TY - JOUR
T1 - Passive Alzheimer's immunotherapy
T2 - A promising or uncertain option?
AU - Høilund-Carlsen, Poul F.
AU - Revheim, Mona Elisabeth
AU - Costa, Tommaso
AU - Alavi, Abass
AU - Kepp, Kasper P.
AU - Sensi, Stefano L.
AU - Perry, George
AU - Robakis, Nikolaos K.
AU - Barrio, Jorge R.
AU - Vissel, Bryce
N1 - Publisher Copyright:
© 2023
PY - 2023/9
Y1 - 2023/9
N2 - The US Food and Drug Administration (FDA)’s recent accelerated approval of two anti-amyloid antibodies for treatment of Alzheimer's disease (AD), aducanumab and lecanemab, has caused substantial debate. To inform this debate, we reviewed the literature on randomized clinical trials conducted with eight such antibodies focusing on clinical efficacy, cerebral amyloid removal, amyloid-related imaging abnormalities (ARIAs) and cerebral volumes to the extent such measurements have been reported. Two antibodies, donanemab and lecanemab, have demonstrated clinical efficacy, but these results remain uncertain. We further argue that the decreased amyloid PET signal in these trials is unlikely to be a one-to-one reflection of amyloid removal, but rather a reflection of increased therapy-related brain damage, as supported by the increased incidence of ARIAs and reported loss of brain volume. Due to these uncertainties of benefit and risk, we recommend that the FDA pauses existing approvals and approval of new antibodies until results of phase 4 studies with these drugs are available to inform on these risk-benefit uncertainties. We recommend that the FDA prioritize FDG PET and detection of ARIAs and accelerated brain volume loss with MRI in all trial patients, and neuropathological examination of all patients who die in these phase 4 trials.
AB - The US Food and Drug Administration (FDA)’s recent accelerated approval of two anti-amyloid antibodies for treatment of Alzheimer's disease (AD), aducanumab and lecanemab, has caused substantial debate. To inform this debate, we reviewed the literature on randomized clinical trials conducted with eight such antibodies focusing on clinical efficacy, cerebral amyloid removal, amyloid-related imaging abnormalities (ARIAs) and cerebral volumes to the extent such measurements have been reported. Two antibodies, donanemab and lecanemab, have demonstrated clinical efficacy, but these results remain uncertain. We further argue that the decreased amyloid PET signal in these trials is unlikely to be a one-to-one reflection of amyloid removal, but rather a reflection of increased therapy-related brain damage, as supported by the increased incidence of ARIAs and reported loss of brain volume. Due to these uncertainties of benefit and risk, we recommend that the FDA pauses existing approvals and approval of new antibodies until results of phase 4 studies with these drugs are available to inform on these risk-benefit uncertainties. We recommend that the FDA prioritize FDG PET and detection of ARIAs and accelerated brain volume loss with MRI in all trial patients, and neuropathological examination of all patients who die in these phase 4 trials.
KW - ARIA
KW - Alzheimer's disease
KW - Amyloid PET
KW - Amyloid-beta
KW - Cerebral volumes
KW - Clinical trial
KW - Immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85165270397&partnerID=8YFLogxK
U2 - 10.1016/j.arr.2023.101996
DO - 10.1016/j.arr.2023.101996
M3 - Review article
C2 - 37414156
AN - SCOPUS:85165270397
SN - 1568-1637
VL - 90
JO - Ageing Research Reviews
JF - Ageing Research Reviews
M1 - 101996
ER -