Thread by @AlbertoEspay

#Donanemab for #Alzheimer, misleadingly spun as positive: “donanemab resulted in a better […] ability to perform activities of daily living than placebo at 76 weeks”. The data suggest otherwise. (1/8)

#EliLilly @NEJM #ADPD2021

nejm.org/doi/full/10.10…

https://twitter.com/NEJM/status/1370702429461782529

(2/8) First off, donanemab accomplished exactly what it was designed for: At 76 weeks, the reduction in the amyloid plaque level as assessed by florbetapir PET was 85.06 centiloids greater in the donanemab group than in the placebo group (−84.13 vs. 0.93 centiloids)

(3/8) However, the primary outcome, the composite iADRS (range, 0 - 144), showed a difference of only 3.20 points in favor of donanemab. While with a p=0.04, the trial was powered to show a 6-point difference. This goal was not reached, as the authors admit in the discussion.

(4/8) Contributing to the very modest iADRS change was the likely unblinding due to survivorship bias (adverse events related to treatment). Tellingly, all secondary outcomes were negative: CDR-SB, ADAS-Cog13, ADCS-iADL, and MMSE.

(5/8) What was significant but underemphasized was the reduction in brain volume and the increase in ventricular volume (a surrogate of brain volume) in donanemab vs. placebo:

(6/8) The authors brushed off the increase in brain atrophy as likely due to the removal of the aggregates. But can any amyloid burden reduction (measured in picograms/PET centiloids) significantly impact brain volume (measured in much larger MRI voxels)?

(7/8) 20 of 131 patients discontinued due to adverse events (AE), p = 0.007 vs placebo. Nearly 40% of patients developed amyloid-related imaging abnormalities (ARIA), 35 of which were with edema. These patients were allowed to continue, contributing to a positive iADRS bump.

(8/8) This “promising” phase 2 study will be taken as justification for moving on to a phase 3 trial as with all other anti-amyloid drugs. More lives are yet to be harmed on the unending pursuit inspired by our blind allegiance to anti-amyloid strategies.