The executives packed into the room, eager to hear the good news on their blockbuster-to-be.
Medivation, a California startup, was developing a treatment for Alzheimer’s disease, and pivotal results from a major clinical trial were finally available. An earlier study, conducted in Russia, had generated what Alzheimer’s experts hailed as the best results the field had ever seen. Dr. David Hung, the CEO, believed he had a billion-dollar product.
But the results disclosed that day in 2010 were disastrous. The drug, Dimebon, failed all five of the trial’s key metrics, performing even worse than placebo on two of them. Medivation lost more than $1 billion in value in the first hour of trading as the company’s leaders struggled to process the startling failure.
Drugs that modulate receptors involved in memory such as serotonergic receptors (as is the case of Axovant’s drug) and muscarinic acetylcholine receptors are almost bound to fail for the treatment of Alzheimer’s disease because these receptors are already damaged in Alzheimer’s disease. Unless you find drugs to reverse the oxidation, cognitive function will not improve.
By inhibiting protein kinase C activity early in Alzheimer’s disease and NMDA receptors as the disease progresses you can help slow down the progression of Alzheimer’s disease. But the current set of approved drugs that do each (acetylcholinesterase inhibitors such as Aricept limit Protein kinase C activity and Namenda which inhibits NMDA receptor activation) are not particularly effective inhibitors and thus only slow down the progression of Alzheimer’s disease for awhile. They only slow down the production of amyloid and much more importantly they only slow down the production of oxidants. It is like turning down the faucet in a sink with a stopper. The sink fills up more slowly but it still fills up.
Now if current treatments are used in conjunction with antioxidants (particularly antioxidants that effectively scavenge peroxynitrite and partially reverse the damage done to the brain) then Alzheimer’s disease can be partially reversed and stabilized. This was the case with a recent study using donepezil (Aricept) and Chinese herbs (the most important one likely being panax ginseng) in which a patient with probable Alzheimer’s disease showed some improvements in cognitive function that were stabilized for eight years. The researchers are now using the treatment in a pilot study involving 200 patients. They hint at positive results to be published soon. In another study using Korean red ginseng, around 60 patients saw improvements in cognitive function that were stabilized for two years.
The key is this many factors contribute to oxidative stress including amyloid oligomers. If you remove any one of these factors you have only delayed the onset of the disease and slowed down its progression (unless an individual has just one factor causing the disease, which is rarely the case). The oxidation process needs not only to be slowed down, the damage done by oxidation needs to be partially reversed. If you do that you can partially treat Alzheimer’s disease.
Targeting acetylcholine may be like fishing too far downstream. I have read about prions and midfolded proteins that could play a role in degenerative disease. Is there a way to detect them either with histochem or sophisticated optical trchniques? I know that there are anti prion drugs available.
I don’t think that flipping a coin 10 times and getting 7 heads is statistically significant? In this case the p-value would actually be between 0.19 and 0.22 (depending on z test or t test), both of which are well above any reasonable standard cutoff for significance.
I, as a physician, am ever so proud to belong to the consortium of doctors trying to improve all people’s care. Dr. Hung is a magnificent person and scientist. My mother and two grandparents had (what appeared to be) Alzheimer’s. Thank you for your tremendous effort and commitment.
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