Clinical pharmacology of novel anti-Alzheimer disease modifying medications.
In recent years, efforts have been directed to develop "disease-modifying" medications to treat Alzheimer's disease (AD), able to halt or slow the pathological process. Because the earlier the treatment starts, the greater is the possibility of efficacy, it is important to set up biomarkers for early diagnosis of functional brain abnormalities, before the clinical manifestation of the overt disease. Up to now, strategies to develop disease-modifying drugs have mainly targeted β amyloid (Aβ, accumulation, aggregation, clearance) and/or tau protein (phosphorylation and aggregation). Active and passive immunotherapy is the main strategy aimed at increasing Aβ clearance. Unfortunately several candidate diseasemodifying drugs have failed in phase III clinical trials conducted in mild to moderate AD. More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. Several methological problems have been recently pointed out to explain the lack of clinical efficacy of novel disease-modifying drug-treatments; moreover, new insights in pathophysiology of AD give the premise to develop novel drug targeting. Clinical trials recently completed and/or still ongoing are discussed in the present review.
Department of Educational Sciences, University of Catania, Catania, Italy.
Filippo
F
Caraci
Paolo
P
Bosco
Gian Marco
GM
Leggio
Michele
M
Malaguarnera
Filippo
F
Drago
Claudio
C
Bucolo
Salvatore
S
Salomone
D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D017326:Clinical Trials, Phase III as Topic; D015195:Drug Design; D042241:Early Diagnosis; D005427:Flocculation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy; D018697:Nootropic Agents / Q000627:therapeutic use*; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D007155:Immunologic Factors; D018697:Nootropic Agents; D016875:tau Proteins; C550616:solanezumab; C545458:bapineuzumab