Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease

Jeffrey L. Cummings; Kate Zhong; Jefferson W. Kinney; Chelcie Heaney; Joanne Moll-Tudla; Abhinay Joshi; Michael Pontecorvo; Michael Devous; Anne Tang; James Bena

doi:10.1186/s13195-016-0173-2

Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease

Jeffrey L. Cummings, Kate Zhong, Jefferson W. Kinney, Chelcie Heaney, Joanne Moll-Tudla, Abhinay Joshi, Michael Pontecorvo, Michael Devous, Anne Tang, James Bena

Radiology

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

Abstract

Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer's disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10-20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ_1-40 and Aβ_1-42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ_1-42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. Conclusions: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ_1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. Trial registration: ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.

Original language	English (US)
Article number	4
Journal	Alzheimer's Research and Therapy
Volume	8
Issue number	1
DOIs	https://doi.org/10.1186/s13195-016-0173-2
State	Published - Jan 29 2016

Keywords

Alzheimer's disease
Amyloid
ApoE genotype
Bexarotene
Clinical trial
MRI
PET

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cognitive Neuroscience

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10.1186/s13195-016-0173-2

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title = "Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease",

abstract = "Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer's disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10-20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1-40 and Aβ1-42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ1-42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. Conclusions: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. Trial registration: ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.",

keywords = "Alzheimer's disease, Amyloid, ApoE genotype, Bexarotene, Clinical trial, MRI, PET",

author = "Cummings, {Jeffrey L.} and Kate Zhong and Kinney, {Jefferson W.} and Chelcie Heaney and Joanne Moll-Tudla and Abhinay Joshi and Michael Pontecorvo and Michael Devous and Anne Tang and James Bena",

note = "Funding Information: This study was funded by generous philanthropists and Keep Memory Alive, a 501(c)(3) nonprofit organization in support of the Cleveland Clinic. Avid Pharmaceuticals provided the florbetapir ligand for amyloid imaging. The funding sources had no influence on trial design or interpretation. Publisher Copyright: {\textcopyright} 2016 Cummings et al.",

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doi = "10.1186/s13195-016-0173-2",

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T1 - Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease

AU - Cummings, Jeffrey L.

AU - Zhong, Kate

AU - Kinney, Jefferson W.

AU - Heaney, Chelcie

AU - Moll-Tudla, Joanne

AU - Joshi, Abhinay

AU - Pontecorvo, Michael

AU - Devous, Michael

AU - Tang, Anne

AU - Bena, James

N1 - Funding Information: This study was funded by generous philanthropists and Keep Memory Alive, a 501(c)(3) nonprofit organization in support of the Cleveland Clinic. Avid Pharmaceuticals provided the florbetapir ligand for amyloid imaging. The funding sources had no influence on trial design or interpretation. Publisher Copyright: © 2016 Cummings et al.

PY - 2016/1/29

Y1 - 2016/1/29

N2 - Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer's disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10-20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1-40 and Aβ1-42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ1-42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. Conclusions: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. Trial registration: ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.

AB - Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer's disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10-20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1-40 and Aβ1-42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ1-42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. Conclusions: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. Trial registration: ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.

KW - Alzheimer's disease

KW - Amyloid

KW - ApoE genotype

KW - Bexarotene

KW - Clinical trial

KW - MRI

KW - PET

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Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease

Abstract

Keywords

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