Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis.

Azeliragon is an inhibitor of the receptor for advanced glycation end products being developed for the treatment of Alzheimer's disease. The objective of the current analysis was to evaluate the relationship between plasma azeliragon concentrations and QT interval. Simultaneous QT values and plasma concentrations were available from 711 subjects (6236 records), pooled from 5 studies in healthy volunteers, 2 studies in patients with mild to moderate Alzheimer's disease, and 1 study in patients with type 2 diabetes and persistent albuminuria.

Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer's Disease.

Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer's disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow.

A randomized, double-blind, placebo-controlled phase 2 study of the augmentation of a nicotinic acetylcholine receptor partial agonist in depression: is there a relationship to leptin levels?

This randomized, double-blind, placebo-controlled trial evaluated the efficacy of CP-601,927, an α4β2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors (SSRIs). After open-label treatment with an SSRI for 8 weeks, subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and randomized to CP-601,927 2 mg twice daily or placebo for 6 weeks. The primary end point was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from double-blind baseline to week 14.

A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer's disease.

Background: PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3',5' - cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (Aβ) production (Tg2576).

Objective: This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer's disease (AD).

Barriers to Alzheimer disease drug discovery and development in the biotechnology industry.

The major barrier to Alzheimer disease (AD) drug discovery and development in the biotechnology industry is scale. Most biotechnology companies do not have the personnel or expertise to carry a drug from the bench to the market. Much effort in the industry has been directed toward the elucidation of molecular mechanisms of AD and the identification of new targets.