Replies to post #332476 on Anavex Life Sciences Corp (AVXL)

[Steady_T]

Nicely done sokol.

[Investor2014]

Great summary!

S1R agonism hasn't yet clinically been proven efficacious, as in drug approvals, in any indication let alone Alzheimer's.

Without precedence of S1R approvals, mRNA expression showing that the SIGMAR1 gene through treatment with A2-73 achieves target modulation is IMO unlikely on its own to be accepted as a surrogate endpoint biomarker.

If on the other hand using CSF it can be established that amyloid plaque load is being reduced through treatment with A2-73, then the FDA might in future trials accept that increases in mRNA SIGMAR1 expression is cause for a reasonable assumption of efficacy. We are not quite there yet.

If A2-73 does reduce amyloid and tau, then why we might ask do we need to have mRNA expression of SIGMAR1 accepted as a surrogate endpoint?

Also simply showing higher mRNA expression of the SIGMAR1 gene is likely not equivalent to an S1R agonist drug docking just right with receptor binding sites achieving modulation for efficacy. Perhaps mRNA expression for the SIGMAR1 gene before and after administration of Donepezil will also increase, but as we know Donepezil's efficacy is minimal we might assume because its binding sites and modulation are not as fortuitous as A2-73.

The P2b/3 AD trial endpoints does include a list of AD relevant biomarkers, although success in the primary and secondary outcome measures I think will need to and hopefully will be stronger than was seen with Aduhelm. If so perhaps in turn mRNA expression of the SIGMAR1 gene may in future become an accepted surrogate endpoint for at least some CNS diseases and perhaps just for A2-73 since SIGMAR1 expression, as on its own it may not be a diseases specific pathological biomarker.

For now IMO mRNA expression of SIGMAR1 is limited to but usefully so as a clear marker that A2-73, A3-71 and other similar drugs are engaging with their intended target receptor and having an effect.

Outcome Measures 
 Go to  sections 
 Primary Outcome Measures  : 
 ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition) [ Time Frame: 48 weeks ] 
 Change from baseline to week 48 in cognition according to the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) compared to placebo 
  
 ADCS-ADL (Activities of Daily Living) [ Time Frame: 48 weeks ] 
 Changes from baseline to week 48 in ability to perform daily activities according to the Activities of Daily Living Scale (ADCS-ADL) compared to placebo 
  
  
 Secondary Outcome Measures  : 
 Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 48 weeks ] 
 Assess the safety and tolerability of ANAVEX2-73 compared to placebo 
  
 CDR-SB (Clinical Dementia Rating Scale Sum of Boxes) [ Time Frame: 48 weeks ] 
 Change from baseline to week 48 on Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo 
  
 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) 
  
  
 Other Outcome Measures: 
 Number of participants with change of brain volume assessed by MRI [ Time Frame: 48 weeks ] 
 Structural (and optional ASL) MRI scan assessments characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks 
  
 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

[xodcode]

Much appreciated sokol.