Anavex Life Sciences Corp (AVXL)

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Anavex Life Sciences Corp. - Things To Know. (Due Dillgence for prospective AVXL investors with special thanks to falconer66a.)

A Promising New Alzheimer’s Treatment Drug

The Problem. Alzheimer’s disease debilitates and kills ever-increasing numbers of aging Americans. The Alzheimer’s Foundation of America estimates that as many as 5.1 million Americans may have the disease, and the number is increasing with our large, aging population. The disease is devastating to both its victims and their care givers. Treatments and care-giving costs are massive, stretching collectively into the many billions of dollars.

Treatments. Effectively, there are none presently. A few, very expensive drugs can temporarily, for just a few weeks or months, merely slow the aggravating progression of symptoms. No treatment drug or protocol either stops or cures the inevitable progression to profound disability and ultimate death from the disease. A diagnosis of Alzheimer’s disease is a curse for which modern medicine offers no hope.

Treatment Research. The cause of Alzheimer’s symptoms is almost universally perceived to be the accumulation in or near nerve cells (neurons) of two waste proteins, agglomerations of beta-amyloid plaque, and neurofibrillary tangles, insoluble twisted fibers composed largely of the protein tau, composing the tau tangles.

Current research has strived to remove these neuron wastes that complicate normal brain nerve functions. Plainly, and tragically, all of these efforts have failed. The research drugs targeted at waste proteins have either failed to reduce their presence, or have concomitantly caused serious, even lethal side effects.

The other approach has been to prompt the immune system to chemically destroy and remove the waste proteins. These efforts, too, have failed in every case.

Until now, there have been no drugs that have demonstrated any safe, effective potential to successfully treat Alzheimer’s in any useful way. The disease continues to be an un-treatable curse.
Until now.

A Successful New Drug in Development. A different treatment approach is required. Instead to attempting to pharmaceutically remove beta-amyloid plaques and tau tangles, one company’s researchers have intelligently targeted — successfully — the root cause of those waste protein agglomerations. Instead of attempting to remove them after their formation, after they persist and continue to cause nerve dysfunction, the new approach is to keep them from ever forming, or facilitate their removal by natural, innate cellular processes (as occurs in normal, non-diseased neurons).

This approach will revolutionize Alzheimer’s treatment (along with a number of other neurodegenerative diseases). Children and young adults virtually never get Alzheimer’s. It appears in middle to older aged individuals; after earlier years of mental normalcy. With age, neurons in many people fail to work normally. The new drug restores youthful “homeostasis,” consistent, normal cell status or function, in a powerfully unique and successful way.

The proper function of two structures, organelles, in the neuron are essential. Mitochondria are tiny cellular structures that extract energy from digested food molecules and store that energy in adenosine triphosphate, ATP. ATP is then used in virtually all cellular reactions and processes to power them. ATP is the cell’s energy resource. Without adequate ATP, cellular processes are diminished or inhibited, and disease ensues.

The other essential organelle is the endoplasmic reticulum. Endoplasmic reticula (among other things) take ATP from adjacent, connected mitochondria and use its energy to properly fold and lock together complex proteins, primarily essential enzymes. Virtually all cellular chemistry is mediated by controlling enzymes, much as a key unlocks a lock. If a key, in this case an enzyme in a neuron, is bent or misfolded, the lock, or the life-supporting chemical reaction cannot occur.

In most neurodegenerative conditions, especially Alzheimer’s, endoplasmic reticula become separated from the mitochondria. They no longer can receive sufficient ATP to properly fold proteins into normal reaction-controlling enzymes. The cell fails to function properly, or even dies (as in the case of advanced Alzheimer’s neurons).

The solution? Find a molecule that re-connects and maintains the mitochondrion-endoplasmic reticulum connection. Keep the two organelles connected, so proper, healthful enzymes can be normally synthesized — as was the case before Alzheimer’s struck.

The Revolutionizing Molecule. Wonderfully, such a molecule has been engineered, and has been tested in early trials on humans, with extremely positive results. The molecule is Anavex 2-73, a patented proprietary chemical of Anavex Life Sciences Corp. (AVXL:NASDAQ).

Early clinical trials of Anavex 2-73 have established the following facts:

1. Few or No Side Effects. After a year of administration to people with mid to moderate levels of Alzheimer’s, no serious, debilitating, or disqualifying side effects appeared. For drugs treating nerve or brain conditions, this is exceptionally rare.

