TY - JOUR
T1 - BACE inhibitors in clinical development for the treatment of Alzheimer’s disease
AU - Daniele, Antonio
AU - Panza, Francesco
AU - Lozupone, Madia
AU - Solfrizzi, Vincenzo
AU - Sardone, Rodolfo
AU - Piccininni, Carla
AU - Dibello, Vittorio
AU - Stallone, Roberta
AU - Giannelli, Gianluigi
AU - Bellomo, Antonello
AU - Greco, Antonio
AU - Seripa, Davide
AU - Logroscino, Giancarlo
AU - Imbimbo, Bruno P.
PY - 2018
Y1 - 2018
N2 - Introduction: The amyloid hypothesis of Alzheimer’s disease (AD) affirms that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represent the major pathological event of the disease. Several anti-Aβ small organic molecules, monoclonal antibodies and antigens were developed to interfere with Aβ production and clearance, including β–site amyloid precursor protein cleaving enzyme (BACE) inhibitors, blocking the first enzymatic step of Aβ formation. All these approaches, including BACE inhibitors, have failed in large randomized clinical trials (RCTs) in mild-to-moderate AD, but further studies are now being carried out in patients at early AD stages and in asymptomatic subjects at risk of developing AD. Areas covered: The paper provides a comprehensive review of BACE inhibitors for AD treatment, focusing on the most advanced compounds in Phase III RCTs. Expert commentary: BACE inhibitors inhibited robustly, and dose-dependently, Aβ formation in cerebrospinal fluid of AD patients, but without cognitive, clinical, or functional benefit in large RCTs. BACE inhibition may be not sufficient to decrease brain Aβ plaques and aggregates. Indeed, several BACE inhibitors were found to be poorly tolerated and some of them failed also in patients with prodromal AD. This may indicate that blocking the formation of nascent Aβ is not useful in AD.
AB - Introduction: The amyloid hypothesis of Alzheimer’s disease (AD) affirms that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represent the major pathological event of the disease. Several anti-Aβ small organic molecules, monoclonal antibodies and antigens were developed to interfere with Aβ production and clearance, including β–site amyloid precursor protein cleaving enzyme (BACE) inhibitors, blocking the first enzymatic step of Aβ formation. All these approaches, including BACE inhibitors, have failed in large randomized clinical trials (RCTs) in mild-to-moderate AD, but further studies are now being carried out in patients at early AD stages and in asymptomatic subjects at risk of developing AD. Areas covered: The paper provides a comprehensive review of BACE inhibitors for AD treatment, focusing on the most advanced compounds in Phase III RCTs. Expert commentary: BACE inhibitors inhibited robustly, and dose-dependently, Aβ formation in cerebrospinal fluid of AD patients, but without cognitive, clinical, or functional benefit in large RCTs. BACE inhibition may be not sufficient to decrease brain Aβ plaques and aggregates. Indeed, several BACE inhibitors were found to be poorly tolerated and some of them failed also in patients with prodromal AD. This may indicate that blocking the formation of nascent Aβ is not useful in AD.
KW - CNP520
KW - Dementia
KW - Neurology (clinical)
KW - Neuroscience (all)
KW - Pharmacology (medical)
KW - atabecestat
KW - elenbecestat
KW - lanabecestat
KW - lifestyle
KW - mild cognitive impairment
KW - verubecestat
KW - β-amyloid
KW - β-secretase inhibitors
KW - CNP520
KW - Dementia
KW - Neurology (clinical)
KW - Neuroscience (all)
KW - Pharmacology (medical)
KW - atabecestat
KW - elenbecestat
KW - lanabecestat
KW - lifestyle
KW - mild cognitive impairment
KW - verubecestat
KW - β-amyloid
KW - β-secretase inhibitors
UR - http://hdl.handle.net/10807/134453
UR - http://www.tandfonline.com/loi/iern20
U2 - 10.1080/14737175.2018.1531706
DO - 10.1080/14737175.2018.1531706
M3 - Article
VL - 18
SP - 847
EP - 857
JO - Expert Review of Neurotherapeutics
JF - Expert Review of Neurotherapeutics
SN - 1473-7175
ER -