Anavex Life Sciences Corp (AVXL)

[Doc328]

This is very important and relevant guidance to address multiplicity. Until the last 5-6 years, almost all AD trials were in mild AD and with clinical rather than PET entry criteria. As the anti-amyloid drugs showed some activity in the mildest patients but no activity in the moderate patients, trials evolved to test either MCI (with proof of amyloid) only or Mild Ad / MCI (with proof of amyloid). ADAS-Cog is more sensitive to follow progression of mild AD than it is for MCI. Therefore, some studies the past 5 years have used CDR-SB (lecanemab among others as example) or iADRS (donanemab as only example). iADRS is basically the subset of ADAS-Cog found to be most sensitive for MCI and mild AD combined with the ADCS-iADL scale (a modified instrumental ADL for MCI and milder AD). Therefore the 2017 example for AD in the draft guidance became a poor example and not included in the final guidance to industry.