Angela Tian Hui Kwan1,2,3, Saman Arfaie2,3,4,5, Joseph Therriault2,3,6, Pedro Rosa-Neto2,3,6, Serge Gauthier7,8,9. 1. Department of Chemical & Physical Sciences, University of Toronto, Toronto, Ontario, Canada. 2. Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Mental Health University Institute, McGill University, Montreal, Québec, Canada. 3. Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada. 4. Faculty of Medicine, McGill University, Montreal, Québec, Canada. 5. Department of Molecular Cell Biology, University of California, Berkeley, California, USA. 6. Department of Psychiatry, McGill University, Montreal, Québec, Canada. 7. Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Mental Health University Institute, McGill University, Montreal, Québec, Canada, serge.gauthier@mcgill.ca. 8. Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada, serge.gauthier@mcgill.ca. 9. Department of Psychiatry, McGill University, Montreal, Québec, Canada, serge.gauthier@mcgill.ca.
Abstract
BACKGROUND: Alzheimer disease (AD) is a chronic neurodegenerative disorder with complex pathophysiology that affects over 50 million people worldwide. Most drug therapies, to date, have focused on targeting the amyloid-beta (Aβ) pathway, but clinical outcomes of anti-Aβ antibodies have been unsuccessful and unable to meet their primary endpoints. Similar trends have also been observed in treatments that target the tau pathway. SUMMARY: This paper reviews recent anti-Aβ passive monotherapies, since Bapineuzumab, that have progressed to phase 3 clinical trials. Specifically, we discuss the 4 clinical trial programs of Solanezumab (targets Aβ monomers), Aducanumab (targets Aβ oligomers and plaques), Crenezumab (targets Aβ oligomers), and Gantenerumab (targets Aβ fibrils) which are all exogenous monoclonal antibodies. We conclude with potential reasons for why they have not met their primary endpoints and discuss lessons learnt from these trials. Key Message: Future disease-modifying trials (DMTs) for AD should be conducted in asymptomatic, Aβ-positive individuals. Moreover, potential additive and/or synergistic benefits focusing on anti-Aβ and anti-tau drug combinations merit further investigation.
BACKGROUND:Alzheimer disease (AD) is a chronic neurodegenerative disorder with complex pathophysiology that affects over 50 million people worldwide. Most drug therapies, to date, have focused on targeting the amyloid-beta (Aβ) pathway, but clinical outcomes of anti-Aβ antibodies have been unsuccessful and unable to meet their primary endpoints. Similar trends have also been observed in treatments that target the tau pathway. SUMMARY: This paper reviews recent anti-Aβ passive monotherapies, since Bapineuzumab, that have progressed to phase 3 clinical trials. Specifically, we discuss the 4 clinical trial programs of Solanezumab (targets Aβ monomers), Aducanumab (targets Aβ oligomers and plaques), Crenezumab (targets Aβ oligomers), and Gantenerumab (targets Aβ fibrils) which are all exogenous monoclonal antibodies. We conclude with potential reasons for why they have not met their primary endpoints and discuss lessons learnt from these trials. Key Message: Future disease-modifying trials (DMTs) for AD should be conducted in asymptomatic, Aβ-positive individuals. Moreover, potential additive and/or synergistic benefits focusing on anti-Aβ and anti-tau drug combinations merit further investigation.
Authors: Hannah W Haddad; Garett W Malone; Nicholas J Comardelle; Arielle E Degueure; Salomon Poliwoda; Rachel J Kaye; Kevin S Murnane; Adam M Kaye; Alan D Kaye Journal: Health Psychol Res Date: 2022-07-28
Authors: Hannah W Haddad; Garett W Malone; Nicholas J Comardelle; Arielle E Degueure; Adam M Kaye; Alan D Kaye Journal: Health Psychol Res Date: 2022-01-30
Authors: Aldo Peschiulli; Daniel Oehlrich; Michiel Van Gool; Nigel Austin; Sven Van Brandt; Michel Surkyn; Michel De Cleyn; Ann Vos; Gary Tresadern; Frederik J R Rombouts; Gregor J Macdonald; Diederik Moechars; Andrés A Trabanco; Harrie J M Gijsen Journal: ACS Med Chem Lett Date: 2021-12-01 Impact factor: 4.345
Authors: Joseph Therriault; Tharick A Pascoal; Marcus Sefranek; Sulantha Mathotaarachchi; Andrea L Benedet; Mira Chamoun; Firoza Z Lussier; Cécile Tissot; Bruna Bellaver; Pamela S Lukasewicz; Eduardo R Zimmer; Paramita Saha-Chaudhuri; Serge Gauthier; Pedro Rosa-Neto Journal: Ann Clin Transl Neurol Date: 2021-10-07 Impact factor: 4.511
Authors: Micha M M Wilhelmus; Elisa Tonoli; Clare Coveney; David J Boocock; Cornelis A M Jongenelen; John J P Brevé; Elisabetta A M Verderio; Benjamin Drukarch Journal: Cells Date: 2022-01-24 Impact factor: 6.600