Anavex Life Sciences Challenges the Basic Assumptions In Treating Alzheimer’s Disease

Anavex Life Sciences Corp. is a biopharmaceutical company engaged in the discovery and development of new drugs for the treatment of neurological diseases and cancer, utilizing its proprietary drug discovery SIGMACEPTOR™ platform. The Anavex portfolio comprises novel, wholly owned sigma receptor agonists and antagonists. The company’s lead drug candidate for Alzheimer’s Disease (AD), ANAVEX 2-73, has successfully completed a Phase 1 single ascending dose (SAD) clinical trial. The company has also started scale-up manufacturing for ANAVEX 1-41, its second lead compound, targeting depression and AD. With sufficient quantities of ANAVEX 1-41 in hand, the company will be in a position to advance the program and begin preclinical studies on large animals in the near term. Below, Dr. George Tidmarsh gives us the story behind Anavex and the hurdles yet to be overcome when it comes to Alzheimer’s Disease.

Please click below for interview audio and see below for a full transcript.

Malini Chatterjee:     Good morning, Dr. Tidmarsh, and good morning, Christine. Welcome to this OneMedRadio conference call. Today is Friday November 18th. Why don’t I open up the discussion by just talking a little bit about the story behind Anavex. Basically, the story of Anavex precedes Anavex, right? It has to do with Alzheimer’s disease and in the last 10, 15 years, there have been a few different biotech companies who have been developing Alzheimer’s drugs, yet the marketplace has very few Alzheimer’s drugs. So my question to you is even before we get into your company, what lessons in clinical trials and disease have you learned from the historic pitfalls and historic successes of other Alzheimer’s companies?

George Tidmarsh:      Good morning. Thank you for the introduction and I think that the most important lesson right now in Alzheimer’s disease is that some of the basic paradigms of assumption of the disease are being challenged such as is the accumulation of amyloid the key to the neurotoxicity that is the hallmark of Alzheimer’s disease? There have been failures attacking that specific root. And that’s a 10 or 15-year period of time where people have taken a certain hypothesis, made a therapeutic challenge, and now we’re seeing that that hypothesis might not be correct. I think that’s the state where we’re at in Alzheimer’s and Anavex has a novel target of the sigma-1 receptors and we believe that’s just a very different paradigm. So the paradigm is changing.

MC:   If amyloid is a suspect candidate in Alzheimer’s disease, if it is not the central culprit, then what is the parallel hypothesis now?

GT:    Well it maybe that amyloid is simply a byproduct of the process, which leads to neuron death. The clear, clear fact is that the neurons die and this is true for Parkinson’s, it’s true for other neurodegenerative diseases. And what we believe is the key is a failure in the intracellular, inside the neurons signaling between the endoplasmic reticula and the mitochondria and the sigma-1 proteins play a very important role in that signaling so that cell death occurs because of failure of that signaling, which involves calcium ions. And that’s a degenerative process that occurs with aging and the failure to have appropriate signaling leads to cell death. And our molecules address that fundamental problem with neuron degeneration.

MC:    Got it. So then can we now then bring it to these sigma-1 receptors and to the ligands that your drugs are. You said this is a parallel pathway, how does this sigma-1 receptor fit into the current body of knowledge of Alzheimer’s disease? How do these receptors act innately and why will controlling the sigma-1 receptor be beneficial to this disease?

GT:   Sure. What we do know is that as cells die and in particular neurons that this is also true for other cells in the body. There is a failure, there’s a stress response and a failure to address that stress response. And the stress response comes out of the endoplasmic reticulum and the results of that is improper calcium flux and we believe that calcium flux is between the endoplasmic reticulum and mitochondria. That is well known that the failure to maintain appropriate calcium flux between these intracellular organelles leads to cell death.

