Replies to post #257316 on Anavex Life Sciences Corp (AVXL)

[georgejjl]

APOE (rs429358/rs7412) N = 32 (N* = 21)
genotype e2/e3 e3/e3 e3/e4 e4/e4
n (n*) 1 (1) 14 (10) 13 (7) 4 (3)
N: Number of total patients.
N*: Number of patients with WES data.
n: Number of patients in each genotype group.
n*: Number of patients in each genotype having WES data.

Anavex Phase 2a trial

This analysis showed that the higher blarcamesine (ANAVEX2-73) mean concentration arm had improved therapeutic responses of 78% and 88% in adjusted MMSE and adjusted ADCS-ADL, respectively, relative to the low/medium arm at 148 weeks (P-values < .0008 and <.0001, respectively). In addition to time, APOE e4 status (P < .0001), and blarcamesine (ANAVEX2-73) mean concentration were significant predictors (Figure 2a and 2b and Supplementary Tables 4b, 4c ). Additional significant variables in this model were SIGMAR1 p.Gln2Pro, COMT p.Leu146fs, and APOE4 e4 status interactions with time.

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12013

See slide 16 at the following link

In addiBon to ConcentraBon,
the significant covariates
identified in MMRM-LME
model are:
SIGMAR1 (p<0.0080),
COMT (p<0.0014) and
APOE e4 status (p<0.0001)

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12013

Good luck and GOD bless,

[frrol]

Group 4 includes Groups 1, 2, and 3. So what it may show, in our extremely small Phase 2A sample, is that wtSIGMAR1 is the biggest efficacy factor, and that it potentiates all other factors like APOE allele, disease stage, and drug concentration. That's good because wtSIGMAR1 is by far the most common.

If this proves out in the advanced Phase 2's, we could use it for qualification criteria in Phase 3's, or just continue to use it for results stratification. Regulators would say what they want to see.

[georgejjl]

Supplementary Figure 4: Exceptional therapeutic response Longitudinal change in MMSE and ADCS-ADL over 148 weeks of combined studies of two patients (a and b) having SIGMAR1 gene wild type, mean high concentration levels of ANAVEX2-73 in plasma in Part B and baseline MMSE ≥20. All n=6 subjects, including patients a and b, with these response characteristics are shown in Figure 3.

An additional ten patients had “unexpected positive benefit” described by their investigator in the CRF data e.g. improved mood, increase attention, improved sleep. Eight of these patients recorded a high ANAVEX2-73 plasma concentration (≥4.0ng/ml) in Part B.

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12013

Good luck and GOD bless,

[Investor2014]

A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study

As far as I am aware the stratification to include the APOE3 alleles has not been mentioned in any previous presentations from Anavex. The only difference between Group 1 and 2 is the APOE3 alleles, which appears to make a very significant difference to response, much more so than the SIGMAR1 and COMT variants vs. wild type analysis.

Why was APOE3 alleles not highlighted in the initial KEM Analysis?

Comparing Group 1 to Group 3, it seems clear that the APOE3 alleles are far more significant to response than SIGMAR1 variants vs. wild type.

Of note is also that COMT does not figure in any of the groups. Similarly APOE3 alleles do not figure in the table 2a analysis?

The KEM Analysis approach is great, but to me it is a concern that we only have these findings in such a small trial that we end up with subgroups consisting of 2 patients.

What does this all mean for the Anavex Precision Medicine strategy as it applies to A2-73 - this is a good question, which I can't answer.

Btw. yesterday checking clinicaltrials.com there is no pre-specified subgroup analysis mentioned for PDD, but for Rett and AD only. Missling has however mentioned several times that all trials would have the pre-specified subgroup analysis, so perhaps also including APOE variants.

All we can do is wait and hope for a good PDD readout and yet again for more clarity, perhaps...