Fire in the ashes: can failed Alzheimer's disease drugs succeed with second chances?

Background: Since Cognex, more than 200 Alzheimer's disease (AD) drug candidates have failed. Investigations have identified vulnerabilities of these AD drug developments to methodological errors. (-)-Phenserine has been discussed as possibly failing due to flawed methods and practices in development.

Methods: We analyzed documentation of (-)-phenserine's development for vulnerabilities to errors and designed interventions for a redevelopment that could provide fair or unbiased assessments of (-)-phenserine target engagement, target relevance for human diseases, and adequate presumptive evidence of efficacy as a therapeutic for one or more diagnoses to justify registration-required clinical trials.

Results: Similar to studies of 40 other AD developments, with (-)-phenserine, we found little evidence of preemptive interventions against potentially invalidating errors, grounds to judge progress in development through stages as not scientifically justifiable, and variance excess and placebo group improvements as capable of accounting for outcomes from various studies in the development. We propose to compare a redevelopment resourced to counter these deficiencies with the original development as historical control to evaluate further our hypothesis that errors in development accounted for the (-)-phenserine failure, specifically, and other AD drug failures, potentially.

Conclusions: We find support for our earlier proposal that (-)-phenserine did not fail, but the methods of development did fail, to provide conditions where efficacy could be tested. We propose that redevelopment under conditions aimed to correct methodological deficiencies common in AD drug developments will successfully test efficacy for (-)-phenserine and hopefully lead to a disease-modifying addition to the AD therapeutic armamentarium.