Now the sigma receptors are endoplasmic reticulum chaperone proteins so what they do is they sit in the organelle that’s responsible for responding to stress and when active, sigma receptors control and augment and allow the calcium flux to occur, which keeps the cell alive. And so sigma receptors are extraordinarily important as a category of proteins called chaperones meaning what they do is that they stabilize and augment the activity of other proteins and in this case, calcium channels and those calcium channels are essential to keep the cell alive. So the Anavex molecules bind to the sigma-1 receptor. We know it’s a receptor and activate it and allow it to carry out its fundamental ability to chaperone and maintain the appropriate calcium flux to keep a cell alive.

MC:    So then your drugs are not antagonists of the sigma-1 receptor, they’re the agonist of the receptor?

GT:    That’s correct.

MC:  Okay. So in molecular models of your disease, of Alzheimer’s disease and in the molecular models of your drug, adding in these sigma-1 ligand agonists, do you see a re-initiation of calcium flux?

GT:   So first of all, the Anavex program is designed to identify and maximize small molecules, which bind to an activate the sigma-1 receptor. So that’s in a very specific model, that’s in vitro and it’s without even cells. So we’ve modified molecules, test them for their binding ability to the sigma-1 receptor. Then once we’ve shown that they bind to the sigma-1 receptor, extensive studies have been done to show in cells and these are neurons in culture, that first of all the compound protects the neurons from toxicity. So you can put into the cell culture toxins, which stress can and are known to kill neurons, which again we know happens in Alzheimer’s disease. And the Anavex molecules protect from that neurotoxicity. And what’s also been shown is that protection is correlated with maintaining the appropriate calcium flux inside the cell and in particular between the two organelles, the endoplasmic reticulum and the mitochondria.

MC:    When I was reading through your website, I learned that you have a cancer program too, I mean somewhat behind in development than the Alzheimer’s program. So I’m just curious is it that sigma-1 receptor agonists are also used in cancer models and, if so, how do you compare and contrast a sigma-1 receptor in Alzheimer’s versus that in cancer?

GT:   Well it’s as you mentioned, it’s a very early program. What we do know is that sigma receptors and the pathway of calcium flux likely maintain cell viability.

GT:  Cancer cells obviously need to stay alive and so through various stresses that they have, whether it’s hypoxia or nutrient deprivation, cancer cells have adapted to stay alive and we believe one of the ways they stayed alive is by maximizing the sigma-1 receptor to maintain the appropriate calcium flux. So we hypothesized and again it’s early, we still have a lot of work to do, that then antagonizing the sigma-1 receptors maybe beneficial to treat cancer.

MC:   So in Alzheimer’s models, you would use an agonist as a drug and in a cancer model, you would use an antagonist as a drug?

GT:   Well certainly, we have very good evidence with Alzheimer’s the agonist no question about it and we’re investigating the cancer and then go to the sigma-1 receptors.

MC:     Are there any other companies currently in development that focus on the sigma-1 receptor for Alzheimer’s or cancer?

GT:      Not that we’re aware of. The only company that I do know of is a small Japanese company that is still in preclinical development. I think the name is M2, I’m not certain of that and they’re very small and very early on. Because many of the work, much of the work with the sigma receptors came out of Japan and they are looking to agonize the sigma receptors to treat depression. And that is, in our estimation, a very viable approach. We find that agonizing the sigma-1 receptors has effects in animal models with depression and of course, depression is a very important clinical part of Alzheimer’s disease itself.

GT:     And so yes, there are small companies beginning to work on it, but we are part of that network that’s at the foundation of sigma-1. So our key scientific collaborator is Tangui Maurice, a professor in France and he trained as a postdoc in the lab in Japan where the work is coming out about the work on sigma-1 receptors and depression and so it’s a very, very small group. The third group that’s really involved in this is the NIH and Tangui Maurice has a close collaboration with the folks at the NIH. So it’s a small group that is really now at the forefront of the sigma-1 receptors and Anavex is by far in the lead having now completed our first phase 1 trial. And so to our knowledge, there’s no one that has a sigma-1 directed therapy that is already into phase 1.