2. Stops or Improves Alzheimer’s Symptoms. Remarkably, Anavex 2-73 in dosing ranges between 10 to 50 mg (very small amounts) in a one-year clinical trial period, either a) stopped the progression of symptoms, keeping them at the initial dosing level; or b) remarkably reversed the severity of symptoms, trending at the end of the 52-week trial toward mental and functional normalcy.

Larger, substantiating clinical trials of Anavex 2-73 for Alzheimer’s should be forthcoming. But preliminary lab data in animals, followed by the profound findings of the recently-reported clinical trial in humans are revolutionary. Now, there is profound hope for a) successful treatment of Alzheimer’s, and b) termination of the progression of the disease at its earliest, mildest degrees.

The Future. Anavex 2-73 holds the promise of solving the expanding Alzheimer’s problem, first in America, and then in the rest of the world. The sooner Food and Drug Administration (FDA) approval is attained for this safe and effective drug, the sooner millions will no longer be medically and financially ruined by this frightful disease.

Summary. Not only are there greater than 106 peer-reviewed scientific papers on the positive effects of S1R agonists, there is specific preclinical validation of A2-73 in not one but ten neurodegenerative diseases. Anavex has had preclinical financial backing by MJFF, the Rett Foundation and the Fraxa Foundation. The A2-73 P2 trial has been funded largely by the Australian government.

The Rett Foundation has agreed to fund the A2-73 P2 Rett trial, a 3 month trial with a price tag of about $1 million. Remember that Retts girls frequently have seizures, so this 3 month trial is in some respects a seizure trial. Jackie French, a world expert on epilepsy and a member the Anavex SAB, has said, "I am extremely impressed with the positive preclinical epilepsy data for 2-73, which demonstrates a significant increase in anti seizure efficacy relative to 3 currently approved epilepsy drugs as well as significant synergy with each of these drugs.

Remember too that A2-73's non sedating feature is very attractive, as most other epilepsy medications are sedating. Also, A2-73's positive cognitive effects are attractive, as epilepsy patients often show cognitive decline. A2-73's use may also be to reduce the dose of the 3 above-mentioned epilepsy drugs and thus decrease the side effects of those medications. Comparing the frequency and magnitude of seizures before and after treatment won't be nearly as ambiguous as analyzing Alzheimer's data.

Harald Hampel, a world expert on AD, said the A2-73's positive effects in AD had "a degree of confidence we did not anticipate" and that this drug deserved to enter a P2/3 trial. This is a high recommendation in that only 25-30 drugs tested for AD ever made it to P3. Of these, only 5 were FDA approved and their efficacy, as we all know, is marginal and they do not affect the course of the disease. I would be much more worried about A2-73 if its MOA were similar to the above mentioned drugs or to the many downstream drugs that have all failed.

It seems significant that George Perry, editor of the Journal of AD, said "Although this is an open-label study with 32 patients, I have never seen mild to moderate AD patients maintain near baseline cognitive and ADL function and positive correlation with all other measures over a 41 week trial period in any prior study with an approved or experimental drug. It is quite plausible that complex CNS diseases like AD may require a comprehensive approach, including restoration of cellular homeostasis."

This statement seems to me to suggest that Dr. Perry thinks treatment of AD will be multimodal, just as, for example, hypertension frequently requires treatment with 2, 3, or even four agents, and cancer is almost always treatment with multiple drugs, and AIDS is treated with triple drug antiviral compounds. It may be that AD drugs that have already failed may still be useful in combination with other agents and, if A2-73 is successful, BP companies will likely want to study their drugs in combination with A2-73.

Paul Maruff, CSO of Cogitate, said "Cogitate tests measure ability to store and use information. The P2a results show A2-73 improved psychomotor function, attention and working memory. The latter two were drastically significant and their magnitude clinically important. We have not yet seen a drug that has improved quantitatively working memory to such an extent."

Neuronetrix indicated that they had yet to see drug with better EEG/ERP effects than A2-73. Macfarlane said that "these are the kinds of studies that got donepezil approved by the FDA." The P2 study showed "the P300 wave amplitude showed a small initial increase from about 6 microvolts to 7 microvolts by four weeks, and then returned to about 6 microvolts until about week 32. Thereafter it steadily improved to about 8 microvolts by 57 weeks--a level usually seen in healthy age-matched controls.

There was a significant separation from the P300 decline seen in a matched historical AD cohort, which decreased to about 4 microvolts over a 52 week period while taking donepezil." The P300 brain waves not only increased in amplitude, but did so faster and higher than donepezil, and the shape of the wave was closer to normal. Consider these comments in the context of a P2 study that was not dose optimized and was designed to fail early.

