High-clearance anti-amyloid immunotherapies in Alzheimer’s disease. Part 2: putative scenarios and timeline in case of approval, recommendations for use, implementation, and ethical considerations in France

Villain N(1), Planche V(2), Levy R(3).

Author information:
(1)AP-HP Sorbonne Université, Hôpital Pitié-Salpêtrière, Department of Neurology,
Institute of Memory and Alzheimer’s Disease, Paris, France; Sorbonne Université,
INSERM U1127, CNRS 7225, Institut du Cerveau – ICM, Paris, France. Electronic
address: .
(2)University Bordeaux, CNRS, IMN, UMR 5293, 33000 Bordeaux, France; Centre
Mémoire Ressources Recherches, Pôle de Neurosciences Cliniques, CHU de Bordeaux,
33000 Bordeaux, France.
(3)AP-HP Sorbonne Université, Hôpital Pitié-Salpêtrière, Department of Neurology,
Institute of Memory and Alzheimer’s Disease, Paris, France; Sorbonne Université,
INSERM U1127, CNRS 7225, Institut du Cerveau – ICM, Paris, France.

In 2021, aducanumab, an immunotherapy targeting amyloid-β, was approved for
Alzheimer’s disease (AD) by the US Food and Drug Administration thanks to
positive results on a putative biological surrogate marker. This approval has
raised an unprecedented controversy. It was followed by a refusal of the European
Medicine Agency, which does not allow the marketing of drugs solely on biological
arguments and raised safety issues, and important US coverage limitations by the
Centers for Medicare & Medicaid Services. Two other anti-amyloid immunotherapies
showed significant results regarding a clinical outcome in phase II trials, and
five drugs are being studied in phase III trials. Lecanemab is currently under
examination for an ‘Accelerated Approval’ in the US, with an expected decision in
January 2023. The common feature and novelty of these anti-amyloid
immunotherapies, compared to those tested in previous trials of the 2010s, is
their ability to induce a high clearance of amyloid load, as measured with
positron emission tomography, in the brain of early-stage biomarker-proven AD
patients. In the first part of this review, we underlined through a meta-analysis
that the pooled data from high-clearance anti-amyloid immunotherapies trials
demonstrated a significant but slight clinical effect after 18 months. Still,
safety remains an issue with serious and symptomatic amyloid-related imaging
abnormalities, which are seldom (∼1 per 200 treated patients) but occur beyond
chance. In the second part of this review, we hypothesized that there is a high
probability that some phase III trials of high-clearance anti-amyloid
immunotherapies in early AD will finally be unarguably positive on clinical
outcomes in the next five years with acceptable safety data. This may, in turn,
lead to approval by the European Medicine Agency if the risk-benefit profile is
deemed favorable. Such approval would be a game-changer in managing AD patients
and for the organization of memory clinics in France. We review the possible
timeline and scenarios for putative approval in France and make propositions
regarding putative use in clinical practice, putative implementation in a
real-life setting, and ethical considerations.

Copyright © 2022 The Author(s). Published by Elsevier Masson SAS.. All rights
reserved.

 

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