Name:	PF-04494700
Other Names:	TTP488
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Oral small molecule
Mechanisms:	Inhibitor of Receptor for Advanced Glycation Endproducts (RAGE)
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	PF-04494700 inhibits the activation of RAGE, a member of the immunoglobulin superfamily, a multi-ligand, cell surface receptor expressed by neurons, microglia, astrocytes and cerebral endothelial cells.
Role in Alzheimer's Disease:	RAGE plays multiple roles in the pathogenesis of AD. RAGE mediates the effects of Aβ on microglia, blood-brain barrier (BBB) and neurons through activating different signaling pathways. The adverse consequences of RAGE interaction with Aβ include perturbation of neuronal properties and functions, amplification of glial inflammatory responses, elevation of oxidative stress and amyloidosis, increased Aβ influx at the blood brain barrier and vascular dysfunction, and induction of utoantibodies. Data from autopsy brain tissues, in vitro cell cultures and transgenic mouse models suggest that Aβ-RAGE interaction exaggerates neuronal stress, accumulation of Aβ, impaired learning memory, and neuroinflammation. Inhibition of RAGE protects against Aβ-mediated cellular perturbation.
Contraindications:	Exclusion Criteria of the Phase II clinical trial include: 1. Current evidence or history of neurological, psychiatric and any other illness that could contribute to dementia or any form of dementia other than AD 2. Known history of familial AD or any evidence for early onset AD known or possibly associated with genetic mutations; individuals from families with late onset AD with 2 or more affected family members may participate 3. History of clinically significant stroke or significant cerebrovascular disease 4. Poorly controlled hypertension or a history of either a myocardial infarction or signs or symptoms of unstable coronary artery disease within the last 6 months 5. Pulmonary disease or evidence of clinically significant pulmonary symptoms 6. History of cancer within the last 5 years (treated basal cell or squamous cell carcinoma of the skin allowed, stable localized prostate cancer not requiring treatment allowed) 7. Evidence or history of clinically significant allergic reactions, including severe drug allergies (such as resulting in dyspnea or severe rash) 8. Weight less than 40 kg or greater than 100 kg (and BMI greater than 30 kg/m2) within past two years 9. Evidence or history of diabetes mellitus Type 1 or Type 2, or participants on insulin or oral hypoglycemics 10. Clinically significant hepatic or renal disease 11. History or symptoms of autoimmune disorders 12. Use of another investigational drug within 90 days of the study screening visit or plans to take another investigational drug within 90 days of study completion; participants with prior exposure to active immunotherapy for AD are excluded from participation in this study; participants with prior exposure to passive immunotherapy for AD may not be screened in the current study until 6 months after the last dose of passive immunotherapy has been given. 13. Prohibited Medications: a. Drugs that may prolong the QT interval (some may be allowed with limited use and low dose only--check with principal investigator) b. Drugs known to be potent CYP 3A4 inhibitors/inducers c. Any use of steroid treatment (topical application to the skin is allowed) d. Chronic use (daily use of more than 3 out of 4 weeks) of nonsteroidal anti-inflammatory drugs (NSAIDs) including Cox 2 selective NSAIDs; spontaneous or occasional use of NSAIDs is allowed e. Insulin and oral hypoglycemics
Companies:	Pfizer, Inc.
Notes:	In December 2007, Pfizer initiated a Phase II clinical study in mild to moderate AD. (See ARF related news story.) This study NCT00566397, to evaluate efficacy and safety is currently recruiting up to 400 participants at 44 U.S. research sites. trial details Last updated: Feb 4, 2009