Compounds target for cognitive improvement in AD and their combination treatments
| Name | Target and rationale | Status on clinical trials (start date–end date) | AD stage | Results | Clinical trials identifier (NCT number) |
|---|---|---|---|---|---|
| CT1812 | Antagonists for the sigma 2 and progesterone receptor membrane component 1 (PGRMC1) receptors | Phase 1–2 (2018–2020) | Mild to moderate | No alteration of synaptic density, insignificant changes in cognition memory task | 03493282 |
| Rasagiline (Azilect) | MAOB inhibitor, reducing reactive astrocytes | Phase 2 (2015–2019) | Mild to moderate | Glucose metabolism declining less showed benefit in quality of life only | 02359552 |
| Ladostigil | AchE inhibitor and MAO inhibitor, promoting cholinergic and serotonergic/dopaminergic neurotransmission | Phase1/2 (2019) | Mild | Failed to meet the primary endpoint | 01429623 |
| Idalopirdine | AchE inhibitor and 5-HT6 receptor, stimulating 5-HT and cholinergic receptor (as an adjunct therapy for AchE inhibitor) | Phase 1–3 (2014–2017) | Mild to moderate | Weak efficacy in phase 3, discontinued (2017) | 02079246 |
| Rivastigmine | Inhibitors of AchE and butyrylcholiesterase | Phase 4 (2016–2018) | Mild to moderate | Showing some symptomatic improvement [13] | 02703636 |
| Intepirdine (RVT-101) | The antagonist of the 5-HT6 receptor, CNS-specific | Phase 2 (2016–2017)Phase 3 (2016–2018) | Mild to moderate | Did not meet primary efficacy endpoints | 0258690902910102 |
| BI 409306 | Inhibitor of phosphodiesterase (PDE) 9A, increasing cGMP | Phase 2 (2015–2017) | Prodromal | No difference between drug and placebo groups on measures of efficacy | 0224069302337907 |
| Neflamapimod (VX-745) | Inhibitor of p38 MAPK (mitogen-activated protein kinase) alpha | Phase 2 (2015–2016)Phase 2 (2017–2019) | Mild | Failed to meet the primary endpoint of improving episodic memory | 0242312203402659 |
| BI 425809 | Inhibitor of glycine transporter, keeping a higher level of glycine at the synapse promoting NMDA R activation | Phase 2 (2016–2019) | Mild to moderate | No improvement in the primary or secondary measures compared with the placebo [20] | 02788513 |
| Candesartan | Blocker of Angiotensin II | Phase 2 (2016–2020) | MCI | Superior in primary and secondary outcomes of executive function by TMT(B) and Hopkins Verbal Learning Test-Revised delayed recall [21] | 02646982 |
| Donepezil plus solifenacin (CPC-201) | Inhibitor of AchE and muscarinic receptor M3 treating overactive bladder, respectively | Phase 2 (2015–2017) | Moderate | Allowing the safe use of higher AchE inhibitors doses that may augment cognitive and global benefits [22] | 02549196 |
| Donepezil + memantine + masupirdine (SUVN-502) | Antagonists of the AChE, NMDA R, and 5-HT6 receptor | Phase 1–2 (2018) | Moderate | No additional benefit with the combination treatments | 02580305 |
| Memantine + bryostatin | NMDA R antagonist, macrolide lactones which increase the α-secretase activity and reduce Aβ accumulation | Phase 2 (2015–2017) | Moderate to severe | No additional benefit with the combination treatments | 02431468 |
AD: Alzheimer’s disease; 5-HT6: 5-hydroxytryptamine 6; MAOB: monoamine oxidase-B; MCI: mild cognitive impairment; TMT(B): Trail-Making Test-B; Aβ: amyloid-beta; NMDA R: N-methyl-D-aspartic acid receptor