MC:    Talking about your phase 1 study, I read the press release that came out a couple of days ago and can we talk a little bit about that study? So there were healthy volunteers who received single doses of the drug. You were able to find out a maximum tolerated dose for Anavex 2-73 and what else did you learn? Other than for the dose itself, which is already a great piece of information, what else did you learn from this study and how do you plan to use this information to generate your next multiple ascending dose study?

GT:   What we learned was that first of all, the drug was well tolerated when you look at below the maximum tolerated dose, there were no adverse events of any significance, they were all mild and unrelated to the drug. You look even at the maximum tolerated dose and below, there were no changes in any laboratory parameters, no changes in any measurements of cardiac electronics, the ECG, which is obviously very important for everyone. And that at the maximum tolerated dose, the adverse events seemed more moderate in severity and reversible and interestingly all of them were central nervous system adverse events, meaning euphoria, lightheadedness, a little bit of dizziness and that is very common in drugs that are active in CNS disorders.

And the final piece we learned is that if one converts our maximum tolerated dose to the appropriate dose in animals, we know it’s at or well above the dose that was given that was effective in mouse models of Alzheimer’s disease. So all of it really was quite positive.

MC:    That’s great. And now when you design your multiple ascending dose study, which I believe that will be the next study that you ought to do, how will you design the protocol, what will be the dosing schedule you’ll follow, and when can we see this trial starting out?

GT:   We are just finalizing the analysis of the pharmacokinetic data.

GT:   And when we have that, we will plan out the dosing for the multiple ascending dose study. It’s fairly straightforward. When the pharmacokineticists look at the data, they make a recommendation on the dosing frequency and the starting dose. And we’re doing that literally right now as we speak and we’re doing the ground work to start the multiple ascending dose. And by the end of the first half of next year, you should see results from us on multiple ascending dose study.

MC:  Dr. Tidmarsh, now just some business related questions. What is your current cash position?

GT:  Our current position is influx. Literally, we are putting money out the door for our multiple ascending dose study and so I can’t give you today’s cash position. I mean it was publicly available as our last quarterly report. And we will, as we analyze this clinical data, be looking for additional financing for the company.

MC:    What is your plan with this drug 2-73? If the result in the toxicity profile permits, would you plan to take it singlehandedly all the way to phase 3 and to commercialization or do you wish to out license? How do you with to proceed?

GT:    Well, I think that the option that would be number one would certainly be to fund development through a definitive phase 2 study that’s randomized, blinded, that has as an endpoint what would be the approvable endpoint of the drug and shows that the — now it defines further the safety of the drug, but also gives us the initial measurement of activity. I don’t want to say efficacy because that’s really phase 3.

GT:   We believe that type of study is fundable by Anavex and investors. We do believe that for the full on phase 3 and for commercialization, we would seek a partner. That’s our sort of option number one right now.

MC:  My last question to you is about the stock. So as I’m looking at your stock profile, I’m just curious, what did Anavex do in the previous years? I mean you guys had been around a little while, your stock has fluctuated some. What is the history behind this company? Where you always developing Alzheimer’s drugs or was there a different product profile or portfolio before?

GT:   No. This has always been direct. The company started and has been focused directly without real deviation on this program. We developed right from scratch the entire portfolio of sigma-1 agonist.

GT:   And as anybody should understand, you know, to develop a screening program for small molecules that target a protein receptor and to bring this through medical chemistry efforts, in vitro studies, animal studies, and then toxicology studies to phase 1, that takes some time and money and that’s all been done in one line without deviation. So the focus of the company I think has been extremely clear since the beginning.

MC:   And with that I will conclude the call. Thank you so much, Dr. Tidmarsh, and thank you so much, Christine, for organizing this call. We are talking Dr. George Tidmarsh of Anavex Life Sciences Corporation, ticker AVXL on the bulletin board, market cap $42M. Please go to OneMedRadio on our website www.OneMedPlace.com to take a listen to today’s interview. Thank you so much.

GT:    Thank you.

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