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Table 1 High profile clinical trials based on the amyloid hypothesis

From: Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease

Mechanism of action Drug name Clinical phase Key results from each trial Current status (August 2014) Reference
Active immunisation with Aβ AN1792 2 Plaque Cleared. NFT reduced in neuronal processes, but not cell bodies. Very few antibody responders (25/239). Reports of encephalitis. Discontinued [49],[50]
CAD106 2 Favourable safety profile. Prolonged antibody titre in responders. Ongoing [51]
ACC001 2 Co-administration of adjuvant required for strong antibody response. Generally safe and well-tolerated, no adverse related event. Discontinued [52]
AD02 2 Favourable safety and tolerability profile. Did not reach primary or secondary outcome measures in phase 2. Ongoing [53]
Passive immunization against Aβ Solanezumab 3 Worsening cognition compared to placebo, multiple adverse events. Terminated [54]
Bapinezmab 3 Engaged target. Reduction in cerebrospinal fluid phospho-tau in APOE4 carriers. Decreased rate of amyloid accumulation in APOE4 carriers. No improvement in clinical outcomes in carrier or non-carriers of APOE4. Negative amyloid scans in 36% of non-carriers. Discontinued [55]
Gantenerumab 2/3 Safe and well-tolerated at phase 1. Focal inflammation in areas with amyloid reduction a concern. Amyloid reductions compared to placebo. Recruiting for Phase 3 DIAN trial [56]
Crenezumab 2 Did not meet co-primary endpoints. Trend of improved cognition in people with mild disease. Ongoing [57]
Ponezumab 2 Safe and well-tolerated at phase 1. Plasma Aβ40 increased at phase 2. No effect on primary endpoints in phase 2. Recruiting for further Phase 2 trials [58]
γ-Secretase inhibitors Avagacestat 2 Gastrointestinal and dermatological side effects at Phase 1. Also dose-dependent pharmacodynamic effects on CSF biomarkers in some patients. Trend towards worsening cognition at higher doses compared to placebo. Amyloid related imaging abnormalities. Discontinued [59]
Semagacestat 3 Dose-dependent reduction in Aβ synthesis at Phase 1. Reduced plasma Aβ at Phase 2, but no differences in cognition. No improvement in cognition and worsening cognition at higher doses compared to controls at Phase 3. Discontinued [60]
γ-Secretase modulators CHF5074 2 Anti-inflammatory at Phase 2. Trend towards improved function in APOE4 carriers. Ongoing [61]
EVP-0962 2 Does not inhibit cleavage of γ-secretase substrates other than APP. Ongoing [62]
Tarenflurbil 3 Small functional benefit at higher doses in mild AD but no cognitive benefit at Phase 2. No changes in CSF Aβ42. Failed to meet primary and secondary endpoints at phase 3. Discontinued [63]
β-Secretase modulators MK-8931 3 Reduced CSF Aβ compared to controls. Safe and tolerable at Phase 2. Recruiting for Phase 3 [64]
CTS-21166 1 Dose dependent reduction in plasma Aβ. Completed [65]