Anavex Life Sciences Corp (AVXL)

[Investor2014]

Missling said in yesterday's Cantor presentation that Functional MRI and PET scans would be used in the P2b/3 AD trial.

It prompted the question in my mind how much change could be expected over 48 weeks (the length of the study) in the brains of mild cognitively impaired Alzheimer's patients?

Also what change to look for e.g. amyloid load (PET), hippocampal atrophy (shrinkage in volume using MRI), A2-73 Sigma-1 Receptor occupancy (PET)?

First of all the whole Amyloid debacle seems to confuse the issue, since a great deal of patients with early signs of dementia are diagnosed with Alzheimer's and prescribed Aircept or Namenda, but then found not to have any signs of amyloid load in the brain based on PET scans.

PET Scans Show Many Being Treated for Alzheimer’s May Not Have Disease

The “Imaging Dementia-Evidence for Amyloid Scanning (IDEAS)” study found that of the 4,000 participants tested so far, only 54.3% of people with mild cognitive impairment (MCI) and only 70.5% of people with dementia had beta-amyloid plaques. Alzheimer’s was the suspected culprit of cognitive impairment in over 76% of participants.

Or is this another good reason to think of amyloid as a pathological consequence triggered in some patients and at some stage of disease with different rates of accumulation?

So how do we define Alzheimer's, must it be associated with amyloid load?

Alzheimer Disease Imaging

Preferred examination
Structural imaging, preferably with MRI when possible and computed tomography (CT) when not, should be obtained as a first-tier approach. MRI can be considered the preferred neuroimaging examination for Alzheimer disease because it allows for accurate measurement of the 3-dimensional (3D) volume of brain structures, especially the size of the hippocampus and related regions. Second-tier imaging with molecular methods, preferably with fluorodeoxyglucose PET (or single-photon emission CT if PET is unavailable) can provide more diagnostic specificity. [7]

Neuroimaging is widely believed to be generally useful for excluding reversible causes of dementia syndrome, such as normal-pressure hydrocephalus, brain tumors, and subdural hematoma, and for excluding other likely causes of dementia, such as cerebrovascular disease. [3]

So at least to me, it seems PET is not going to be particularly relevant for monitoring plaque formation or for showing that A2-73, as a by product of its MOA, reduces or prevents amyloid load over the course of the 48 week trial. Clearly no one knows the expected amyloid load burden history in Alzheimer's patients.

My guess would be that correlation of A2-73 Sigma-1 Receptor target occupancy with endpoints being met would be strong evidence of drug effectiveness.

Likewise, MRI showing reduced or no hippocampal atrophy or even volume returning towards normal (don't know if that is even possible) would be another strong indication that A2-73 is doing the work.

Missling also mentioned that the gut microbiome is being analysed and will be added. Will that be part of the pre-planned analysis stratification to calculate response without the group of patients that cannot achieve therapeutic blood concentration level of A2-73?

I think Missling is determined to show Precision Medicine at work for the first time in CNS!