Anavex Life Sciences Corp (AVXL)

[hooperg83]

The Science of Anavex 2-73: PART 2

To say that the pathogenesis of Alzheimer’s Disease (AD) is complex is a monumental understatement. For the past 30 or so years, science has been postulating, testing, treating, and revising its approach to Alzheimer’s Disease, and the advances have been steady. Initially, the disease was thought secondary to direct neurotoxic effects of beta amyloid plaques (extracellular) and neurofibrillary tangles (intracellular). Indeed, the burden of neurofibrillary tangles, which are hyperphosphorylated tau polymers, is correlated to the severity of dementia [1]. However, we have discovered that this is only part of the story – autopsies of some elderly patients without clinical dementia have shown a significant enough plaque burden to qualify them for the histopathologic diagnosis of Alzheimer’s Disease [2]. So what gives? This brings us to the “chicken or the egg” conundrum, or as Swerdlow more eloquently queried: does the histopathology drive the disease or does the disease drive the histopathology? Well, according to the literature, it could be a bit of both. Two theories lie at the heart of the discussion of Alzheimer’s Disease pathogenesis – The Amyloid Cascade Hypothesis and the Mitochondrial Cascade Hypothesis – and each offers clues to the nature of the disease.

In the Amyloid Cascade Hypothesis, Alzheimer’s Disease is labeled as a primary amyloidosis, meaning it is the accumulation of amyloid plaques that results in neurotoxicity. This hypothesis is supported by the fact that certain perturbations of the amyloid precursor protein (APP) on chromosome 21, such as what occurs with Down Syndrome (Trisomy 21 – APP overexpression) will result in early clinical AD. Further evidence to support this is seen with an autosomal dominant, early form of Alzheimer’s, which results from mutations to Presenilin proteins on chromosomes 1 and 14. The presenilin proteins are smaller subunits of the gamma secretase complex, which is critical in the proper processing of the APP. Improper proteolytic cleavage of the APP yields toxic forms of ABeta, including the less soluble ABeta-42 [3]. Indeed, up to 70% of early Alzheimer’s Disease may results from any of the dozens of possible mutations to these critical proteins [4]. In the highly simplified review of the Amyloid Cascade Hypothesis, we discussed a linear process that ends with neuronal death secondary to neurotoxic plaques. However, as mentioned before, some elderly patients without clinical dementia would regardless qualify for the histopathologic diagnosis of AD on autopsy due to their plaque burden. One interesting study addresses this, and concludes, naturally, that plaque burden isn’t the be-all-end-all, but rather only those with concomitant loss of neurons will demonstrate clinical Alzheimer’s Disease [5].

More recent literature, including the Mitochondrial Cascade Hypothesis, addresses the inflammatory nature of Alzheimer’s Disease and the possible contributions of oxidative stress, toxic soluble ABeta, synaptic inhibition, and high intracellular calcium concentrations, lending to glutamate excitotoxicity.

Mitochondria are ancient and fascinating. They are the “powerhouse” of the cell, and are encoded by maternal genetics on the X chromosome. Mitochondria are essential in the aerobic respiratory process of all higher life, and allow the production of mass amounts of ATP, which drives every biologic process. Unfortunately, mitochondria are also blamed for the very process of aging, as these little dynamos produce free radicals en masse, which damage and degrade DNA over time. The mitochondria cascade hypothesis is relevant to sporadic late-presentation Alzheimer’s Disease, and suggests that somatic mutations over a lifetime as well as de novo maternal contributions (what momma bestowed on you at birth) are instrumental in the pathogenesis of the other aforementioned components of Alzheimer’s Disease, including ABeta formation, Tau phosphorylation, and local inflammation [6]. Indeed, this entire process may also engender a positive feedback loop, as mitochondrial dysfunction lends itself to oxidative stress products, inactivation of glutamine synthetase, and ABeta formation, which itself is known to contribute to free radical formation, at least in vitro [7].

Now let’s talk about efficacy. Anavex 2-73 is a mixed sigma-1/muscarinic receptor agonist, meaning that when it binds, it activates a downstream pathway, whether it be inhibitory or excitatory. With respect to the central nervous system, Sigma-1 receptors are chaperone proteins found at contacts between mitochondria and the endoplasmic reticulum of the cell. Activation of the sigma-1 receptor promotes a myriad of downstream regulatory effects on calcium, potassium, sodium, and chloride channels, as well as regulation of NMDA receptors and the apoptosis pathway. It goes without saying that the complexity is way beyond the scope of this discussion, and my ability to synthesize it, but in vitro studies have shown that sigma-1 receptor agonism not only alleviates cognitive defects, but also attenuates oxidative stress, decreases cell loss in the pyramidal layer of the hippocampus, and downregulates the induction of apoptosis [8].

