Summary

Doctor Tangui Maurice is a professor at Montpellier University.

He is a co-discoverer of ANAVEX 2-73 and a well-regarded authority on sigma 1r pharmacology.

In this interview, he discusses the latest trial of ANAVEX 2-73, among other things.

This email interview with Professor Tangui Maurice, done over the weekend of November 14 and 15, is a reference for my Anavex (NASDAQ:AVXL) article (LINK) that has been published simultaneously. The context for this interview is also discussed in that article, as well as my opinions and interpretations. Briefly, though, Anavex, a small company, published data on its Alzheimer's trials that is the focus of a major debate today, participants including Adam Feuerstein from thestreet.com, and a few authors on SeekingAlpha, including myself. Professor Maurice is the scientific authority on the subject, and a co-inventor of the compound Anavex 2-73. He is also in the field for more than 25 years, so his words are critical to the debate.

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Dear Professor Maurice

My name is Dr Kanak Kanti De. I have read many of your research notes on sigma 1 receptors. I recently emailed Professor Angela Nilsson who referred me to you as the world expert on sigma 1 receptor pharmacology.

I cover a small company called Anavex which recently posted phase IIa trial results at CTAD for Anavex 2-73. However, Alzheimer's is not my area of expertise, and I was wondering if I could have your expert opinion on the trial results.

If you have knowledge of this trial, could you give me your opinion on it?

This is a first trial in human for this kind of drug in this indication. The purpose is mainly to demonstrate an effect in human together with a safe profile, in order to be able to design larger scale double blind trial in the future. This is the reason why the company selected an open- label trial. The idea is to be able to adapt the protocol and get the maximum information they can.

The data disclosed at present are the very preliminary ones. The main idea I retain is that no "red flag" has been raised. The drug is safe (adverse effects ('AE) reported are very minimal) and the first cognitive or physiological data obtained are positive. But at this timepoint, we can not conclude to a neuroprotective effect, as it is expected for this kind of drug, and the result may be related mainly to a symptomatic effect.

Professor Maurice also wrote in a second email:

After carefully checking the mail I sent to you, I want to clarify some points that could be misunderstood:

1) The mail reflects only my personal thoughts, as a preclinical researcher involved in the pionnering work on the compound. I demonstrated the symptomatic and neuroprotective effects of the compound in several mouse models of AD. But I have no competence to discuss the clinical protocol used by the company.

2) In answer of question 1, I wrote "The idea is to be able to adapt the protocol and get the maximum information they can." It was too imprecise. To be more accurate, the current trial has been designed purposely by using state-of-the-art Population PK/PD and Adaptive Design. The "adaptive design" is only referring to dosing adaptations. Protocols itself can not be changed. Moreover, the design followed FDA guidelines (see below source). These trials cannot be blinded and do not required a control. Source: Professor Maurice provided links to these two sources (1, 2).

I, myself, with my meager knowledge of AD, have a minimalist, one step at a time approach - so all I want to figure out is whether 2-73 did well in the test for which it was powered - safety and tolerability.

We know, from the previous clinical trials with sigma-1 compounds (igmesine or SA4503 in depression, for instance) or the sigma-1 drugs in clinical use (fluvoxamine, afobasole, nuedexta) that the target itself is very safe and present low levels of AEs per se. We understand that as a result of the mechanism of action of the protein which is mainly a neuromodulatory receptor, devoid of major effects in physiological conditions. In the case of the Anavex compound, the phase I led to low effects, particularly at the therapeutic doses, and the cumulative dose trial led to AEs only at >50 mg/day IV dose, if I remember correctly.

In this assay, ANAVEX2-73 led mainly to mild dizziness and headache events in 74% of the patients, moderate in 26%, and a few cases of GI tract and psychiatric disorders, in 8 cases over 32 both. But no AE of grades 3-5 were observed. The result is acceptable. The question of how these AEs will evolve in time when the treatment will be longer, remains open. But at present, with the data we have, the benefit/risk ratio is very positive.

However, as an expert, you will have a much better idea of possible indications of efficacy (or no efficacy) even from this early date. Do you think the data is good enough for a phase 3 trial?

The data released at present are very preliminary for this phase 2a study. So we must wait for the completion of the study. Also, we must see what the clinical trial scheduled with ANAVEX PLUS will give. This is the combination of ANAVEX2-73 and donepezil, and it appeared to be synergic in pre-clinical and systemic biology models. But the main question will be the duration of the efficacy under chronic (several months or years) administration. These compounds are expected to be neuroprotective and possibly decrease the main pathological events in the disease (the generation of amyloid species and the appearance of hyperphosphorylated Tau protein leading to neurofibrillary tangles). We have evidences at the pre-clinical level that these drugs are able to do so. And this is the main mechanism by which a disease-modifying effect is expected. It must be investigated at the clinical level in large scale and duration trials. Another point is that ANAVEX company has also other molecules in the pipeline, that could be even more effective, I think to 1-41 and 3-71.

