Abstract
Introduction: To date there is no cure for Alzheimer’s disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects.
Methods: This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. Results: A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. Conclusion: This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.Keywords: Adverse events, Alzheimer’s Disease, clinical trial, cognitive tests, thalidomide, tolerability.
Current Alzheimer Research
Title:Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial
Volume: 14 Issue: 4
Author(s): Boris Decourt, Denise Drumm-Gurnee, Jeffrey Wilson, Sandra Jacobson, Christine Belden, Sherye Sirrel, Michael Ahmadi, Holly Shill, Jessica Powell, Aaron Walker, Amanda Gonzales, Mimi Macias and Marwan N. Sabbagh
Affiliation:
Keywords: Adverse events, Alzheimer’s Disease, clinical trial, cognitive tests, thalidomide, tolerability.
Abstract: Introduction: To date there is no cure for Alzheimer’s disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects.
Methods: This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. Results: A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. Conclusion: This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.Export Options
About this article
Cite this article as:
Decourt Boris, Drumm-Gurnee Denise, Wilson Jeffrey, Jacobson Sandra, Belden Christine, Sirrel Sherye, Ahmadi Michael, Shill Holly, Powell Jessica, Walker Aaron, Gonzales Amanda, Macias Mimi and Sabbagh N. Marwan, Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial, Current Alzheimer Research 2017; 14 (4) . https://dx.doi.org/10.2174/1567205014666170117141330
DOI https://dx.doi.org/10.2174/1567205014666170117141330 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Halogenated Derivatives of Aromatic Amino Acids Exhibit Balanced Antiglutamatergic Actions: Potential Applications for the Treatment of Neurological and Neuropsychiatric Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Zebrafish Model in Drug Safety Assessment
Current Pharmaceutical Design Signaling Pathways that Regulate Basal ABC Transporter Activity at the Blood- Brain Barrier
Current Pharmaceutical Design Patient Involvement and Shared Decision-Making in Mental Health Care
Current Clinical Pharmacology Memory-Enhancing Drugs: A Molecular Perspective
Mini-Reviews in Medicinal Chemistry Preserving Brain Function During Development and Aging with Erythropoietin
Current Neurovascular Research Diversity and Variability of the Effects of Nicotine on Different Cortical Regions of the Brain. Therapeutic and Toxicological Implications
Central Nervous System Agents in Medicinal Chemistry Cell Biological Consequences of Mitochondrial NADH: Ubiquinone Oxidoreductase Deficiency
Current Neurovascular Research Potassium Channels in Peripheral Pain Pathways: Expression, Function and Therapeutic Potential
Current Neuropharmacology Current Approaches for Drug Delivery to Central Nervous System
Current Drug Delivery Preface: Vitamin D and QT Interval in Epilepsy: More than an Association?
Current Clinical Pharmacology Histamine H<sub>4</sub> Receptor Antagonists: A New Approach for Tinnitus Treatment?
Recent Patents on CNS Drug Discovery (Discontinued) Intracellular and Extracellular Zinc Detection by Organic Fluorescent Receptor
Current Organic Chemistry HMG-CoA Reductase Inhibitors (Statins) and their Drug Interactions Involving CYP Enzymes, P-glycoprotein and OATP Transporters-An Overview
Current Drug Metabolism Latest Advances Towards the Discovery of 5-HT7 Receptor Ligands
Mini-Reviews in Medicinal Chemistry Synthesis and Structure-Activity Relationship on Anticonvulsant Aryl Semicarbazones
Medicinal Chemistry 3D QSAR Studies on 1, 3, 4-Thiadiazole Derivatives: An Approach to Design Novel Anticonvulsants
Medicinal Chemistry Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer's Disease
Current Alzheimer Research Therapeutic Efficacy of Selegiline in Neurodegenerative Disorders and Neurological Diseases
Current Drug Targets AMPK As A Target in Rare Diseases
Current Drug Targets