The ineffectiveness of Merck's (NYSE:MRK) beta secretase inhibitor is the latest in a string of clinical trial failures for Alzheimer's disease. The number of flops involving amyloid as a target has garnered much of the attention as for more than two decades this has been the major hypothesis for the cause of the disease. So far amyloid monomer antibodies, gamma secretase inhibitors, and beta secretase inhibitors have all failed to significantly slow down the loss of cognition in Alzheimer's patients. The removal of amyloid oligomers and plaques is the last amyloid-based strategy that has yet to be disproven. On the surface, Biogen's (NASDAQ:BIIB) drug Aducanumab seems to give credence to this approach by significantly slowing down the progression of the disease early on. But the results for Aducanumab are partly a chimera. A substantial portion of ApoE4 carriers dropped out of the drug group due to severe adverse reactions but very few participants with the ApoE4 gene dropped out of the placebo group. This is important because ApoE4 carriers advance more rapidly during the early stages of Alzheimer's disease. So part of the reason the placebo group declined more rapidly than the drug group is that they had more people with the ApoE4 gene who completed the trial.
Why is the amyloid approach failing? Those who cling to the hypothesis argue that amyloid is the trigger for the disease; once the disease has been triggered removing amyloid does not help. They then contend that anti-amyloid drugs have to be given well before the onset of the disease.
There is a sliver of truth in this contention. Various forms of amyloid are one of the triggers for oxidative stress which is the likely cause of Alzheimer's disease. But there are also many other triggers for oxidative stress including various environmental toxins (such as mercury, several air pollutants, pesticides, and industrial solvents), an unhealthy diet (a diet high in sugar, carbohydrates, high fructose corn syrup, and salt), psychological stress, and chronic smoking. When amyloid is one of the primary triggers for Alzheimer's disease (as is the case with some genetic mutations), its removal may have some value as a preventive measure. In late onset cases, where amyloid plays less of a role in causing oxidative stress, its early removal likely does very little good.
In any case, amyloid only does damage when it causes oxidative stress. When oxidative stress is inhibited, or when oxidants are removed amyloid ceases to be neurotoxic. And as the disease progresses, amyloid does almost no damage, for several reasons: the receptors through which it leads to oxidative stress are ironically damaged by oxidation, the secretion of the amyloid precursor protein declines, and most amyloid is converted into plaques which apparently are not toxic.
As the disease progresses, there is a specific pathway that leads to perpetual stress and the resulting death of neurons. This pathway is as follows: NMDA receptor activation, peroxynitrite formation, and increased caspase 3 activity. Peroxynitrite by inhibiting the transport and uptake of glutamate ensures the constant activation of NMDA receptors.
Three options (perhaps in combination) exist for the effective treatment of the disease. One is to inhibit NMDA receptor activation. Unfortunately, the drug approved for this purpose-Namenda-is not a strong NMDA receptor antagonist. The second option is to inhibit intermediate molecules between NMDA receptor activation and the subsequent production of peroxynitrite and caspase 3 activation. One such drug-Anavex 2-73 (NASDAQ:AVXL)-does precisely this by inhibiting neuronal nitric oxide synthase. The initial trial results indicate improved cognition followed by stabilization. The third option is to employ effective peroxynitrite scavengers that also partially reverse oxidation and nitration that cause so much damage to the brain in Alzheimer's disease (approaches to treating Alzheimer's disease). One such substance--Korean red ginseng--led to improvements in cognition at 24 weeks that were sustained for two years (clinical trial).
It is possible that some anti-amyloid interventions will delay the onset of Alzheimer's disease and slow down its early progression. But the "fact" that other drugs and certain natural products appear to partially reverse and then stabilize the disease does not bode well for those companies (such as Merck and Eli Lilly--LLY) trying to push failed drugs for earlier use in potential Alzheimer's patients. For, drugs and natural products that sharply curtail oxidation are more effective at both delaying the onset of Alzheimer's disease and in treating the disease itself than those which remove amyloid.
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