A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer's disease

Martin Farlow, Richard E. Thompson, Lee Jen Wei, Alan J. Tuchman, Elaine Grenier, David Crockford, Susanne Wilke, Jeffrey Benison, Daniel L. Alkon, Paula Moreira

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and dropout issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin-without memantine-to treat AD.

Original languageEnglish (US)
Pages (from-to)555-570
Number of pages16
JournalJournal of Alzheimer's Disease
Volume67
Issue number2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Bryostatins
Alzheimer Disease
Placebos
Safety
Memantine
Therapeutics
Protein Kinase C-epsilon
Patient Dropouts
Patient Safety
Double-Blind Method
Amyloid
Cognition
Apoptosis
bryostatin 20

Keywords

  • Bryostatin
  • memantine
  • neurorestorative
  • PKC (Protein Kinase C)
  • severe Alzheimer's disease
  • severe impairment battery
  • synaptic growth factors
  • synaptogenesis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer's disease. / Farlow, Martin; Thompson, Richard E.; Wei, Lee Jen; Tuchman, Alan J.; Grenier, Elaine; Crockford, David; Wilke, Susanne; Benison, Jeffrey; Alkon, Daniel L.; Moreira, Paula.

In: Journal of Alzheimer's Disease, Vol. 67, No. 2, 01.01.2019, p. 555-570.

Research output: Contribution to journalArticle

Farlow, Martin ; Thompson, Richard E. ; Wei, Lee Jen ; Tuchman, Alan J. ; Grenier, Elaine ; Crockford, David ; Wilke, Susanne ; Benison, Jeffrey ; Alkon, Daniel L. ; Moreira, Paula. / A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer's disease. In: Journal of Alzheimer's Disease. 2019 ; Vol. 67, No. 2. pp. 555-570.
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abstract = "Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and dropout issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin-without memantine-to treat AD.",
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T1 - A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer's disease

AU - Farlow, Martin

AU - Thompson, Richard E.

AU - Wei, Lee Jen

AU - Tuchman, Alan J.

AU - Grenier, Elaine

AU - Crockford, David

AU - Wilke, Susanne

AU - Benison, Jeffrey

AU - Alkon, Daniel L.

AU - Moreira, Paula

PY - 2019/1/1

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N2 - Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and dropout issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin-without memantine-to treat AD.

AB - Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and dropout issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin-without memantine-to treat AD.

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KW - neurorestorative

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KW - severe Alzheimer's disease

KW - severe impairment battery

KW - synaptic growth factors

KW - synaptogenesis

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