Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer's disease.
Expert Opin Drug Discov
; 19(6): 639-647, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38685682
ABSTRACT
INTRODUCTION:
In the last decade, the efforts conducted for discovering Alzheimer's Disease (AD) treatments targeting the best-known pathogenic factors [amyloid-ß (Aß), tau protein, and neuroinflammation] were mostly unsuccessful. Given that a systemic failure of Aß clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aß monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results. AREAS COVERED The present Drug Discovery Case History analyzes the failures of RCTs of solanezumab on AD. Furthermore, the authors review the pharmacokinetics, pharmacodynamics, and tolerability effect of solanezumab from preclinical studies with its analogous m266 in mice. Finally, they describe the RCTs with cognitive, cerebrospinal fluid and neuroimaging findings in mild-to-moderate AD (EXPEDITION studies) and in secondary prevention studies (A4 and DIAN-TU). EXPERT OPINION Solanezumab was one of the first anti-Aß monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aß level by acting on soluble monomeric form of Aß peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aß cascade hypothesis of AD.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Ensaios Clínicos Controlados Aleatórios como Assunto
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Peptídeos beta-Amiloides
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Doença de Alzheimer
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Anticorpos Monoclonais Humanizados
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article