Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease

Abstract

Patients: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years, 58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups.

Characterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions

“…Second, for the first time we show that ␥-secretase catalyzed processing at every third or fourth amino acid continues beyond A␤40 and A␤38 and we show how this mechanism results in major shorter A␤ peptides including A␤30, A␤31, A␤34, A␤37, and A␤39. Third, we identify A␤34 as a major convergence point for the product lines, which may also explain the particular sensitivity of this A␤ species in recent human trials with two different ␥-secretase inhibitors (19,24). Fourth, and perhaps most importantly, we identify cross-talks between the major A␤ product lines, and several novel reactions resulting in A␤46 -43, A␤42-40, A␤40 -38, and A␤40 -37 and that directly impact A␤40 and A␤42 production opening up new opportunities for modulation of A␤42 production and the A␤42/40 ratio.…”

Human Cardiac Stem Cells With Reduced Notch Signaling Show Enhanced Therapeutic Potential in a Rat Acute Infarction Model

“…34 In addition, regarding the duration of the existence and localization of the transplanted cells, human-derived cardiomyocytes survived at least for 3 weeks after transplantation and resided mainly in the infarct-border zone. In this study, CSCs of human origin were transplanted into athymic nude rats.…”

Update on Alzheimer's Disease Therapy and Prevention Strategies

“…The interaction with Notch is among the reasons why numerous γ-secretase inhibitors have failed advanced-phase clinical trials ( Table 1). Semagacestat (Eli Lilly & Co.) not only failed to achieve endpoints related to slowing disease progression but also appears to have worsened some patients' symptoms (13), and Avagacestat (Bristol-Myers Squibb) caused serious adverse events such as cerebral microbleeds, dose-dependent glycosuria, and nonmelanoma skin cancer (14).…”

“…Crenezumab binds to the central epitope region of Aβ [12][13][14][15][16][17][18][19][20][21][22][23] , which seems to be most responsible for aggregation. Importantly, crenezumab contains a human IgG4 backbone that translates into reduced effector function on microglia, promotion of microglial Aβ phagocytosis, and reduced proinflammatory response.…”