Table 1.
List of failed therapeutic interventions in Alzheimer’s disease over the last 10 years, ordered according to the general mechanism. Many drugs failed in Phase II proof-of-concept, some failed in Phase III pivotal trials.
| Drug | Mechanism | Clinical Phase |
|---|---|---|
| Amyloid-beta modulation | ||
| Bapineuzumab | Passive vaccination | PhIII |
| Solanezumab | Passive vaccination | PhIII |
| Semagecestat | Gamma-secretase inhibitor | PhII : irreversibly worsens cognition |
| avagacestat | Gamma-secretase inhibitor | PhII : irreversibly worsens cognition |
| ponezumab | Passive vaccination | PhII |
| Tramiprosate | Plaque destabilizer | PhIII |
| Scyllo-inositol | Block Abeta accumulation | PhII |
| tarenflurbil | Abeta lowering agent | PhIII |
| Neuroprotective | ||
| Latrepirdine (dimebon) | Mitochondrial stabilizer | PhIII |
| PF-04494700 | RAGE inhibitor | PhII |
| cevimeline | Sensitizes neurons to growth factors | PhII |
| idebenone | Anti-oxydant | PhIII |
| buprofen, naproxen, rofecoxib | Anti-inflammatory | PhII |
| Atorvastatin, simvastatin | Cholesterol modulation | PhII |
| Leuprolide, neotrofin | Modulates growth factor | PhII |
| rosiglitazone | PPAR agonist | PhIII |
| Sabeluzole, T817-MA | Neuroprotectant | PhIII |
| Symptomatic Treatment | ||
| H3 antagonism, linopirdine, LU25-109, H4 agonism (PRX-03140), NS2330, ST101 | Neurotransmitter modulator | PhII |
| Ispronicline, TC6683 | A4b2 nAchR modulator | PhII |
| CX516 | AMPAkine | PhII |
| Eptastigmine, huperzine, metrifonate, phenserine, physostigmine, propentofylline | AChE inhibitor | PhII |
| MEM1003 | L-type Ca channel inhibitor | PhII |
| Milameline, sabcomeline, xanomeline, NGX267 | Partial mAChR agonist | PhII |
| MKC-231 | Improves cholinergic signalling | PhII |
| SGS-742 | GABA-B antagonist | PhII |
| suritozole | Inverse GABA agonist | PhII |
| Nefiracetam, piracetam | Cognitive enhancer | PhII |
| Neramexane | NMDA antagonist | PhII |