A list of therapeutic approaches to target Aβ and their adverse events in clinical trials
| Mechanism of action | Drug | Trial phase | Adverse events in clinical trials | Main reason for failure | References |
|---|---|---|---|---|---|
| BACE1 inhibitor | Verubecestat | III | Worsened cognition, increased mortality, and reduced brain volume in the whole-brain and hippocampal region | Lack of efficacy | Egan et al. (2018) [185], Sur et al. (2020) [186] |
| Umibecestat (CNP520) | II / III | Worsened cognition and brain atrophy | Toxicity | NCT02565511, NCT03131453 | |
| Atabecestat | II / III | Worsened cognition and liver toxicity | Toxicity | Novak et al. (2020) [187], Sperling et al. (2021) [188] | |
| Lanabecestat (AZD3293, LY3314814) | III | Worsened cognition | Lack of efficacy | Wessels et al. (2020) [189] | |
| BI1181181 | I | No SAEs reported | Further study required | NCT02044406, Nicolas et al. (2015) [190] | |
| LY2886721 | II | Liver toxicity | Toxicity | Lahiri et al. (2014) [191] | |
| AZD3839 | I | Heart rhythm disturbance | Toxicity | Yan (2016) [192], NCT01348737 | |
| RG7129 | I | Liver toxicity | Toxicity | NCT01664143, NCT01592331 | |
| Elenbecestat (E2609) | III | No SAEs reported | Lack of efficacy | NCT02956486, NCT03036280 | |
| LY3202626 | II | No SAEs reported | Lack of efficacy | Lo et al. (2021) [193] | |
| γ-secretase inhibitor | Semagacestat | III | Worsened cognition and increased skin cancers and infections | Toxicity and lack of efficacy | Doody et al. (2013) [194] |
| Begacestat (GSI-953) | I | No SAEs reported | Further study required | NCT00547560 | |
| Avagacestat | II | Worsened cognition and increased nonmelanoma skin cancer | Toxicity and lack of efficacy | Coric et al. (2012) [195], Coric et al. (2015) [196] | |
| MPC-7869 (Flurizan, Tarenflurbil) | III | No SAEs reported | Lack of efficacy | NCT00322036 Green et al. (2009) [197] |
|
| Aβ antigen | AN-1792 (AIP001) | II | Brain inflammation (meningoencephalitis) | Toxicity and lack of efficacy | Gilman et al. (2005) [198], Boche et al. (2010) [199] |
| Affitope AD02 | II | No SAEs reported | Lack of efficacy | Schneeberger et al. (2015) [200] | |
| Vanutide cridificar (ACC-001) | II | No SAEs reported | Lack of efficacy | Pasquier et al. (2016) [201] | |
| CAD 106 (Amilomotide) | II | Worsened cognition, decreased cortical gray-matter volume, and ARIAs (ARIA-E & ARIA-H) | Lack of efficacy | Vandenberghe et al. (2017) [202] | |
| Monoclonal antibody | Aducanumab (BIIB037, Aduhelm) | III | ARIA-E | Lack of efficacy | Ferrero et al. (2016) [203], Sevigny et al. (2016) [204], NCT02477800, NCT02484547 |
| Bapineuzumab (AAB-001) | III | Increased risk of serious treatment-emergent adverse events and ARIA-E | Toxicity and Lack of efficacy | Salloway et al. (2014) [205], Vandenberghe et al. (2016) [206], Abushouk et al. (2017) [207] | |
| AAB-003 | I | ARIA-E | Further study required | Delnomdedieu et al. (2016) [208], NCT01193608 | |
| Gantenerumab | III | ARIAs | Lack of efficacy | Ostrowitzki et al. (2017) [209] | |
| Solanezumab (LY2062430) | III | ARIAs | Lack of efficacy | Doody et al. (2014) [210], Honig et al. (2018) [15], Siemers et al. (2016) [211] | |
| Crenezumab | III | No SAEs reported | Lack of efficacy | Yang et al. (2019) [212], NCT02670083 | |
| Ponezumab | II | No SAEs reported | Lack of efficacy | Landen et al. (2017) [213], NCT00722046 | |
| Immunoglobin | III | No SAEs reported | Lack of efficacy | Relkin et al. (2017) [214] | |
| Donanemab (LY3002813) | III | Reduced brain volume and ARIA-E | Lack of efficacy | Lowe et al. (2021) [215], Ayton (2021) [216] NCT04437511 |
|
| Lecanemab (BAN2401) | II | ARIA-E | Lack of efficacy | Swanson et al. (2021) [217] NCT03887455 |
|
| SAR228810 | I | No SAEs reported | Further study required | Pradier et al. (2018) [218], NCT01485302 | |
| MEDI1814 | I | No SAEs reported | Further study required | NCT02036645 | |
| GSK933776 | II | No SAEs reported | Lack of efficacy | Leyhe et al. (2014) [219], NCT01342926 | |
| Aβ vaccine | ACI-24 | II | No SAEs reported | Further study required | Ritchie et al. (2003) [220] |
| UB-311 | II | No SAEs reported | Further study required | Wang et al. (2017) [221], NCT02551809 | |
| ABVac40 | II | No SAEs reported | Further study required | Lacosta et al. (2018) [222] NCT03461276 | |
| Aβ aggregation inhibitor | Alzhemed (Tramiprosate, 3-APS) | III | No SAEs reported | Lack of efficacy | NCT00314912, Aisen et al. (2006) [223], Gauthier et al. (2009) [224] |
| Scyllo-inositol (AZD-103, ELND005) | II | Higher incidence of SAEs and respiratory tract infections in high dose groups | Lack of efficacy, Further study required | Salloway et al. (2011) [225] | |
| PBT1 (Clioquinol) | II | SAEs such as visual impairment and intracranial hemorrhage | Toxicity and lack of efficacy | Sampson et al. (2014) [226] | |
| PBT2 (Hydroxyquinoline) | II | No SAEs reported | Lack of efficacy | Lannfelt et al. (2008) [227] NCT00471211 | |
| GV-971 (Sodium oligo-mannurarate) | III | Higher incidence of hyperlipidemia and nasopharyngitis | Further study required | Xiao et al. (2021) [228] NCT02293915 |
SAE, serious adverse events; ARIA-E, amyloid-related imaging abnormalities with vasogenic edema; ARIA-H, amyloid-related imaging abnormalities with microhemorrhages.