Status and rationale of selected compounds targeting various amyloid proteins tested in AD clinical trials
| Invested agent name | Target and rationale | Status on clinical trials (start date–end date) | AD stage | Results | Clinical trial identifier (NCT number) |
|---|---|---|---|---|---|
| Posiphen tartrate (Buntanetap) | APP synthesis reduction | Phase 1–2 (2021) | Mild to moderate | Terminated due to business decision | 04524351 |
| Bryostatin | α-Secretase activity enhancer, reducing Aβproduction | Phase 2 (2019) | Moderate to severe | Ineffective | 03560245 |
| LY3202626 | β-Secretase activity reduction [targeting BACE1 (β site APP cleaving enzyme 1)] | Phase 2 (2018) | Mild | Terminated due to low likelihood of identifying a statistically significant treatment effect | 02791191 |
| Lanabecestat (LY3314814) | β-Secretase activity reduction (targeting BACE1) | Phase 2/3 (2018) | Mild | Lack of efficacy or terminated due to unlikely to meet the primary endpoint and brain volume reduction | 0224573702783573 |
| Verubecestat(MK-8931) | β-Secretase activity reduction (targeting BACE1) | Phase 2–3 (2017) | Mild to moderate | Terminated due to injuries and lack of efficacy | 01739348 |
| Umibecestat(CNP520) | β-Secretase activity reduction (targeting BACE1) | Phase 2/3 (2019 and 2021) | Mild, or at risk of AD with one allele of APOE4 and elevated brain amyloid | Worsening cognition, and terminated due to safety reasons | 03131453 |
| Elenbecestat (E2609) | β-Secretase activity reduction (targeting BACE1) | Phase 3 (2020) | Mild/Early | Ended Due to an unfavorable risk-benefit ratio including lack of efficacy, and the adverse event being worse than the placebo with brain volume loss | 02956486 |
| Semagacestat | γ-Secretase inhibitor, preventing Aβ production (not selective) | Two phase 3 trials (2017–2020) | Mild to moderate | Significant deterioration of cognitive function, side effects (GI and skin cancer) | 0242312203402659 |
| ELND005 | Inhibiting Aβ formation | Phase 2 (2012–2015) | Moderate | Adverse effect (infection) | 01735630 |
| Exendin4 | A glucagon-like peptide, binding to soluble Aβ fragments, lowering Aβ burden | Phase 2 (2016) | Prodromal/Mild | Adverse effect (infection), terminated due to lack of support | 01255163 |
| (Azeliragon) TPP488 | RAGE (cell surface receptor linked to an increase in Aβ plaque formation) antagonist, increase Aβ clearance and targeting neuroinflammation | Phase 2 (2019–2021)Two phase 3 trials (2015–2018, 2016–2018) | Mild | Primary endpoints not met | 039807300208036402916056 |
| Pioglitazone | Agonizing peroxisome proliferator-activated receptor (PPAR) to increase Aβ phagocytosis | Phase 3(2015–2018) | MCI | Terminated due to lack of efficacy | 02284906 |
| Crenezumab (MABT5102A, RG7412) | Human monoclonal antibody (hmAB) targeting the clearance of Aβ oligomers and fibrillar species | Phase 3 (2016, 2017, 2018–2019) | Prodromal to mild | Discontinued by the sponsor due to lack of efficacy [23] | 026700830311465703491150 |
| Solanezumab | hmAB targeting soluble Aβ peptide | Phase 3 (2013–2017) | Mild to moderate | Lack of efficacy | 01900665 |
| Gantenezumab | hmAB binds to insoluable Aβ plaques and removes them via phagocytosis | Phase 3(2010–2020,2014–2021) | Mild/Prodromal | Lack of efficacy, its primary endpoints not met | 0122420602051608 |
| Aducanumab (BII3037) | hmAB targeting the clearance of Aβ plaques | Phase 2 (2018–2019)Phase 3 (2015–2019, 2015–2019, 2020–2024, 2022–2024) | Mild/Early | Two identical trials (ENGAGE and EMERGE) were terminated due to futility analysis. Substudies for both trials showed a dose-dependent reduction of Aβ and CDR-SB. In the EMERGE trial (NCT 02484547), aducanemab at a high dose significantly reduced dementia rating score CDR-SB. The trial (NCT05310071) would be terminated due to the sponsor’s decision | 0363998702484547024778000424106805310071 |
| Donanemab (LY3002813) | hmAB targeting the clearance of Aβp3-42 plaques | Phase 1–3(2017–2021, 2023, 2020–2024) | Mild/Early | Reduced Aβ plaques and tau, are under review for standard approval [14] | 03367403044375110510892204640077 |
| Lecanemab (BAN2401) | hmAB targeting the clearance of soluble Aβ aggregates | Phase 1–3(2012–2023 2019–2027) | Mild | Reduced Aβ plaques and tau, with less decline of cognition and function. Received full FDA approval | 0209472903887455 |
| UB-311(AD vaccine) | Active immunotherapy with Aβ peptide (N-terminal amino acid 1-14), inhibiting Aβ aggregates | Phase 2 (2015–2018) | Mild | Robust immune response with adverse events such as microhaemorrages (14%), supporting phase 3 trials [24] | 02551809 |
AD: Alzheimer’s disease; Aβ: amyloid-beta; APP: Aβ precursor protein; MCI: mild cognitive impairment; CDR-SB: clinical dementia rating-sum of boxes; GI: gastrointestinal; APOE 4: apolipoprotein E 4
