Anavex Life Sciences Corp (AVXL)

[Investor2014]

I am going to make some contentions based on my full review of CTAD 2018
1) There were NO tolerability issues, not even in the high dose (50mg) cohort of 8 patients
2) No patients were moved to lower dose at any point during Part B and its extensions, they stayed on their respective 10, 20, 30 and 50mg doses
3) High Concentration/Dose is THE determining factor for A2-73 Response
4) Next most impactful factor is MMSE Baseline score, hence the P2b/3 study enrol Early AD patients only
5) The Precision Medicine SIGMAR1 and COMT variants has some impact on response (highly stat sig), but in clinical terms not much in comparison to 2 & 3
6) Drop-out methodology finally accounted for
7) If Donepezil has any impact on outcomes, it is so insignificant that it doesn't get flagged in KEM Analysis

Here are the reasons that IMO allows me to make the above contentions:

1) Slide 9, "Safety update through 148 weeks" -> "No ANAVEX®2-73 related AE or SAE", could hardly be clearer could it?

Slide 14, Low/Med (<4ng/ml) ; High (≥4ng/ml), which to me means high is the 50mg group only, with Low/Med including 10, 20 and 30mg.

Slide 15, "6 out of 8 patients, 75% APOE e4 carriers in High AV2-73 concentration cohort". Hence 8 on 50mg as High group. Of course the other important point of this slide, is that APOE e4 carriers respond just as well to A2-73, this in context of other drugs, such as BAN, that seem to worry a lot about APOE 4.

2) Slide 8, Part A 32 patients, where 1 was excluded right from the start as outside inclusion criteria and never included in calculations, so really an n=31 trial all along. Part B was completed by 27 patients, "Part B extension administration of ANAVEX®2-73: Oral once daily: 10 mg, 20mg, 30mg, 40mg, 50mg. The 003 extension the same dose groups and no switching dose of any patients. How else could we still have 8 in the High Dose group at 148 weeks!

Divide 32 by 4 (dose levels) is 8!

3) Slide 16 & 17, "High Concentration cohort shows 88 % difference to low concentration cohort", and "High Concentration cohort shows 64 % less decline than low concentration cohort". The p-value of these statements are highly statistically significant and clearly concentration/dose is THE determining factor of response.

4) Slide 16, "In addition to Concentration, the significant covariates identified in MMRM-LME model are: SIGMAR1 (p<0.0080), COMT (p<0.0014) and APOE e4 status (p<0.0001). The gene factors stand out as very significant from a statistical point of view and have clinical impact, just not nearly as much as concentration/dose.

Slide 17, "Other significant covariates identified in MMRM-LME model are: APOE e4 status (p<0.0001)". APOE e4 status has a positive impact that appears clinical meaningful in the high concentration cohort, but tails of over time. I think this is noteworthy, since other recent Amyloid fighting AD drugs seems to work worse for APOE e4 carriers.

5) Dealt with in point (3) and (4), but
From Doc238 post "So, how much precision medicine is still in play at 3 years?". IMO a lot from a process perspective and as it turns out not so much from a clinical impact perspective. The point being, how would you know that without doing a thorough piece of PM work - and that IMO is important!

6) 1 patient excluded for (all) calculations right from the beginning, so really n=31 trial before drop-outs. Then, based on Slide 14 ¹ Lane , P. W. (2008). Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharmaceutical Statistics 7 : 93–106. , Anavex chose MMRM as per ² Verbeke , G. , Molenberghs , G. (2000). Linear Mixed Models for Longitudinal Data. New York : Springer.

7) There is just no data in Anavex presentations to date supporting the Donepezil naive theory. Conversely there isn't any data that I am aware that supports the AnavexPlus patent claims?

Remarks:

Slide 19, "Data rich study (scores, PK, DNA, RNA) provides a unique opportunity to characterize response". Bold is mine just to point what the whole point of the P2a trial design was!

Slide 20, These conclusions are also the only ones I can come to having read the slides and taking into account all information to date. The very good news is that ALL patients enrolled in the high dose arm of the P2b/3 trial should do very well over 48 weeks (and beyond) somewhat independent of gene variants.

Regarding Activities of Daily Living, which are impressive in the high concentration cohort, MacFarlane has several times stressed the clinically meaningful importance of that over MMSE.

Yes MMSE does very gradually decrease with age in healthy non-demented people: The Association of Age With Rate of Cognitive Decline in Elderly Individuals Residing in Supporting Care Facilities.

A drop in MMSE score clearly measurable early in suspected AD is a good diagnostics method, whereas maintaining Activities of Daily Living is what counts as clinically meaningful as we all age.

Now Anavex just have to get those damn trials on the go to confirm, I think we a high degree of likelihood, that A2-73 does work and isn't t****!

I suspect, as others point out, that overall the market is not aware of or have turned the blind eye towards Anavex and their small n un-controlled open label trial. A2-73 is everything other than what the old school have learned about AD. I think over the weeks to follow this will gradually change not least on the backdrop of increasing scepticism and reviews of Biogen and other BP attempts in the Antibody space of Amyloid plaque and Tau tangle fighting.

Time and science is on our side!