Background
AD therapeutic strategies | |
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Mechanism-based Approaches | |
1. Therapies Targeted at Amyloid 1.1 Inhibiting Aβ Production 1.2 Accelerating Aβ Clearance 1.3 Preventing Aβ Aggregation 2. Therapies Targeted at Tau 2.1 Tau Stabilizers and Aggregation Inhibitors 2.2 Therapies Targeted at Tau Post-translational Modifications 2.3 Anti-tau Immunotherapy 3. Therapies Targeted at ApoE 4. Neuroprotective Therapies 4.1 Neurotrophins and Their Receptor-based Therapies 4.2 Therapies Targeted at Neuroinflammation and Oxidative Stress | |
Non-mechanism Based Approaches | |
1. Symptomatic Cognitive Enhancers 2. Therapies and Interventions for AD Prevention 2.1 Secondary Prevention Interventions 2.2 Primary Prevention Interventions |
Mechanism-based approaches
Therapies targeted at amyloid
Reducing Aβ generation
AD drugs tested in clinical trials | |||||
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Drug | Phase | Subject | NCT | Summary | Reference |
1.Therapies Targeted at Amyloid | |||||
1.1 Reducing Aβ Generation | |||||
MK-8931 (BACE inh.) | III | Prodromal AD | NCT01953601 | lack of efficacy | 14-16 |
LY450139 | III | Mild to moderate AD | NCT00762411; NCT00594568 | lack of efficacy | 15,18, 19, |
(γ-secretase inh.) | NCT01035138 | 34, 36, 37 | |||
Avagacestat | II | Prodromal AD | NCT00890890 | no efficacy | 35 |
NIC5-15 | II | Probable AD | NCT01928420 | completed | 15,40 |
R-flurbiprofen | III | Probable AD | NCT00105547; NCT00322036 | lack of efficacy | 42 |
EVP-0962 | II | Healthy, MCI or early AD | NCT01661673 | terminated | 15 |
1.2 Accelerating Aβ Clearance | |||||
AN-1792 | II | Mild-to-moderate AD | NCT00021723 | severe meningoencephalitis | 44 |
Affitope AD02 | II | Early AD | NCT02008513; NCT01117818 | no efficacy | 46 |
CAD106 | II/III | Mild AD | NCT02565511 | ongoing | 15, 47 |
Bapineuzumab | III | Mild-to-moderate AD | NCT00667810; NCT00575055 NCT00574132 | no efficacy | 43, 48 |
Solanezumab | III | Mild-to-moderate AD probable AD | NCT00905372; NCT00904683 NCT01900665 | no efficacy | 43, 49 |
BAN2401 | II | MCI due to AD and mild AD | NCT01767311 | positive results | 50 |
Crenezumab | III | Probable AD or prodromal AD | NCT03114657; NCT02670083 | ongoing | |
Gantenerumab | III | Probable AD or prodromal AD | NCT03443973; NCT03444870 | ongoing | |
Aducanumab | I | Prodromal or Mild AD | NCT01677572 | positive results but ARIA | 51 |
III | MCI due to AD or mild AD | NCT02484547; NCT02477800 | ongoing | ||
1.3 Other Anti-amyloidogenic Compounds with Diverse Mechanisms of Action | |||||
ALZT-OP1 | III | Early AD | NCT02547818 | ongoing | 43 |
GV-971 | III | Mild-to-moderate AD | NCT02293915 | completed | 43 |
Posiphen | I | MCI or probably AD | NCT02925650 | ongoing | 52 |
ELND005 | II/III | Mild-to-severe AD | ongoing | 53 | |
ALZ801 | III | Mild AD (ApoE4 carriers) | ongoing | 43 | |
2. Therapies Targeted at Tau | |||||
2.1 Tau Stabilizers and Aggregation Inhibitors | |||||
TPI 287 | I | Probable AD | NCT01966666 | ongoing | |
Rember™ | II | Mild or moderate AD | NCT00684944; NCT00515333 | no efficacy | 62, 63 |
TRx0237 | III | Mild-to-moderate AD/BvFTD | NCT01689233; NCT01689246 NCT02245568 | no efficacy | 64 |
TauRx | II/III | Mild or moderate AD | NCT03539380 | ongoing | |
2.2 Therapies Targeted at Tau Post-translational Modifications | |||||
Lithium and Valproate | II | AD | NCT00088387 | no efficacy | 67, 68 |
NP-12 | IIb | Mild-to-moderate AD | NCT01350362 | no efficacy | 69-71 |
2.3 Anti-tau Immunotherapy | |||||
