Anavex Life Sciences Corp (AVXL)

[Investor2014]

By popular demand and Bottom Line Up First - BLUF

I believe Anavex likely need to run a P3 Precision Medicine trial for approval of A2-73 in AD. I also suspect Anavex expect the same.

My central reasoning is that the correlation between dose, concentration and response to A2-73 is Strongly non linear, which I will demonstrate below using Anavex slides.

Strongly non linear relationships in themselves is not necessarily an issue, but a fact that makes analysis more complex.

The Ariana KEM Formal Concepts analysis method is ideal for identifying multifactorial one and two-directional correlations. Using this type of analysis require binary bins of values rather than discrete datapoints e.g. a low, mid-high and high range is bound by some values. similar with say an Odds Ratio threshold of cognitive scores ADAS-Cog along with the n that meets the threshold etc. analysis bin.

There is some important forethought and work required for arranging these bins of data to yield the answers sought. This includes all this stuff:



And now also this to be factored in along with new P2b/3 dataset:

Number of participants with change of brain volume assessed by MRI [ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2-73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration

Blood assessment [ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration

CSF assessment [ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks treatment differences within subgroups will be performed

Number of participants with pre-specified genetic variants [ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed

RSCAQ sleep score [ Time Frame: Weeks 0, 4, 12, 24, 36, and 48 ]
To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess reported sleep continuity (RSCAQ)

as well as:



The KEM analysis, as before, will identify the likely reason that some patients responds to A2-73 significantly better than others. For these results it is my long held opinion that we will not see more data/results prior to the expected publication in a peer reviewed journal a process that takes time, but hopefully this year.

I certainly believe and expect the above analysis to show both strong responders actually improving from baseline as well as a group of patients with reduced rate of decline. As before responders will fall into several groups based on genetics, concentration achieved etc. I think approval from such an exercise is unlikely, but not impossible. It will also depend on the n for strong responders no matter whether they happened to be in the 30mg or 50mg cohort.

I will say again that I believe, based in the P2a KEM analysis Group1, about 20 patients will show improvement from baseline to EOT and some greater number will experience reduced rate of decline. How many in the latter category I have no means of estimating. But who, expect Georgejjl, knowns until we see the analysis.

Using the KEM method for pre-specified subgroup analysis will at minimum deliver very clear indications of the patient characteristics required for clinically meaningful response to A2-73, which if enrolled in a P3 Precision Medicine trial is very likely to produce clear results demonstrated through classic endpoints and analysis methods leading to full approval albeit with a label identifying right patients, at the right time for A2-73.

Anavex presented P2b/3 readout results on the combined 30mg and 50mg dose cohorts vs. placebo on the Primary endpoints and key Secondary endpoint at CTAD 2022. A first version of the slide deck, which was shortly after revised and finally now both removed from anavex.com had errors and were not the complete readout per clinicaltrials.gov definition of endpoints.

If I was in the position of Anavex, I would not throw about the n values either on this until after the detailed analysis peer reviewed publication. So here I agree with Anavex, but intensely dislike their cagy way of avoiding the imo inevitable admission that the data doesn't lend itself to classic data analysis and presentation in terms of a clear WGT message.

This leaves us with a again revised and reduced set of slides from the Januar 12, 2023 J.P. Morgan Healthcare Conference Presentation. Slides 16, 17 and 18 are dedicated to the P2b/3 AD trial readout.

ADAS-Cog - Odds Ratio only with no indication of how many patients met the treshold applied and only 90% CI
ADCS-ADL - Odds Ratio only with no indication of how many patients met the treshold applied and only 90% CI
CDR-SB - A chart showing a non linear response that ends a positive -.42 point improvement at 48 weeks with a relatively modest P = 0.040.

How on this basis the company can claim to have met all endpoints will remain an unsubstantiated mystery to me.

It seems to me that Anavex want to leave it at that until the detailed analysis is presented in a peer reviewed journal. In parallel with the detailed analysis publication, Anavex will seek guidance from regulators on next steps. Our best hope is that perhaps Australia, given their long term involvement and large P2b/3 trial population or the U.K. given their independent of EMA, could give accelerated approval monitored by a P4 trial.

Background to my conclusion above:

Notice the title regarding Strong non linear Relations.



Below second table are the 6 x ADCS-ADL strong responders from the P2a trial. These patients, as I will show below, are the same as in the peer reviewed analysis Group2 and its subset Group1.



The two strongest responders from above is 101014 and 102006 corresponding to the peer reviewed analysis Group1 that were the only two that improved and stayed that way out to 148 weeks. Group2 that included Group1, saw reduced decline with a later onset at about 54 weeks then trendig similar to SoC.

In below KEM analisys chart we see the 6 strong responders:
Group2 1009, 1011, 1013, 2010 + Group1 1014, 2006

The Strong non linearity is evident here since:
Group1 1014 and 2006 both fall within the therapeutic window of 4ng/mL A2-73 concentration but with quite a difference for the two and the lower contraction patient 2006 with the best ADCS-ADL delta from baseline.

From Group2 1009 achieved literally no A2-73 concentration and 1011 very little, yet was among the 6 strong responders, whereas patient 1013 and 2010 were both within the therapeutic window concentration.

Here we also need to keep in mind that the n=21 peer reviewed open label trial was very small and posthoc analysis. We cannot assume that the P2b/3 larger controlled trial population will exhibit the same multifactorial results. E.g. perhaps the distribution of APOE4 and APOE3 alleles status patients between low and high dose versus concentration and response will be different and more reliable based on the n=509 trial population.



Further evidence of the non linear relationship are given in the below Anavex slide. The scatter plots for the two P2a trial time periods have significant outliers. This is borne out by the low R-squared values. R-squared is always a value between 0% to 100%, where 70% is regarded a meaningful linear fit.



Here is a reminder of analysis groups and a bit of Set Theory referenced from the peer reviewed P2a data paper.



Finally, Anavex have consistently included the below graph in their presentations over the last few years.

The point of this slide is that using "Patient selection biomarkers" increases the probability of success.

Hence, Anavex have for a long time expected to run P3 Precision Medicine trials selecting patients for enrollment that they have been sneaking up to the right biomarkers for throughout their trials programme.

We know that such a P3 PM trial is planned for PDD and imo one will be planned in AD post the P2b/3 detailed analysis.