The BACE1 research looks very solid. Any side effects that have managed not to be recognized by this point should be fairly subtle or only likely to emerge after prolonged treatment.
There were quite a few problems when they tried to target gamma secretase. However, with BACE1 the biology has not created such a logjam for development.
Sometimes life defeats you no matter how smart you are. The BACE1 research has shown what is possible
when you find a target that can be druggable (with a few workarounds). They have cranked the supercomputers for the third generation BACE1 inhibitors that
do not also inhibit BACE2 (It has been reported that this product should enter clinical trials next year). BACE2 is a powerful amyloid degrading enzyme, so it would be best not to inhibit it.
The market potential is almost limitless.
Everyone over 90 has Alzheimer pathology. They would likely want to consider BACE1 treatment.
There are 40 million Americans who are over 65. It would also not be unreasonable for everyone over 65 to consider treatment.
Nor would it be beyond question that many of the over 100 million Americans over 50 think about it.
The 60 million epsilon 4 carriers would also be candidates. Perhaps some of them might like to start treatment even in their 40s.
For those with particularly aggressive early onset, treatment beginning in childhood might be warranted.
One of the interesting implications of the nature of this market is that the price that these drugs will actually command in the market will be much less than would
be ordinarily expected. To entice all of these tens of millions of consumers to buy a lifestyle drug that might show minimal benefit for decades the price would
need to be on the low side. However, as was seen with statins, pharmaceuticals that are broadly consumed even with modest prices can generate overwhelming
amounts of revenue for the pharmas. Considering the numerous pharmas with inhibitors in the pipe, the proper market structure to model expected behavior would be
closer to a free market instead of a monopoly (meaning price moves to marginal cost instead of that of a profit maximizing monopolist?).
Research suggests that long term reduction in amyloid leads to better cognitive health. The trajectory of "normal" cognitive aging might now be rewritten.
"This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease."
https://www.ncbi.nlm.../22801501
There are also implications for the mission of this forum. This forum is dedicated to Advocacy and Research for Unlimited Lifespans. If BACE1 inhibitors can truly protect against Alzheimer's dementia that is essentially hardwired into the genetic blueprint of humanity, then a new era of longevity research can begin. Much of modern medicine
has retreated into the pragmatic point of view that its role is to help people who have lived a long life to accept that human life span is limited and to prepare to transition
for this next stage of the journey. Without a nearly universal presence of Alzheimer's at older ages, these people might be able to more forcefully advocate for themselves and
express the opinion that they are not interested in that next stage of the journey: they just want to journey on.
There will in fact be a substantial amount of dementia left in the community even if BACE1 drugs were to have therapeutic effects. The current treatment trials (i.e. people with prodromal, and mild-moderate AD) require that enrollees have positive amyloid scans. BACE1 lowers amyloid levels; allowing those without amyloid into the trial would add much noise into the analysis.
Some of the previous Alzheimer's clinical trials found that 30-40% of the patients did not actually have amyloid (This was especially enriched in the non-epsilon4 arms). It will be interesting to know how many of those in the current BACE1 trials were rejected because they had "non-amyloid Alzheimer's". [It is currently thought that this term is oxymoronic. Amyloid is required for an Alzheimer's diagnosis.] It is not obvious what treatment pathway might emerge for those with non-amyloid dementia. It is entirely possible that such a group might be highly heterogeneous which could make developing any socio-political movement to address the problem more difficult.
Edited by mag1, 06 November 2016 - 04:25 AM.
