Anavex Life Sciences Corp (AVXL)

[Doc328]

I've seen a lot of posts saying the new FDA guidelines are a game changer and Dr. Missling endorses this in some of his presentations.

However, seeing the breakdown of patients by CDR-global shows why the new FDA guidance is irrelevant (see below)

About 65% of blarcamesine patients are CDR-G 0.5, most of the rest were CDR-G 1.0 Placebo had more mild AD than MCI with 41.5% mild (AD stage 4) and 57% MCI. Most patients do not fall under the new guidance as they are stage 3 and stage 4 not stage 2.

Though a different issue, we know mild AD progresses faster than MCI clinically and with MRI changes - wonder if the difference in the cohort severity (placebo were more advanced) affected results since it was not corrected for (difference between placebo vs 30 mg was p < 0.05 on ADAS-COg at entry?



For some definitions:
Most MCI patients are CDR-G 0.5 and AD Stage 3
Most Mild AD patients are CDR-G 1.0 and Stage 4.
The FDA essentially says Stage 3 should still use cognitive plus functional scales (i.e ADAS-Cog and ADCS-ADL)

Patients with Stage 3 AD approaching the onset of overt dementia have relatively mild but304 
 noticeable impairments in their daily functioning. As patients have detectable cognitive and305 
 functional impairment at this stage of disease, it is important to demonstrate that a therapy306 
 favorably affects the observed impairments in both cognition and daily functioning. The307 
 independent assessment of daily function and cognitive effects remains an acceptable approach.308 
 However, it is important to note that many of the assessment tools typically used to measure309 
 functional impairment in patients with later dementia stages of AD (Stages 4 through 6) may not310 
 be suitable for use in early AD patients. An integrated scale that adequately and meaningfully311 
 assesses independent effects on both daily function and cognition is also acceptable as a single312 
 primary efficacy outcome measure in early AD patients. FDA encourages the development of313 
 novel approaches to the integrated evaluation of subtle functional impairment that arise from314 
 early cognitive impairment (e.g., facility with financial transactions, adequacy of social315 
 conversation).316 
 317 
 In early Stage 3 AD (which may be difficult to distinguish from late Stage 2 AD), FDA will318 
 consider strong justifications that a persuasive effect on cognition as measured by sensitive319 
 neuropsychological tests may provide adequate support for a marketing approval. It would320 
 generally be expected that such effects on cognitive measures would be supported by similarly321 
 persuasive effects on the characteristic pathophysiological changes of AD, and positive trends on322 
 functional outcome assessments. As previously described, a time-to-event analysis approach323 
 could also be considered (see section IV. B.). Whether effects on cognitive outcome measures324 
 would, in the absence of a meaningful change in function, support either traditional or325 
 accelerated approval would require detailed discussion with the Agency