High-clearance anti-amyloid immunotherapies in Alzheimer’s disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects

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

Author information:
(1)Assistance Publique – Hôpitaux de Paris, Department of Neurology, Institute of
Memory and Alzheimer’s Disease, Pitié-Salpêtrière Hospital, Paris, France;
Sorbonne Université, Inserm U1127, CNRS 7225, Institut du Cerveau – ICM, Paris,
France. Electronic address: .
(2)CNRS, IMN, UMR 5293, University Bordeaux, 33000 Bordeaux, France; Pôle de
Neurosciences Cliniques, Centre Mémoire Ressources Recherches, CHU de Bordeaux,
33000 Bordeaux, France.
(3)Assistance Publique – Hôpitaux de Paris, Department of Neurology, Institute of
Memory and Alzheimer’s Disease, Pitié-Salpêtrière Hospital, 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 2 trials, and
five drugs are being studied in phase 3 trials. Compared to those tested in
previous trials of the 2010s, the common feature and novelty of these
anti-amyloid immunotherapies 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. Here, we review the available evidence
regarding efficacy and safety data and medico-economical aspects for
high-clearance anti-amyloid immunotherapies. We also perform frequentist and
Bayesian meta-analyses of the clinical efficacy and safety of the highest dose
groups from the two aducanumab phase 3 trials and the donanemab and lecanemab
phase 2 trials. When pooled together, the data from high-clearance anti-amyloid
immunotherapies trials confirm a statistically significant clinical effect of
these drugs on cognitive decline after 18 months (difference in cognitive decline
measured with CDR-SB after 18 months between the high dose immunotherapy groups
vs. placebo = -0.24 points; P=0.04, frequentist random-effect model), with
results on ADAS-Cog being the most statistically robust. However, this effect
remains below the previously established minimal clinically relevant values. In
parallel, the drugs significantly increased the occurrence of amyloid-related
imaging abnormalities-edema (ARIA-E: risk ratio=13.39; P

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