verubecestat was stopped because of futility. The monitoring committee, after looking over the data so far (the trial's been running since 2012) concluded that there was no real chance of seeing efficacy.
[...] The list of Alzheimer's clinical failures is impressive, but the list of failures to clinically validate the amyloid hypothesis is even more so.
[...] Beta-secretase inhibitors have failed in the clinic. Gamma-secretase inhibitors have failed in the clinic. Anti-amyloid antibodies have failed in the clinic. Everything has failed in the clinic. You can make excuses and find reasons – wrong patients, wrong compound, wrong pharmacokinetics, wrong dose, but after a while, you wonder if perhaps there might not be something a bit off with our understanding of the disease. Remember, every time one of these therapies comes around, it builds on the failures before it. Better and better attempts are made – I mean, verubecestat seems to be a pretty good compound, from the preclinical drug discovery perspective. It's surely the best swing anyone's taken at beta-secretase (and there have been many). But it just flat out did not work.
The good news about this study is that it adds to the evidence that the amyloid hypothesis of Alzheimer's Disease is a blind alley and that the presence of amyloid plaques is simply correlative and not causative. As more data comes in from the study, I hope that the evidence will be conclusive enough that more effort will be spent on pursuing other therapeutic targets.
See also: https://en.wikipedia.org/wiki/Alzheimer's_disease#Amyloid_hypothesis
It has been shown that the amyloids are responsible - we don't know if they are the *only* factor.
One proof is really quite simple - give the amyloid gene of different lengths (up to 42) to mice, and they develop symptoms in 10 months which mice normally don't (10 months is ancient for a mouse).Trisomy 21(Downs) carriers in humans get Alzheimers very quickly (before 40), as the ABgene is on chr 21 a bad dosage gets amplified.
The length of the ABeta product matters - aggregation of the fibrils into plaques occurs more aggressively, and is harder to break up.
There are many compounds we can get to break up ABeta. There are fewer we can get into the body. There are a few (like this) that looked to down regulate AB production.
There is a strong correlation between diabetes and Alzheimers - yet another reason to stay slimmer than is easy...
There are no compounds we know that currently work sufficiently to arrest the conditions.
Drug Design is Hard (TM).
Both the drug mentioned in TFA and the anti-amyloid antibodies from Lilly reduced amyloid in patient CSF (we'll have to wait to see their brains) and they had great results in animal models. If these therapies reduce amyloids, but do not affect disease in any measurable way (despite Lilly running many PIII trials) then at what point do you stop trying to reduce amyloids (at least directly)?
The animal models were specifically designed to have an amyloid-driven disease and trisomy is not really great genetic evidence. There is better amyloid hypothesis-supporting genetic evidence in some early onset patients but there are also the ApoE4 carrying Nigerians that complicate things by not having the expected phenotype.
Targeting amyloids seem to be a blind therapeutic alley. Amyloids may still be bad or they may be a biomarker for something bad, but the therapeutic targets that need to be pursued are probably upstream amyloid production or downstream (caspase activation or the immune system).
Too bad biomed programs are driving away all the competent people with their pointless and endless statistical significance hunts. The more money you give them, the more BS they will produce. Amyloids are the most thermodynamically stable state of peptides in general, it is so obvious this idea has cause and effect reversed.
If everything is so fucking obvious to you, then why don't you cure Alzheimer's?
There is plenty of evidence that plaque formation can be pathological. Prion diseases such as Mad Cow, CJD, and CWD show very direct evidence of transmissible disease.
Alzheimer's is complicated and there doesn't seem to be anything that is obvious about the causal mechanisms.
First, knowing something is the wrong approach doesn't mean you know the right approach. You can just tell when people are wasting time/money. Second, I can't stand the culture of the biomedical community. Really, I was so angry and depressed all the time when I had to work with those people.
knowing something is the wrong approach
You apparently know the amyloid hypothesis is wrong because it is obvious to you. How is all the genetic evidence so obviously wrong?
I've been skeptical of the amyloid hypothesis for a while and new evidence keeps adding doubt to it being a complete explanation of the causal mechanism of disease, but it is certainly not obvious that it is entirely wrong.
As mentioned, all peptides can form amyloids, they are a generic structure. Beta-sheet aggregates are the lowest energy state for peptides, so there is no mystery they start forming when things get messed up.
Prions also form amyloids and their formation directly induces disease. How is it obvious that the amyloids in Alzheimer's are benign?
Populations with genetic determinants that specifically predispose them to producing amyloid beta in the brain develop early onset Alzheimer's at a much higher rate than non-carriers. How is it obvious that all these cases are simply a coincidence?
Populations with genetic determinants that predispose them to have inefficient clearance of amyloid beta in the brain have increased Alzheimer's risk than non-carriers. How is it obvious that these cases are a coincidence?
Would you mind jotting down the answer in the margin so we may study your works in the future?
The obvious rebuttal is that the FDA is holding these companies back.If they didn't have to actually prove that these drugs work, the drugs would already be on the market.I demand we let the free market decide!! That's the only sane way to operate anyway.