Anavex, GV-971, Cyclo, East Asian Herbs: Alzheimer’s Drugs

Success in the treatment of Alzheimer’s disease likely requires the deployment of specific antioxidants. This may include Anavex’s (AVXL) Anavex 2-73, Cyclo Therapeutics’ (CYTH) Trappsol Cyclo, and Green Valley’s GV-971. It may also include various East Asian herbs. The following through a series of quotes tries to explain what has not worked in the treatment of Alzheimer’s disease and what has worked and why.

Multiple Receptors; Multiple Triggers

Dr. Carrasco and his team think a clinical trial of anti-fungal drugs is the next logical step. But there is yet another possibility. In the absence of a definitive ultimate cause, it may be that the symptoms of Alzheimer’s disease can arise from many different types of insult to the brain. There have been several papers, says Dr. Le Guillou that have found correlations between various infectious organisms and Alzheimer’s disease. “It could be a bit like the Mississippi river,” says Dr. Hardy. “You can start in all sorts of places, but eventually you’re going to end up in New Orleans.” If Alzheimer’s is a general response to all sorts of neurological triggers then it may be that the fungal infections found by Dr. Carrasco are simply one of a long list of causes (quote behind paywall).

There are three main receptor types – G-protein-coupled receptors, receptor tyrosine kinases, and ionotropic receptors – whose over-activation can lead to the onset and early progression of Alzheimer’s disease. In addition, there are over forty modifiable risk factors for Alzheimer’s disease, many of which act as agonists of these receptors. These include various bacterial, viral, and fungal infections, environmental toxins such as air pollutants, pesticides and herbicides, heavy metals, and industrial solvents, a diet high in sugar and other carbohydrates, salt, and high fructose corn syrup, heavy smoking, heavy drinking, psychological stress, and amyloid oligomers (the last is a secondary trigger which is a product of the primary triggers). Inhibiting particular receptors or removing or blocking individual factors only slows down the progression of the disease in subgroups of individuals. For example, Cortexyme (CRTX) has a drug candidate that treats gingipain-based infections; thus slowing down Alzheimer’s disease in individuals with these infections (results). As another example, anti-amyloid drugs very modestly slow down the progression of the disease in ApoE4 carrier, but has almost no effect on non-ApoE4 carriers because they have less amyloid in their brains (Aduhelm/aducanumab pp. 12/58, BAN2401/lecanemab, ALZ-801/tramiprosate). Usually it would make sense to treat a disease at its point of origin, but since Alzheimer’s disease has so many points of origin, this strategy does not work well.

Three Kinds of Antioxidants

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of the damage caused by peroxynitrite (source of quote).

There are multiple steps from the activation of receptors to the formation of peroxynitrite. These include increased levels and/or activity of phospholipase C, intracellular calcium release, diacylglycerol, protein kinase C, Src kinase, interleukin-1, NMDA receptor, calcium influx, neuronal nitric oxide synthase, p38 MAPK, Nuclear factor Kappa-B, inducible nitric oxide synthase, and NADPH oxidase. Drugs have been developed or are being developed to address many of these steps, but to date none of them have been particularly effective. Limiting the formation of peroxynitrite is like turning down the tap in a sink with a stopper, the sink fills up more slowly but it still fills up. A few drugs may be more successful, because in addition to slowing down the formation of peroxynitrite, they also accelerate the breakdown of peroxynitrite. For example, Aricept/donepezil and Anavex 2-73/blarcamesine – a tetrahydrofuran derivative – inhibit peroxynitrite formation via inhibiting the release of intracellular calcium and accelerating the decomposition of peroxynitrite via ketones (Aricept: sigma-1 receptor agonist and ketones; Anavex 2-73: sigma-1 receptor agonist, step one – the formation of a precursor to the ketone hydroxybutyrate).

Cassava Sciences’ (SAVA) simufilam also contains a ketone group and may also be a sigma-1 receptor agonist.

Anavex 2-73 may in addition be a peroxynitrite scavenger and repair part of the damage that this nitro-oxidant does to the brain.

Aricept, Anavex 2-73, and simufilam lead to cognitive improvements for a while at least. Aricept and Anavex 2-73 slow down the long-term progression of the disease, but Anavex 2-73 does better in this regard than Aricept (a decline of between 1.5 points and 2 points in MMSE and 6 and 8 points in ADAS-Cog scores are expected per year during the early stages of Alzheimer’s disease). Long-term data for simufilam is not available yet.

Caveat: some of the following numbers are eye-balled off of charts and in some cases a range is given where there are differences between studies.

