Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings
- 14 July 2014
- journal article
- research article
- Published by Informa Healthcare in Current Medical Research and Opinion
- Vol. 30 (10), 2021-2032
- https://doi.org/10.1185/03007995.2014.939167
Abstract
Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable risk-benefit profile in a Phase 3 study of patients with Alzheimer's disease (IDENTITY trials), and clinical development was halted. To assist in future development of γ-secretase inhibitors, we report detailed safety findings from the IDENTITY study, with emphasis on those that might be mechanistically linked to γ-secretase inhibition. The IDENTITY trial was a double-blind, placebo-controlled trial of semagacestat (100 mg and 140 mg), in which 1537 patients age 55 years and older with probable Alzheimer's disease were randomized. Treatment-emergent adverse events (TEAEs) are reported by body system along with pertinent laboratory, vital sign, and ECG findings. Semagacestat treatment was associated with increased reporting of suspected Notch-related adverse events (gastrointestinal, infection, and skin cancer related). Other relevant safety findings associated with semagacestat treatment included cognitive and functional worsening, skin-related TEAEs, renal and hepatic changes, increased QT interval, and weight loss. With few exceptions, differences between semagacestat and placebo treatment groups were no longer significant after cessation of treatment with active drug. Many of these safety findings can be attributed to γ-secretase inhibition, and may be valuable to researchers developing γ-secretase inhibitors.Keywords
This publication has 45 references indexed in Scilit:
- Pharmacodynamics of Selective Inhibition of γ-Secretase by AvagacestatThe Journal of pharmacology and experimental therapeutics, 2012
- Not(ch) just development: Notch signalling in the adult brainNature Reviews Neuroscience, 2011
- Activity-Induced Notch Signaling in Neurons Requires Arc/Arg3.1 and Is Essential for Synaptic Plasticity in Hippocampal NetworksNeuron, 2011
- Synaptic activity prompts γ-secretase–mediated cleavage of EphA4 and dendritic spine formationThe Journal of cell biology, 2009
- A γ‐secretase inhibitor decreases amyloid‐β production in the central nervous systemAnnals of Neurology, 2009
- Phase 2 Safety Trial Targeting Amyloid β Production With a γ-Secretase Inhibitor in Alzheimer DiseaseArchives of Neurology, 2008
- The many faces of Notch signaling in skin‐derived cellsPigment Cell Research, 2007
- Notch Signaling, γ-Secretase Inhibitors, and Cancer TherapyCancer Research, 2007
- Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cellsThe Journal of cell biology, 2006
- Clinical diagnosis of Alzheimer's diseaseNeurology, 1984