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

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, Marwan N. Sabbagh

Research output: Contribution to journalReview article

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalCurrent Alzheimer Research
Volume14
Issue number4
DOIs
StatePublished - Apr 1 2017

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Thalidomide
Alzheimer Disease
Placebos
Safety
Therapeutics
Amyloid Precursor Protein Secretases
Amyloid Plaques
Amyloid
Pharmaceutical Preparations
Immunotherapy
Cognition
Outcome Assessment (Health Care)
Clinical Trials
Education
Brain
Neoplasms

Keywords

  • Adverse events
  • Alzheimer’s Disease
  • Clinical trial
  • Cognitive tests
  • Thalidomide
  • Tolerability

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

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. / 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; Sabbagh, Marwan N.

In: Current Alzheimer Research, Vol. 14, No. 4, 01.04.2017, p. 403-411.

Research output: Contribution to journalReview article

DeCourt, B, Drumm-Gurnee, D, Wilson, J, Jacobson, S, Belden, C, Sirrel, S, Ahmadi, M, Shill, H, Powell, J, Walker, A, Gonzales, A, Macias, M & Sabbagh, MN 2017, '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, vol. 14, no. 4, pp. 403-411. https://doi.org/10.2174/1567205014666170117141330
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 ; Sabbagh, Marwan N. / 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. In: Current Alzheimer Research. 2017 ; Vol. 14, No. 4. pp. 403-411.
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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.",
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AU - Wilson, Jeffrey

AU - Jacobson, Sandra

AU - Belden, Christine

AU - Sirrel, Sherye

AU - Ahmadi, Michael

AU - Shill, Holly

AU - Powell, Jessica

AU - Walker, Aaron

AU - Gonzales, Amanda

AU - Macias, Mimi

AU - Sabbagh, Marwan N.

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N2 - 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.

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