Continuing, in a normal brain, acetylcholine is the main neuromodulator, acting on both nicotinic and muscarinic receptors. Early literature indicated that cholinergic deficit was key to the disease’s symptoms, and therefore a reasonable solution at the time was to inhibit acetylcholinesterase, which would in turn lead to increased presynaptic concentrations of acetylcholine, thus delivering a therapeutic response. Enter: Donepezil – and indeed, it does deliver a limited therapeutic response to about 9% of patients. However, recent discoveries show, as we’ve discussed, that the manifestations once thought causing the disease are actually resulting from it—including cholinergic deficit. Hence, we can better understand why directing a therapeutic initiative at a symptom rather than a cause has a limited benefit [9].

So, how does A2-73, which is an agonist of muscarinic (M1-2-3-4) receptors, namely M1—the most common muscarinic receptor in the brain, important in motor control, sleep-wake cycle regulation, memory, and attention—presume to do any better than Donepezil [10]? I can only speculate. Given that the M1 receptor is coupled to a 7-transmembrane G-protein, activating it directly must have more longevity downstream than simply making more acetylcholine available in the synaptic cleft, but the literature is quite clear that M1 activation alone has promise in the field of Alzheimer’s therapy. Coupled with the hypothesis in early A2-73 literature that suggests a possible synergistic effect with S1/M1 receptor agonism, and the possibilities, in my opinion, favorably expand [11].

Finally, and of relevance to the company's long-term prospects, we can now hypothesize why other contemporary pharmacologic agents in development – aducanumab (Biogen), solanezumab (Lilly), RVT-101 (Axovant) – are not showing as promising results. The first two are monoclonal antibodies which directly target beta amyloid peptides or aggregated beta amyloid, which we’ve discussed is incompletely targeting the base of the disease. RVT-101 antagonizes the 5HT6 serotonin receptor as an alternative means of increasing acetylcholine concentrations (essentially re-inventing the Donepezil wheel).

In my opinion, A2-73 has the greatest potential of any drug in development that I know of, because it targets an additional (theoretical) pillar of the disease: inflammation and oxidative stress within the mitochondria. Time will tell whether or not it is successful, but the early indications are promising as has been elaborated upon time and time again (just read the PR!). At this point, Anavex simply needs to expand the clinical trials to include greater numbers of patients with more stringent controls (blinding, etc…).


** I have made every attempt to present factual and accurate data. If you see any errors, please point them out, as I will use them to make subsequent posts stronger, and hopefully better contribute to a meaningful discussion. My opinions are my own, and in no means do I mean to detract from other company working to treat this disease. I am long AVXL, and this will not change unless the fundamentals of the company leadership, science, or clinical trials dictate otherwise.

-Dr. H


Sources:

1. Brion JP. Neurofibrillary Tangles and Alzheimer’s Disease. Eur Neurol. 1998; 40(3):130-140.
2. Swerdlow RH. Pathogenesis of Alzheimer’s Disease. Clin Interv Aging. 2007;2(3):347-359.
3. O’Brien RJ, Wong PC. Amyloid Precursor Protein Processing and Alzheimer’s Disease. Annu Rev Neurosci. 2011; 34: 185-204.
4. PSEN. Genetics Home Reference. December 2013. http://ghr.nlm.nih.gov/gene/PSEN1
5. Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC. Neuron Number in the entorhinal cortex and CA1 in preclinical Alzheimer’s disease. Arch Neurol. 2001; 58(9):1395-1402.
6. Swerdlow RH, Burns JM, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis: Progress and perspectives. BBA – Molecular Basis of Disease. 2014; 1842(8): 1219-1231.
7. Sewell RD. Protein Misfolding in Neurodegenerative Diseases: Mechanisms and Therapeutic Strategies. Taylor and Francis Group. 2008; 77-80.
8. Tangui M, Tsung-Ping S. The Pharmacology of Sigma Receptors. Pharmacol Ther. 2009;124(2): 195-206.
9. Cacabelos R. Donepezil in Alzheimer’s disease: From conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat. 2007; (3)3: 303-333.
10. Xiang Z, Thompson AD, Jones CK, Lindsley CW, Conn PJ. Role of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson’s Disease. JPET. 2012; 340(3) 595-603.
11. Fisher A, et al. A Novel Multipotent Sigma 1/M1 Muscarinic Activator for Comprehensive Therapeutic Strategy in Alzheimer’s Disease. 13th International Geneva/Springfield Symposium on Advances in Alzheimer’s Therapy. 2014. Abstract Book, page 26.


(In reply to that chart of 1/ADAS-COG vs. Time: I don’t know how the creator made those calculations, as Google Scholar is referenced vaguely, but it seems like they’re calculating an ADAS-COG score based on improvements in the 5-week MMSE and then extrapolating it. That’s the first I’ve seen it.)