Aricept led to around a .4 improvement in MMSE scores at six months and between a 3 to 4 point decline in MMSE scores at three years. Simufilam produced a 3.2 improvement in ADAS-Cog scores at one year, which is the equivalent of about a .8 improvement in MMSE scores. Anavex 2-73 led to a 2-point improvement in MMSE scores at 57 weeks, a 3-point improvement in MMSE scores at 70 weeks, and around a 1 to 2 point decline in MMSE scores at 148 weeks. The general trends may reflect similarities between the mechanisms of each drug; the variations likely reflects differences in the mechanism of action (Anavex 2-73 as a potential scavenger of oxidants, simufilam as a potential inhibitor of various receptors).

Peroxynitrite Scavengers Treat Alzheimer’s Disease

Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s disease do little to slow the deterioration, but instead offer a mild temporary symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer’s disease is a nitrogen derived free radical [sic] called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer’s disease in human clinical trials being repeatedly demonstrated… (original source no longer appears available).

Following is some of the damage done by peroxynitrite in Alzheimer’s disease:

• Nitration of the phosphatidylinositol 3-kinase: restricts blood flow and inhibits the regeneration of neurons, synapses, and axons.
• Tau nitration: inhibits neurotransmissions.
• Oxidation of G protein-coupled receptors: limits the release of neurotransmitters needed for the retrieval of short-term memory, sleep, social recognition, balanced mood, and alertness.
• Damage to DNA and other molecules: leads to neuroinflammation and further production of peroxynitrite.
• DNA repair, disruption of glucose transport, and mitochondrial dysfunction: energy depletion.
• Caspase-3 invocation: death of neurons.

The following drug candidates and natural products all contain compounds that are peroxynitrite scavengers.

Cyclo Therapeutics has begun a phase 2 clinical trial for Alzheimer’s disease. For one individual, Trappsol Cyclo appeared to lead to some improvements in Alzheimer’s disease over the course of 18 months (case study).

GV-971 (a drug derived from brown algae) produced a 2.7 improvement in ADAS-Cog scores at 36 weeks (phase 3 clinical trial).

Various “Chinese”/East Asian herbs have often produced better results when used in conjunction with conventional medicines (Aricept and Namenda) than the conventional medicines did by themselves (review). In one retrospective study, this combination at two years prevented further deterioration in those with mild Alzheimer’s disease and significantly arrested decline in those with moderate Alzheimer’s disease (a 2.5 point decline in MMSE scores versus a 5-point decline using conventional medicines) (retrospective study).

In the case of Panax ginseng, the improvements in cognition were maintained for two years (around a 2-point improvement in MMSE scores and a 10-point improvement in ADAS-Cog scores) (open label trial). The following compounds in Panax ginseng partially explain why it may be a particular good candidate for the treatment of Alzheimer’s disease.

Our analysis revealed that KRGE [Korean Red Ginseng Extract] not only inhibited tau aggregation but also promoted the disassociation of tau aggregates (tau study).

Saponins have long been recognized as key ingredients in traditional Chinese medicines. Accumulated evidence suggest that saponins have significant neuroprotective effects on attenuation of central nervous disorders, such as stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, our understanding of the mechanisms underlying the observed effects remains incomplete. Based on recently reported data from basic and clinical studies, this review highlights the proposed mechanisms of their neuroprotective function including antioxidant, modulation of neurotransmitters, anti-apoptosis, anti-inflammation, attenuating Ca(2+) influx, modulating neurotrophic factors, inhibiting tau phosphorylation, and the regeneration of neural networks (actions of saponins)

In a mouse model, ginseng polysaccharides:

significantly alleviated the accumulation of Aβ [amyloid beta], neuroinflammation, neuronal loss, and mitochondrial dysfunction…and significantly increased AHN (adult hippocampal neurogenesis]. (Study)

In this context, it should be noted that Trappsol Cyclo is also a polysaccharide and GV-971 is an oligosaccharide.

To the best of my knowledge, Anavex 2-73 (most likely), Trappsol Cyclo, and GV-971 are the only three advanced drug candidates for Alzheimer’s disease that limit the formation of peroxynitrite, scavenge peroxynitrite, and reduce part of its damage. At this point, these are the drugs worth investing in where possible. GV-971 and Anavex have the resources to complete their phase three clinical trials. Cyclo Therapeutics has considerably fewer resources, but in any case, its ability to carry out additional Alzheimer’s trials will depend upon results from its phase 2 clinical trial.

Whether the effects of peroxynitrite scavenging drug candidates are enhanced by natural products that also scavenge peroxynitrite remains to be seen. There are no cures for Alzheimer’s disease, but there could be effective treatments for the disease within the next couple of years.