Alzheimer’s Disease: Anavex 2-73 And The Long Road Home – Anavex Life Sciences Corp. (NASDAQ:AVXL)

Of all the drugs currently being tested for Alzheimer’s disease, Anavex 2-73 (AVXL) — by focusing on reducing and possibly reversing nitro-oxidative stress — likely has the best chance of success. Despite this the company faces a number of challenges including skepticism regarding results, and finding funding for phase 3 clinical trials. Everyone on a placebo declines in Alzheimer’s disease, so apparent modest improvements in cognition and activities of daily living in some people on Anavex 2-73 after a year must be due to some other factor. Giving the drug at a higher dose and to a person earlier in the disease may be among the factors that explain differences in responses (trial results).

A phase 3 clinical trial is needed to determine how much longer Anavex 2-73 stabilizes the disease. This would be considerably easier if the company had a partner, but one of the most likely candidates–Biogen (NASDAQ:BIIB)–is still pursuing its anti-amyloid drug in a phase 3 clinical trial. It seems as if the anti-amyloid and anti-tau strategies have to completely fail before larger companies will turn their attention to antioxidant strategies. Whether Anavex 2-73 can run the trial on its own with its current resources is a subject of considerable debate (earlier negative analysis). With the company’s current cash on hand and the cost of running a phase 3 clinical trial it may be a close call.

The following is a scientific case for why Anavex 2-73 provides a better treatment than either current Alzheimer’s drugs or other drugs currently in the pipeline.

Calcium imbalance and declining levels of glutathione are two of the central features of Alzheimer’s disease.

Aricept and Anavex 2-73 as sigma-1 receptor agonists inhibit intracellular calcium release and the subsequent influx of calcium that results in the formation of the nitro-oxidant peroxynitrite, DNA damage, the depletion of glutathione, inflammation (at least early in the disease), mitochondrial dysfunction, and neuronal cell death (diagram) [in the diagram, ONOO- is peroxynitrite and GSH is glutathione].

Anavex 2-73 appears to inhibit intracellular calcium release more effectively than Aricept and thus may provide a more effective treatment of the disease for a longer period of time.

The key to sustaining improvements in cognition and activities of daily living in Alzheimer’s patients is to employ compounds that donate two hydrogen atoms. Such compounds not only scavenge peroxynitrite, they also partially reverse part of the damage that peroxynitrite does to the brain through oxidation and nitration. Oxidation reduces levels of neurotransmitters needed for the retrieval of short-term memory, mood, sleep, social recognition, and alertness by disabling key receptors, enzymes, and transport systems in the brain. The function of these receptors, enzymes, and transport systems can be partially restored by adding back hydrogen atoms. Nitration limits neurotransmissions, restricts blood flow, reduces the transport of glucose, and prevents the regeneration of neurons. When peroxynitrite is scavenged it produces water and water partially reverses nitration.

Anavex 2-73 is a tetrahydrofuran derivative and tetrahdyrofurans donate hydrogen atoms—as such the drug scavenges peroxynitrite and partially reverses the nitro-oxidative damage caused by peroxynitrite in Alzheimer’s disease (tetrahydrofurans as hydrogen donors). Another group of compounds that donate hydrogen atoms are methoxphenols (such as ferulic acid and syringic acid in panax ginseng and eugenol in various essential oils via aromatherapy). Indeed it has been this class of compounds that has been most successful in improving certain types of memory in Alzheimer’s patients.

All of this struck a chord after reading a short article about the potential of stinging nettle in the prevention and treatment of Alzheimer’s disease. Looking up the chemical structure of stinging nettle produced a very rare moment of epiphany in my fourteen year journey to try to understand Alzheimer’s disease:

3,4-Divanillytetrahydrofuran (4,4’-(Tetrahydrofuran-3,4-diyldimethanediyl)bis(2-methoxyphenol) is a lignan found in Urtica dioce (stinging nettle) subspecies.

As compared to Anavex 2-73:

Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride.

Could it be then that a tetrahydrofuran derivative such as Anavex 2-73 used in conjunction with methoxyphenols would make everyone taking the drug a super responder? It may very well be worth the effort to determine if this is the case.

For investors, Anavex is neither a slam dunk nor a scam. By attacking nitro-oxidative stress, Anavex 2-73 may not only help in the treatment of Alzheimer’s disease but also in the treatment of other neurological disorders such as epilepsy, Multiple sclerosis, Parkinson’s, and Rett syndrome. Still the question remains, does it attack nitro-oxidative stress enough. Tertrahdyrofurans may be good peroxynitrite scavengers, but methoxphenols are likely better. Combining the two may partially restore some forms of memory in people who have Alzheimer’s disease.

As a kid, I used to remember avoiding stinging nettles like the plague—the pain produced by the sting was so intense. Until a few days ago, the idea that a compound in stinging nettle might provide an invaluable clue regarding the prevention and treatment of Alzheimer’s disease was beyond my imagination. It has truly been a long road home.

And it may be a long road home for Anavex investors as well. Initial results indicate that the drug is an improvement over existing Alzheimer’s medications. But to convince the FDA of that will require a phase 3 clinical trial. There are two questions outstanding. One, can the company find the resources to carry out a successful phase 3 clinical trial? And two, to what degree can the drug stop and/or partially reverse nitro-oxidative stress? Finding answers to these questions is imperative for the millions of people with Alzheimer’s disease and their care partners.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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