Anavex 2-73 And Alzheimer's Disease: A Partial Picture

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About: Anavex Life Sciences Corp. (AVXL)
by: Lane Simonian
Summary

Anavex's announcements that its drug Anavex 2-73 induces autophagy has led to a renewed interest in the stock.

Anavex 2-73 helped largely stabilize cognition and activities of daily living in a small group of people with mild to moderate Alzheimer's disease at 148 weeks.

Anavex 2-73 inhibits intracellular calcium release which limits oxidation, nitration, and neuronal cell death.

The largest remaining question is whether Anavex 2-73 acts as an effective antioxidant to partially reverse these processes.

Recently, Anvavex (AVXL) announced that its drug Anavex 2-73 helped to induce autophagy. This is potentially important as autophagy leads to the removal of toxic proteins such as amyloid oligomers from the brain. Or put into a larger context by the study’s authors:

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target (source of quote).

On news of the release of this study, Anavex stock increased from $2.51 a share to $2.83 a share during the week of March 4 through March 8.

As one commentator thoughtfully suggested to me, this may be a good time to discuss what we know about Anavex 2-73 and what we still don’t know.

First, we know that at 148 weeks, Anavex 2-73 largely stabilized cognition and activities of daily living at the highest dose in a small group of people with mild to moderate Alzheimer's disease (presentation pp. 16-17). What we don’t know at this point is whether this will be verified in the forthcoming placebo-controlled, double-blinded randomized clinical trial with a much larger number of participants.

Secondly, we know that Anavex 2-73 like the currently approved Alzheimer’s drug Aricept inhibits intracellular calcium release under conditions of oxidative stress. The significance of this is that intracellular calcium release is an important step in the onset and the early progression of Alzheimer’s disease (Anavex 2-73 inhibits intracellular calcium release). The following quotes/titles apply to nearly every trigger for the disease not just amyloid oligomers:

Cytotoxicity of intracellular Aβ amyloid oligomers involves Ca2+ release from ER [endoplasmic reticulum] by stimulated production of inositol trisphosphate [IP3] (study).

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words amyloid beta doesn’t inhibit brain function unless PKC alpha is active (article).

Aβ oligomers stimulate oxidative/nitrosative pathways involving NMDA receptor, nNOS, and NADPH oxidase leading to production of ROS [reactive oxygen species]...(study).

Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vitro (study).

(Source of chart)

What we don’t know is if Anavex 2-73 only reduces the production of peroxynitrite (ONOO-) or whether it also scavenges peroxynitrite and partially reverses the damage this nitro-oxidant does to the brain. One might liken the possibilities to a stopped sink. If you turn down the tap (inhibiting the pathways that lead to nitro-oxidative stress), you only slow down the speed at which the sink fills up. If you bail out the water as fast as the water comes in (remove peroxynitrite), you stabilize the amount of water in the sink. In Alzheimer’s disease, it makes sense to do both (inhibit the pathways that lead to the formation of peroxynitrite and remove peroxynitrite itself).

It could be that Anavex 2-73 is simply a better inhibitor of intracellular calcium release than Aricept. At three years, Aricept performs little better than placebo. Whereas at almost three years, Anavex 2-73 performs much better than Aricept and the placebo (Aricept/donepezil versus placebo). Or it could be that at therapeutic doses Anavex 2-73 acts as an antioxidant whereas Aricept does not.

The clues that Anavex 2-73 works as an antioxidant are at this point indirect. Tetrahdyrofuran derivatives such as Anavex 2-73 donate hydrogen atoms and that is the key to reversing oxidative damage and to scavenging peroxynitrite (hydrogen donation). When peroxynitrite is scavenged, water is formed and water may be a de-nitrating agent (water as a de-intrating agent). Tetrahdyrofurans may also increase the capacity of other antioxidants (increasing antioxidant capacity).

A third clue comes from the present study. Autophagy depends on phoshatidylinositol 3-kinase activity and this activity is inhibited by nitration in Alzheimer’s disease (phosphatidylinositol 3-kinase required for autophagy, nitration of phosphatidylinositol 3-kinase). Inhibition of this enzyme also curtails the regeneration of neurons and synapases in the hippocampus and limits the transport of glucose and blood flow in the brain (which may contribute to delusions) (neuroprotection via the phosphatidylinositol 3-kinase). Anavex 2-73’s ability to induce autophagy would suggest that it is at least partially de-nitrating the phosphatidylinositol 3-kinase.

Most of the interventions in Alzheimer’s disease slow down the progression of the disease by inhibiting particular points in the pathways that lead to oxidation, nitration, and neuronal cell death: removal of amyloid oligomers which decreases intracellular calcium release by lessening the activation of g protein-coupled receptors, inhibition of the release of intracellular calcium (Aricept), inhibition of protein kinase C activity (riluzole), and inhibition of NMDA receptor activity (Namenda/memantine).

The likely key to treating Alzheimer’s disease, though, is to not only inhibit the triggers, receptors, and enzymes that are behind the disease, but to remove peroxynitrite and to reverse part of its damaging effects. If all Anavex 2-73 does is inhibit intracellular calcium release better than Aricept it is still a better drug than Aricept. But if it also acts as an effective antioxidant, then it will do much more.

Longs should continue to hold this stock. For those on the fence, I would keep looking for clues that Anavex 2-73 is a powerful antioxidant. In fact, I would say this is the most important unanswered question.

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.