Anavex Life Sciences Corp (AVXL)

[Investor2014]

I don't doubt you have gone about the analysis objectively and with great skill.

What I worry about is that we still do not have all that much data on A2-73 and still some critical lose ends. In the P2a AD trial there were outliers, seemingly not a clear relationship between dose and blood concentration with the latter being the absolute most significant factor for response. The trial was open label with an initial n=32, down to n=21 with subgroups down to n=2 as the basis for the peer reviewed paper.

One of the most important paragraphs to take into account from that paper is quoted below:

There are some limitations in this study:
• Small sample size, with 32 patients entering the study and 21 patients having available genomic data, which limited the power
of the study.
• Lack of adjustment for multiple comparisons in the analyses of relations between markers and therapeutic response.
• Genomic analysis results reported for only a subset panel of 243 genes; however, an analysis of 39,974 DNA variants (Table S5
in supporting information) showed SIGMAR1 p.Gln2Pro and COMT p.Leu146fs in the top 0.2% association rules linked to outcome.
• Standard of care measure of change in MMSE and change in ADCSADL for calculating effect size were obtained from the literature at 48, 52, and 82 weeks61-64 and extrapolated to 57 weeks, which was the time point used in this study.
• RNA analysis was limited due to collection time (103 to 135 weeks) and lack of baseline transcriptome data for comparison. Nonetheless, an exploratory analysis did find that high SIGMAR1 expression was associated with better therapeutic response (Table S6 in supporting information).
• Newly identified patient selection biomarkers were longitudinally confirmed for change in ADCS-ADL, but not for change in MMSE, over 148 weeks. This result may be due to a higher variability in MMSE scores.

I would usually be tempted to make highlights in bold and red in the above, but I think I don't need to for someone evidently with deep analysis skill.

The data from the PDD Proof of Concept Controlled Phase 2 trial we have been party to has not addressed above issues with any further detail and we are still due further conclusions from the apparently still ongoing analysis.

Also there is not much clinical precedence to go by from human trials of any selective S1R agonists. The few trials that have been conducted have so far at best been inconclusive with promising/intriguing signals e.g. in Huntington disease.

We do have a lot of preclinical papers with information indicative of the importance of S1R as highly preserved all the way out to human biology along with some encouraging signals from trials with A2-73 in humans. Evidently though, not enough yet to file an NDA in any indication.

I am not sure any number of hours reading peer reviewed journals will help us at this point. I have read everything from Anavex and probably read most of the S1R related papers out there feeling intrigued and encouraged, but not in a 'we got this' kind of way. The only thing that will change that for me is waiting for the outcome of the ongoing Anavex trials.

If it works out as we hope, $AVXL will prove both a step advance in medicine and quite some investment. Only time will tell.