Alzheimer's Pathways: An Investor's Guide To Biogen, Anavex, And Neurotrope

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Includes: AVXL, BIIB, NTRP
by: Lane Simonian

Summary

Amyloid oligomers are one of several factors that lead to nitro-oxidative stress in Alzheimer's disease and they do not reverse that stress.

As such, removing amyloid oligomers (a Biogen strategy) may at best only slightly slow down the progression of early Alzheimer's disease.

Anavex 2-73 slows down nitro-oxidative stress by limiting intracellular calcium release and it may act as a direct antioxidant.

Bryostatin-1 (from Neurotrope) may potentially help in the treatment of late Alzheimer's disease by restarting a neuroprotective pathway.

Investing in companies taking an anti-amyloid approach are not likely to produce high dividends (literally and figuratively) while investing in companies like Anavex and Neurotrope may eventually pay off.

At the recent CTAD conference in Barcelona, Spain a number of companies presented new data regarding their Alzheimer’s drug candidates. Much of the attention focused on Biogen (BIIB), but other companies may be pursuing more fruitful strategies against Alzheimer’s disease. In many cases, results reflect the likely mechanisms of the disease whether its Biogen’s efforts to remove amyloid oligomers, Anavex’s (AVXL) focus on inhibiting intracellular calcium release, or Neurotrope’s (NTRP) hopes founded on the activation of protein kinase C. To a degree, each company’s efforts are linked to the chain of events that leads to the onset and progression of Alzheimer’s disease.

The above chart (glutamate neurotoxicity) and this linked diagram (KEGG pathway Alzheimer's disease) likely provide many of the critical pathways that can result in the development of Alzheimer’s disease.

The role of amyloid oligomers in these pathways is highlighted in the following titles and studies:

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).

Removing amyloid oligomers, then, should have some effect on the early progression of Alzheimer’s disease. According the Biogen and Eisai’s results for their drug BAN2401 announced at the CTAD conference, the removal of large amounts of amyloid results somewhere between a 7 percent (in non-APOE4 carriers) to 63 percent (in APOE carriers) decrease in disease progression as measured by ADCOMS. If amyloid oligomers were the primary cause of the disease one would expect their removal to cure the disease. But many other toxins and other compounds produce nitro-oxidative stress through the very same pathways as amyloid oligomers (pertinently, though, these trigger compounds are often what cause the formation of amyloid oligomers in the first place). Furthermore removing amyloid oligomers does not reverse the damage that nitro-oxidative stress has already done to the brain. Thus at best, any attempt to remove or prevent the formation of amyloid oligomers only slows down Alzheimer’s disease early on. It is likely unwise to invest in Biogen, Eisai, or any other company still engaged in efforts to remove or reduce the formation of amyloid in the hopes that this approach will provide a successful treatment for Alzheimer’s disease.

Anavex 2-73 is a sigma-1 agonist that inhibits intracellular calcium release. This limits the early breakdown of acetylcholine and slows down nitro-oxidative stress. Aricept - one of the few drugs approved for the treatment of Alzheimer’s disease - works by the same mechanism. However, Anavex 2-73 is probably a more effective inhibitor of intracellular calcium release than Aricept. At 148 weeks, the high dose of Anavex 2-73 appears to stabilize activities of daily living and significantly reduce cognitive decline (CTAD slides p. 16, 17). This is far superior to Aricept which barely performs better than a placebo at three years (Aricept versus placebo). Whether Anavex 2-73 also partially reverses nitro-oxidative stress remains to be seen.

Neurotrope’s bryostatin-1 at first glance is the hardest to explain if the mechanism and pathways outlined above are correct. Bryostatin-1 is a protein kinase C epsilon and to a lesser extent protein kinase C alpha activator. Without memantine (a NMDA receptor antagonist), the drug appeared to improve the condition of those with late Alzheimer’s disease (CTAD slide). Protein kinase C is a curious enzyme in that it can promote both the degradation of memory through the formation of the nitro-oxidant peroxynitrite (ONOO-) and improve memory via the phosphatidylinositol 3-kinase/Akt pathway (which is in part dependent upon NMDA receptor activation) (diagram) (study). The phosphatidylinositol 3-kinase/Akt pathway is required for the regeneration of neurons and synapses in the hippocampus. However, the phosphatidylinositol 3-kinase is damaged by nitration in Alzheimer’s disease (as is protein kinase C itself) so instead of cell growth, you have cell death (nitration of protein kinase C) (nitration of phosphatidylinositol 3-kinase) (peroxynitrite and cell death). It is possible but far from certain that bryostatin-1 by acting as a protein kinase C agonist helps to reactivate the neuroprotective phosphatidylinositol 3-kinase/Akt pathway and thus can help someone with late Alzheimer’s disease.

The Alzheimer’s field is in limbo these days. Alternative approaches such as that taken by Anavex and Neurotrope are beginning to compete against the older anti-amyloid approach taken by Biogen and Eisai (an approach which several other companies have discontinued based on poor results). For many investors there does not seem to be enough there to entice investment in smaller companies taking a different path to treating Alzheimer’s disease (or they are skeptical of the there that is there). So the stocks don’t advance on news of new trials or further data. Further investigation into the mechanisms of Anavex 2-73 and bryostatin-1 would only be helpful to a few potential investors like myself interested in the science behind how things work. All of that said, there is relatively low risk in holding these stocks with potentially high rewards if present results are confirmed in larger-scale trials.

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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