Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S et al.. Archives of neurology, 2012-11-01
Topic: Amyloid, tau and blood-test diagnosis
Objective To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). Design Randomized, double-blind, placebo-controlled,24-week phase 2 study. Setting Global, multicenter trial. 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. Intervention Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily. Main outcome measures Safety and tolerability of avagacestat. Results Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. Conclusions Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD. Trial registration clinicaltrials.gov Identifier: NCT00810147
Key findings
- Results Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups.
- Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients.
Why it matters
In this 24-week phase 2 trial of 209 patients with mild to moderate Alzheimer disease, discontinuation rates were higher in the 100-mg and 125-mg avagacestat dose groups, and trends for worsening cognition were observed in those groups. Exploratory cerebrospinal fluid biomarker analysis showed dose-dependent but not statistically significant reductions in a small subset of patients, so this drug did not demonstrate benefit and showed signs of harm at higher doses.
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Study details
- Study designclinical trial
- Participants209
- Effect size58.9%
- Evidence strengthHigh
How this study scored 74/100
Published in a peer-reviewed journal, and it is a randomised controlled trial.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of neurology) |
| Journal's citation record | 3 / 4 | Archives of Neurology: journal h-index 353 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A randomised controlled trial (from PubMed type “Randomized Controlled Trial”) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2012 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 209 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | 6 / 7 | Cited 375 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 23.4 citations a year over 16 year(s) since 2012 |
| Impact for its field and year | 4 / 6 | Cited 17.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 19 other studies in this library |
| Still being cited | 3 / 4 | Cited 55 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Robert Berman: h-index 51 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Bristol-Myers Squibb (United States): institution h-index 770 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | PubMed indexes it as a multicentre study |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22892585) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 74 / 100 | — |
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APA 7th
Coric, V., van Dyck, C. H., Salloway, S., Andreasen, N., Brody, M., Richter, R. W., et al. (2012). Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Archives of neurology. https://doi.org/10.1001/archneurol.2012.2194
Vancouver
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Archives of neurology. 2012. doi:10.1001/archneurol.2012.2194. PMID: 22892585.
BibTeX
@article{coric2012-22892585,
author = {Coric, V. and van Dyck, C. H. and Salloway, S. and Andreasen, N. and Brody, M. and Richter, R. W. and Soininen, H. and Thein, S. and others},
title = {{Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease}},
journal = {Archives of neurology},
year = {2012},
doi = {10.1001/archneurol.2012.2194},
pmid = {22892585},
url = {https://doi.org/10.1001/archneurol.2012.2194}
}
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