AADvac1 | II | Mild-to-moderate AD | NCT02579252 | ongoing | 94 |
ACI-35 | I | Mild-to-moderate AD | ISRCTN13033912 | completed | 61 |
ABBV-8E12 | II | PSP; MCI or probable AD | NCT03391765; NCT02880956 | ongoing | |
RO7105705 | I | Healthy | NCT02820896 | ongoing | |
3. Therapies Targeted at ApoE | |||||
Bexarotene | II | Probable AD | NCT01782742 | no efficacy | 142 |
4. Neuroprotective Therapies | |||||
4.1 Neurotrophins and Their Receptor-based Therapies | |||||
NGF | I | Probable early AD | NCT00017940 | positive results | 170 |
AAV2-NGF | II | Mild-to-moderate AD | NCT00876863 | no efficacy | 173 |
LM11A-31 (p75 inh.) | I/II | Mild-to-moderate AD | NCT03069014 | ongoing | |
4.2 Therapies Targeted at Neuroinflammation and Oxidative Stress | |||||
Dimebon | III | AD | NCT00912288 | no efficacy | 209 |
valacyclovir | II | Probable AD | NCT03282916 | ongoing | |
5. Symptomatic Cognitive Enhancers | |||||
Idalopirdine | II | Probable AD | NCT01019421 | positive results | 233 |
(5-HT6 antag.) | III | Mild-to-moderate AD | NCT01955161; NCT02006641 NCT02006654 | no efficacy | 234 |
GSK239512 (H3R antag.) | II | Probable AD | NCT01009255 | no efficacy | 235 |
ABT288 (H3R antag.) | II | Mild-to-moderate AD | NCT01018875 | no efficacy | 236 |
Rasagiline (MAOB inh.) | II | Probable AD | NCT02359552 | ongoing | 237 |
Ladostigil (combined) | II | MCI or Mild-to-moderate AD | NCT01429623; NCT01354691 | no efficacy | 238-241 |
AZD0530 | Ib | Mild-to-moderate AD | NCT01864655 | safety and tolerance | 252 |
(Fyn kinase inh.) | II | Mild AD | NCT02167256 | ongoing | |
Cilostazol | II | MCI | NCT02491268 | positive results | 255-257 |
(PDE3 inh.) | IV | Mild-to-moderate AD | NCT01409564 | ongoing | |
HT-0712 (PDE4 inh.) | II | Age-associated memory impairment | NCT02013310 | completed | 253, 254 |
Roflumilast (PDE4 inh.) | I | Scopolamine-induced CI | NCT02051335 | no efficacy | 253, 254 |
II | Healthy | NCT01433666 | positive results | 253, 254 | |
Age-associated memory impairment | ISRCTN96013814 | completed | 253, 254 | ||
BPN14770 (PDE4 inh.) | I | Healthy | NCT02648672; NCT02840279 | positive results | 253, 254 |
BI 409306 (PDE9 inh.) | I | Healthy | NCT01343706 | safety and tolerance | 253 |
II | MCI due to AD and mild AD | NCT02337907 | ongoing | 253, 254 | |
PF044467943 | I | Mild-to-moderate AD | NCT00988598 | safety and tolerance | 253 |
(PDE9 inh.) | II | Mild-to-moderate AD | no efficacy | 253 | |
6. Therapies and Interventions for AD Prevention | |||||
PROSPER (statin) | II | High risk (with AD parents) | NCT00939822 | no efficacy | 265 |
ACCORD-MIND | III | DM2 | NCT00182910 | no efficacy | 268 |
SNIFF (i.n. insulin) | II; II/III | MCI or AD or probable AD | NCT00438568; NCT01767909 | ongoing | 271-273 |
Metformin | IV | Age >60 years with IGT | NCT02432287 | completed | 274 |
Pioglitazone | II | Mild-to-moderate AD | NCT00982202 | safety and tolerance | 275 |
MIND (diet) | BMI≥25 non-demented | NCT02817074 | ongoing | 277, 278 | |
FABS (fitness) | Non-demented | ACTRN12605000136606 | positive results | 280 | |
ACTIVE (cog. training) | II/III | MCI | NCT00298558 | positive results | 282 |
Vit. E + Memantine | III | Mild to moderate AD | NCT00235716 | positive results | 284, 285 |
Ginkgo biloba | III | Non-demented and MCI | NCT00010803 | no efficacy | 286, 287 |
EGb 761® | IV | Subjects with memory complaints | NCT00276510 | no efficacy | 288 |
MIDAS | Age-associated memory impairment | NCT00278135 | positive results | 290 | |
FINGER | High risk | NCT01041989 | positive results | 291 | |
MIND-ADMINI | Prodromal AD | NCT03249688 | ongoing |