Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease
Open accessAbstract
INTRODUCTION: Lanabecestat, a beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)-modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported. METHODS: AMARANTH and DAYBREAK-ALZ were 104- and 78-week, multicenter, randomized, double-blind, placebo-controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK-ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK-ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aβ neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK-ALZ. Efficacy measures included 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Clinical Dementia Rating-Sum of Boxes, Functional Activities Questionnaire, and Mini-Mental State Examination. These studies stopped early due to futility. RESULTS: Despite previously observed annualized reduction in Aβ neuritic plaque burden, there were no treatment differences in annualized change of aggregated tau neurofibrillary tangle burden (AMARANTH, n = 284; DAYBREAK-ALZ, n = 70), cerebral metabolism (AMARANTH, n = 260; DAYBREAK-ALZ, n = 38) and perfusion (DAYBREAK-ALZ, n = 213). Greater brain volume reduction (AMARANTH, n = 1697 [whole brain]; DAYBREAK-ALZ, n = 650 [whole brain]) occurred on lanabecestat compared to placebo. Higher baseline aggregated tau neurofibrillary tangle burden, lower cerebral metabolism, and lower brain volumes correlated with poorer baseline efficacy scores and greater clinical worsening. Lower baseline cerebral perfusion correlated with poorer baseline efficacy scores. Reduction in cerebral metabolism or whole brain volume correlated with clinical worsening, regardless of treatment assignment. DISCUSSION: Tau pathology and cerebral metabolism assessments showed no evidence of lanabecestat slowing pathophysiologic progression of AD. Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design.
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β-secretase inhibitors such as lanabecestat, verubecestat, and atabecestat target Bace-1 to decrease synthesis of amyloid beta.
“In order to decrease the synthesis of amyloid beta, β-secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8, Figure 5) [157,161,162], verubecestat (labeled as 9, Figure 5) [157,163,164], and atabecestat (labeled as 10, Figure 5) target the enzyme Bace-1 [157,165].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [161]
Atabecestat, elenbecestat, lanabecestat, and umibecestat reached late stages of clinical trials but all failed to receive final approval to reach the market.
“Besides LY2886721, many other candidates have also reached late stages of clinical trials, including atabecestat (Phase 2/3),305 elenbecestat (Phase 3),306 lanabecestat (Phase 2/3)307,308 and umibecestat (Phase 2/3).309 However, all of them have failed to receive final approval to reach the market.”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [308]
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Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
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“In order to decrease the synthesis of amyloid beta, β - secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8 , Figure 5) [157,161,162], verubecestat (labeled as 9 , Figure 5) [157,163,164], and atabecestat (labeled as 10 , Figure 5) target the enzyme Bace-1 [157,165].”
Background
- Authors
- Zimmer, J. A., Shcherbinin, S., Devous, M. D., Bragg, S. M., Selzler, K. J., Wessels, A. M., Shering, C., Mullen, J., Landry, J., Andersen, S. W., Downing, A. M., Fleisher, A. S., Svaldi, D. O., & Sims, J. R.
- Affiliations
- Eli Lilly (United States) (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Zimmer, Jennifer A.
- ORCID
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2021-01
- Volume
- 7
- Issue
- 1
- Pages
- e12123-e12123
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC7882543
- OpenAlex
- W3130107333
- Cited by
- 27
- References
- 33
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 2
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Eli Lilly and Company
- AstraZeneca
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, BACE1 inhibitors, neurofibrillary tangles, brain metabolism, brain volume, neuroimaging biomarkers, florbetapir PET, flortaucipir PET, FDG-PET, mild dementia, treatment efficacy, anti-amyloid therapy, Amaranthus, cerebral perfusion
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