Assumptions Underlying Drug Development for Alzheimer’s Disease


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Whenever a theory strikes you as the only one possible, take that as a sign that you didn’t understand the theory or the problem it was supposed to solve.

Karl Popper, philosopher of Science

Most, but not all, Alzheimer’s treatments are based on four different assumptions for the disease: amyloid, tau, neuroinflammation, and oxidative stress. In this article, I will focus primarily on three drugs designed to reduce neuroinflammation – XPro1595 from INmune Bio, Montelukast and AL002 from Alector – and the limitations of the neuroinflammatory approach. I will address the other three hypotheses, as well as make two key general observations.

First, the same external stimuli acting through the same pathways can produce amyloid, misfolded tau, neuroinflammation, and oxidative stress. These stimuli include environmental toxins, bacterial, viral, or fungal infections, or an unhealthy diet (such as a diet high in sugar and other carbohydrates, salt, and high fructose corn syrup). External factors play a role even when genetic mutations precipitate the early onset of Alzheimer’s disease.

For example, individuals with a presenilin-1 gene mutation in Colombia develop Alzheimer’s disease nearly a decade earlier (late 1940s versus late 1950s) than individuals with the exact same gene in Japan. The main reason for the difference in age of onset is that the Colombian group is exposed to some of the highest levels of mercury in the world due to mining, whereas their Japanese counterparts have an antioxidant diet that is partly seaweed and rice bran. .

Second, amyloid, tau, and neuroinflammation are all partially the product of oxidative stress and can then make that stress worse. Unless the original stimuli are removed early or the nitro-oxidative consequences of those stimuli are addressed, inhibiting or removing misfolded amyloid and tau proteins makes only a small difference in progression. of Alzheimer’s disease.

Neuroinflammation is emerging as a new competitor to the amyloid and tau hypotheses for Alzheimer’s disease, in part because anti-amyloid and anti-tau approaches have not worked well. In Alzheimer’s disease, inflammation is primarily the product of oxidative damage to various molecules, including lipids and DNA (study). This results in the activation of toll-like receptors which causes the overactivation of microglia, which produces more pro-inflammatory cytokines and more oxidants.

Leukotrienes and tumor necrosis factor alpha are two cytokines that may play a role in Alzheimer’s disease. Montelukast as a leukotriene receptor antagonist and INmune Bio’s XPro1595 (INMB) by preventing the binding of soluble tumor necrosis factor-α to its receptor inhibit both oxidation and inflammation. INmune Bio’s drug candidate also maintains transmembrane tumor necrosis factor-α, which helps maintain a beneficial immune response via Akt.

However, since several other cytokines are also implicated in Alzheimer’s disease (notably interleukin-1β), and leukotrienes, tumor necrosis factor α, and other cytokines are primarily secondary triggers of oxidative stress , targeting them can only moderately slow progress. of the disease. In other words, if neuroinflammation were the primary cause of oxidative stress, and most of the brain damage in Alzheimer’s disease was caused directly by neuroinflammation, then this would be the ideal target for treatment of the disease. . But because oxidative stress partially precedes neuroinflammation and is directly or indirectly the cause of most brain damage in Alzheimer’s disease, it is the most appropriate target.

AL002 from Alector (ALEC) increases the activity of TREM2, which stimulates the removal of cellular debris, presumably including misfolded amyloid and tau proteins via the phosphatidylinositol 3-kinase/Akt pathway. The idea is to produce a beneficial immune response while preventing a negative inflammatory response (similar to XPro1595). However, this neuroprotective pathway is largely blocked in Alzheimer’s disease. It seems unlikely that Alector’s somewhat unorthodox approach to Alzheimer’s disease will work.

I have written extensively about drug candidates such as Blarcamesin from Anavex (AVXL), Trappsol Cyclo from Cyclo Therapeutics (CYTH), Green Valley’s GV-971 (derived from brown algae) and natural products (such as panax ginseng and other East Asian herbs) as potentially breakthrough antioxidants for the treatment of Alzheimer’s disease (article). I will recap my case for Anavex and Cyclo Therapeutics at the end of the article for those unfamiliar with this earlier work.

For now, however, I’ll just link panax ginseng to the other three hypotheses of Alzheimer’s disease.

amyloid

Ginsenosides decrease the formation of β-amyloid (Aβ) protein by inhibiting β- and γ-secretase activity or activating the non-amyloidogenic pathway, inhibit acetylcholinesterase activity and Aβ-induced neurotoxicity, and decrease Aβ-induced production of reactive oxygen species and neuroinflammatory responses (study one).

Tau

Our analysis revealed that KRGE (Korean Red Ginseng Extract) not only inhibited tau aggregation, but also promoted the dissociation of tau aggregates (Study 2).

Neuroinflammation

In the APP [amyloid precursor protein] transgenic mice, Rd [a ginsenoside] pretreatment at 10 mg/kg significantly suppresses NF-κB pathway activity, reducing the generation of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and calcium-binding protein B S100 (S100β), which may improve learning and memory abilities (study three).

It’s perhaps no surprise, then, that in an open-label clinical trial, Korean red ginseng/panax ginseng resulted in improvements in cognition that continued for two years.

In summary, inhibiting, trapping, and partially reversing oxidant damage helps prevent amyloid development, partially reverses tau aggregation, and reduces neuroinflammation and thereby limits further oxidation and nitration. On the other hand, eliminating or reducing the formation of misfolded amyloid and tau proteins and decreasing neuroinflammation only slows the production of oxidants without reversing the damage caused by these oxidants. So my semi-humble prediction (somewhat against Karl Popper’s warning) is that antioxidant drugs and natural products will be much more effective in treating Alzheimer’s disease than anti-amyloid drugs, anti-tau and anti-inflammatories.

From a financial perspective, most companies that focus on Alzheimer’s disease and/or other neurodegenerative diseases have entered a downturn for several reasons: they are between results, expectations have been tempered after a period of overmediatization which not only affected the overmediatized companies, but their competitors as well and, in some cases, doubts about the mechanism of action. All of the companies mentioned in this article have or appear to have sufficient resources to complete their ongoing trials, although Cyclo Therapeutics currently has significantly less cash than its competitors (Alector, Anavex, INmune Bio, Cyclo Therapeutics). Ultimately, the specific financial numbers, while not unimportant, are less important than whether a drug candidate will actually effectively treat a disease.

For Anavex’s blarcamesin, the signs of efficacy seen at 148 weeks in a very small trial (results) will need to be replicated in a phase 2b/3 trial, which could be completed later this year. Cyclo Therapeutics is initiating a Phase 2 clinical trial for Alzheimer’s disease based on positive case study results. Anavex reported positive data for Parkinson’s disease dementia and Rett syndrome in adults, and Cyclo Therapeutics did the same for Niemann Pick disease type 3. Anavex is also nearing completion of a trial for pediatric Rett syndrome. The exact timeframe in which the two companies will complete all of their work is difficult to predict, but the results could be critical for treating a range of incurable or poorly treated diseases.

Blarcamesin in Anavex inhibits the formation of oxidants by reducing intracellular calcium release and Trappsol Cyclo does the same by lowering cholesterol levels in lipid rafts. Although the evidence is not complete, it appears that both drug candidates scavenge the nitro-oxidant peroxynitrite. It is therefore expected that the first signs of improvement followed by long-term quasi-stabilization will be maintained in larger trials. The antioxidant approach to Alzheimer’s disease is probably the best route to effective treatment of the disease.

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