Part of the drug approval process under the Twenty First Century Cures Act is the patient's and caregiver's perspectives on how the patient is responding to the medication. "Real world evidence and the stronger inclusion of patient perspectives on endpoints are two examples of the shifts that will impact therapy development." In this regard it seems significant that all patients wanted to continue A2-73 after the end of the trial. Also the Australian media exposure supports a positive patient and caregiver response.

Positive characteristics of A2-73: it is a small molecule that penetrates the blood brain barrier, is safe, and has a positive dose response curve in 2 independent cognitive markers. It causes transient headaches and dizziness, which you want to see in a CNS drug. It has a remarkably fast onset of clinical effect.

Its maximum tolerated dose is known. Its minimum effective dose is known. It has a potent affinity for the S1R and moderate affinity for the M1-4 muscarinic receptors. It has been shown to decrease inflammation and oxidative stress in cells, correct mitochondrial dysfunction and protect various mitochondrial enzymes (allowing effective generation of ATP), enhance endoplasmic reticulum function (so newly synthesized proteins fold and remain folded, otherwise beta amyloid and tau accumulate), prevent neural apoptosis by up regulating bcl-2 and down regulating capsize, up regulate neurotic outgrowth to increase or maintain brain connectivity, normalize BDNF expression in the hippocampus (BDNF polymorphism correlates with higher seizure frequency and severity in Rett's Syndrome as well as cognitive decline and increased A beta accumulation in AD).

It has received ODD for Rett's Syndrome and infantile spasms. Its P2 adaptive trial reduces the chance of a P3 failure. P3 is to be tailored to the strong responder group to decrease the chance of a P3 failure. Genetic testing is being done on trial participants in preparation for upcoming trials. This may help guide patient selection. The extension trial is labelled a "new trial" which should allow dosage adjustments, which should also decrease the chance of a P3 failure.

Positive company issues: Missling is a summa cum laude from the Univ. of Munich and has an MBA from the Kellogg School of Management, where he wrote his thesis on partnership valuations. He has 20 years experience in Big Pharma, Biotech, and investment banking/M&A. The officers are Big Pharma vets. There is no company debt. Missling has stated that his goal is to maximize shareholder value. They have a cash runway for two years. There has been no insider selling. The P2 Rett trial will be funded by the Rett Foundation. He has also received funding from MJFF, FRAXA Foundation and the Australian government. All of these have stated that they want to continue working with Anavex.

There is an in-house patent attorney. They recently received approval of the A2-73/donepezil combo patent (according to some on this board). They recently hired Emmanuel Fadiran, who worked for the FDA for 24 years until this year. He will manage regulatory filing for Anavex. The company stated that it has a considerable number of regulatory filings planned. He has also dealt with several novel therapies including first-in-class approvals. A 2-73 is a novel therapy. Annex enjoys the advice of a world class SAB.

Biogen is conducting a differentiation assay to see whether A2-73 promotes differentiation of oligodendrocyte precursor cells (OPC's) into oligodendrocytes (OD's). Note that Tangui Maurice's 2013 study has already shown that A2-73, by agonizing the S1R, promotes neurogenesis and neuroprotection in the hippocampus. He stated that neurogenesis is characterized by proliferation, survival and differentiation of progenitor cells in the brain.

So if A2-73 promotes differentiation of neural progenitor cells in the hippocampus, hopefully it will promote differentiation of OPC's into OD's in Biogen's study. Lisa's study from Wayne State has already shown that A2-73 protects OPC's and OD's from molecules known to cause damage in MS.

Gottlieb, the new FDA head, believes in the TCCA, adaptive trials, faster timelines, lower costs, and patient and caregiver input. Annex has worked with the FDA on its trial designs, including adaptive features.


Study Data. Scrutinize the clinical results of an early 52-week trial of Anavex 2-73 here:

http://www.anavex.com/wp-content/uploads/CTAD-Anavex-December-2016-2.pdf

Notice the minimal and insignificant adverse events (side effects) on page 18.

The data plot on page 25 (the yellow doted line) shows cognition results.

Page 33 enumerates the positive results of Anavex 2-73


Anavex in the media:


http://www.msn.com/en-au/video/w/alzheimers-breakthrough-in-melbourne-drug-trial/vp-BBsbgnI

https://www.facebook.com/TheProjectTV/videos/10154154448498441/?hc_ref=SEARCH

http://www.msn.com/en-au/video/watch/new-alzhemiers-drug-trial/vp-AA8FFIh

https://www.youtube.com/watch?v=hZEVSxLQbbk