Replies to post #462199 on Anavex Life Sciences Corp (AVXL)

[boi568]

Your question about an exact example misses the point. What matters is if an NDA meets FDA criteria for approval at the time of the Agency's decision, and not whether there was a change in endpoint usage after the original trial design. You are concerning yourself with style points rather than the anticipated regulatory outcome.

[Hosai]

This can happen and clearly was also good enough to be eligible to submit to EMA.
The co primary and secondary that passed were both under 0.025 with 0.05 being the supposed number to beat. The ADL was clearly a miss though still mildly better than nothing in the sense that 0.23 means the 23 in a 100 times that ADL result would have come up by chance. So on it's own is clearly a weak result but potentially slightly trends in the right direction as Missling said when you consider it with the low p values of the other two and the biomarkers p values too.
Obv helps now too that FDA guidance says this end point is likely too hard to show in early AD.

[Doc328]

CGI-I is not listed in the clinicaltrials database either, despite listing several other "Other Outcome Measures". Exploratory (another name for tertiary or Other) endpoints are not generally evaluated in the regulatory process but may be used to help design future studies (hypothesis generating) or for future marketing. In MS, often see patient reported outcomes, novel MRI outcomes and genetic outcomes in this category. I've never seen CGI-I as a primary or secondary endpoint for AD and I don't thnk the results will have much impact on regulatory review. I wonder if an additional clinician determined this vs done by the CDR rater (which would link the outcomes). To some extent, it is a less granular CDR-Global which was probably also done though never reported. It is unusual to even present exploratory endpoints unless ALL primary and secondary endpoints are also presented. There were multiple "Other outcomes" that would have been higher on the hierarchy according to the clinicaltrials.gov listing that are yet to be presented. I think they included it because it was significant and maybe in Missling's mind counterbalances the ADCS-ADL miss.

 Primary Outcome Measures : 
  
     ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition) [ Time Frame: 48 weeks ] 
     Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) 
  
     ADCS-ADL (Activities of Daily Living) [ Time Frame: 48 weeks ] 
     Reduction in decline of the ability to perform daily activities assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Activities of Daily Living Scale (ADCS-ADL) 
  
  
 Secondary Outcome Measures : 
  
     CDR-SB (Clinical Dementia Rating Scale Sum of Boxes) [ Time Frame: 48 weeks ] 
     Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared with placebo using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) 
  
     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 
  
  
 Other Outcome Measures: 
  
     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 weekstreatment 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)