So, on my opinion, data released at present are too preliminary to jump to phase 3 trial. The analyses of the phase 2 trail must be completed as scheduled, first.

If you were leading this study, would you have designed the p2a trial differently?

I am not involved in the trial design and did not participated to the discussion, so I am a bit spectator in this matter and have no specific alternative idea at present. Let's wait and see.

Is blinding necessary, is a control arm necessary for the simple primary endpoint of this trial?

The open-label was chosen to get a very rapid information on the benefit/risk balance, as I told previously. It make sense to get a first clinical validation of the interest of the drug. Of course, a following trial will need to be double-blinded in the future. The control will be placebo and donepezil or memantine treatment, depending on the patient group definition, but with the risks that the control compounds may not lead easily to positive data.

The actual analysis strategy is before/after treatment to use each patient as its own control, and it obviously includes placebo effect.

In the second email, Professor Maurice wrote:

3) In answer of question 5, I wrote "The actual analysis strategy is before/after treatment to use each patient as its own control, and it obviously includes placebo effect."
I want to be very clear: I did not mean that the effects observed are due to a placebo effect. The opposite, the facts that differential effects were observed on the several parameters examined, and that one of the most difficult tests (Cogstate One Back) showed the best degree of improvement with statistical significance of p<0.001 as well as the biomarker test ERP Reaction Time with p<0.0007 clearly confirmed the drug effect. On another note, while placebo effects are common with sedative drugs, they are less common with drugs designed to improve cognition. This is because individuals can not anticipate what it is like to have better thinking. Most individuals know what it is like to have a sense of worse cognition. Taken together these aspects of the data make the placebo effect a less likely explanation for the data.

And again, the take-home message is that: (1) pre-clinical data with sigma-1 receptor agonists showed, in rodent models of AD, PD, ALS, MS, stroke, a highly effective neuroprotective activity of these drugs; (2) the phase I data with ANAVEX2-73 showed a large therapeutic window; and (3) the data released at present in phase 2a study confirmed efficacy and safety for the duration of treatment.

Please, take these precisions into account.********************************************************

Dr Tangui MAURICE

CNRS Research Director

Team II Endogenous Neuroprotection in Neurodegenerative Diseases

INSERM U. 1198, EPHE, University of Montpellier

What do you think about the various scores and their results?

The main impacts are on EEG analysis and working memory scores, which make sense with the symptomatic effect expected from these drugs. Longer duration treatment must be tested to analyse impacts on other parameters, and particularly as compared to placebo treated groups, which may finally show a decrease in the scores.

Also, broadly, can you tell me about sigma 1r in Alzheimer's, what you think, how you were involved in the discovery of ANAVEX 2-73, what do you think of its prospects in AD?

I am working on the behavioural effects of sigma-1 compound since >20 years and particularly analyzed their anti-amnesic, anti-depressant, anti-addictive and neuroprotective effects. I started to work with ANAVEX compounds in 2005, under the request of the CSO of the company. We showed the anti-amnesic, anti-depressant and neuroprotective effects of ANAVEX1-41 and ANAVEX2-73 in mouse models of Alzheimer's disease. We used two complementary models: an acute model induced by ICV injection of amyloid peptide oligomers into the mouse brain, which develops the toxicity in 1 week. We did a lot of behavioural, biochemical and morphological studies in this model. Then, we used a transgenic mouse model, the classical Tg2576 line, to analyze the impact of a long-term treatment (2 months) with ANAVEX2-73 administered per os. In parallel, I used several other sigma-1 drugs, sigma-1 knockout mice, etc..., to analyze the impact of AD-like toxicity on sigma-1 receptors and the effects of sigma-1 activation on the pathological processes, which are complex as you know. We are now focusing on mitochondrial alterations and see the role of the sigma-1 protein on mitochondrial preservation.

The main benefit of targeting the sigma-1 protein is the wide-range neuroprotection it induces. It targets the mitochondria, the endoplasmic reticulum, some nuclear location gene expression, plasma membrane recomposition. So, at the cellular level it affects several cellular components. It is present in the neuron, in glial cells, in vascular cells, to it also affects several components of the organs. This kind of "pleiotropic" as I said, protection is also seen by other actors, like erythropoietin (another of my present interests) and it seems to be the best therapeutic strategy in pathologies where a lot of intricate toxic mechanisms are occurring. It explains why these drugs are effective in several neurodegenerative disorders (AD, but also PD, ALS, stroke, etc..), but also why it may be effective, by a combined action at several targets. I am convinced that such drugs are a good strategy, but we must continue to analyze their mechanism of action, since it appears more complex than expected, due to the variety of targets (sometime inter-related) and to the protein biology still not completely known. For instance, sigma-1 protein acts as homo- or hetero-dimers and this may be a benefit or a risk depending on the nature of the heterodimer partner protein.