BioMed Research International / 2014 / Article / Tab 1

Review Article

Potential Therapeutic Strategies for Alzheimer’s Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials

Table 1

RCTs based on -amyloid in recent years.

MechanismRCTStatusEstimated endDementia stageEnrollmentDurationReported outcomesDetails of drugs/RCTs

↓A production
 BACE1 inhibitorPioglitazonePhase 2; completed2005.1Mild-to-moderate2518 monthsInsulin sensitizer, class of PPAR agonists
CTS-21166Phase 1; completed2008.2Healthy56
MK8931Phase 3; ongoing2018.3Mild-to-moderate1960≈6.5 yearsWith enhanced BBB permeability
E2609Phase 1; completed2013.9MCI/mild AD65
 GSI/GSMNIC5-15Phase 2; ongoing2013.1240Notch-sparing, insulin-sensitizer
BegacestatPhase 1; completed2009.10Elder healthy49Dose-dependent changes in plasma A levelsSelectively inhibits cleavage of APP over Notch [208]
CHF 5074Phase 2; completed2012.4MCI9612 weeksNSAID
EVP-0962Phase 2; completed2013.10MCI/early stage5214 days
-secretase activatorAtorvastatinPhase 3; completed*2007.7Mild-to-moderate60080 weeksTested with AchEI
SimvastatinPhase 3; completed2007.10Mild-to-moderate40018 months
EtazolatePhase 2a; completed2009.8Mild-to-moderate159Safe and well tolerated -secretase activity, acting as a GABA-A receptor modulator and a PDE-4 inhibitor [209]
Epigallocatechin-3-gallate (EGCg)Phase 2/3; ongoing2015.6Early stage5018 monthsPrevents the A aggregation via binding to the unfolded peptide
 ↓A aggregation/oligomersScyllo-inositol (ELND005/AZD103)Phase 2; completed2010.5Mild-to-moderate35018 monthsInsufficient to support/refute benefits [210]
Tramiprosate (3APS)Phase 3unknownMild-to-moderate950Suggesting disease-modifying effects [211]
PBT2Phase 2; completed2007.12Mild AD8012 weeksWell-tolerated, ↓CSF A 42, and improved executive function [212]

↑Aβ clearance
 Active immunotherapyAffitope AD02Phase 2; completed2013.12Early stage335>1 yearN-terminal A 1-6, a synthetic peptide
Affitope AD03Phase 1; completed2011.11Mild-to-moderate28i.h. with or without adjuvant aluminum
UB 311Phase 1; completed2011.4Mild-to-moderate19N-terminal A 1-14
V 950Phase 1; completed2012.186formulated on Aluminum-containing adjuvant
CAD 106Phase 2; completed2012.12Mild AD177A favourable safety profile [213]N-terminal A 1-6; i.m. of adjuvanted CAD106;
 Passive  immunotherapyBAN2401Phase 2; ongoing2016.12MCI/mild AD80018 monthsmAb against A oligomers
BIIB037Phase 1; ongoing2014.11Prodromal to mild160Administered via intravenous (IV) infusions in subjects
PonezumabPhase 2; completed2011.8Mild-to-moderate19824 months
CrenezumabPhase 2/3; ongoing2016.5Mild-to-moderate36124 months
Gammagard (IVIg)Phase 2, completed2010.4Mild-to-moderate246 monthsImproved cognition
Phase 3; completed2012.12Mild-to-moderate39070 weeksShowed no significant effect
Phase 2; ongoing2014.10MCI5024 months
AMBARPhase 2/3; ongoing2016.12Mild-to-moderate350
GantenerumabPhase 3; ongoing2019.3Mild1000>5 monthsPhase 1 RCT↓brain A ; high doses, AEMainly targets A plagues
SolanezumabPhase 3; ongoing2016.12Mild2100No benefits in primary outcomesMainly targets soluble oligomeric A
AAB-003Phase 1; ongoing2014.8Mild-to-moderate10452 weeksPreviously treated with AAB-003
GSK933776Phase 1; completed2011.550
SAR228810Phase 1; ongoing2015.1Mild-to-moderate4814.5–22 months

Anti-tau
 ↓tau productionValproatePhase 3; complete2009.12Mild-to-moderate3132 yearsDid not show cognitive benefits and prevention of behavioral defects; associated with reduced brain volumes
LithiumPhase 2; ongoing2019.480A pilot study was insufficient to support or refute the efficacy [214]
 ↓tau  fibrillization/depositionNicotinamidePhase 1/2; ongoing2014.7Mild-to-moderate5024 weeksVitamin B3
TRx0237Phase 3; ongoing2015.12Mild/mild-to-moderate700/83318 months/15 months
Methylene blue (Rember)Phase 2; completedMild-to-moderate3216 monthsShowed uncertain results
Davunetide (AL108)Phase 2; completed2008.1MCI14412 weeksShowed benefits on memory
BMS-241027Phase 1; completed2013.10Mild409 weeks

RCT: randomized controlled trial; PPAR: peroxisome proliferators activated receptor; BBB: blood brain barrier; MCI: mild cognitive impairment; GSI: secretase inhibitor; GSM: secretase modulator; NSAID: nonsteroidal anti-inflammatory drugs; AChEI: acetylcholinesterase inhibitor; GABA: -aminobutyric acid; PDE: phosphodiesterase; CSF: cerebrospinal fluid; i.h.: subcutaneous injection; i.m.: intramuscular injection; mAb: monoclonal antibody; AE: adverse event.
*RCTs with a combination of another drug.
Data sources: http://www.clinicaltrials.gov/.