TY - JOUR
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 R.
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
N1 - Publisher Copyright:
© 2019 IOS Press and the authors. All rights reserved.
PY - 2019
Y1 - 2019
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.
KW - Bryostatin
KW - PKC (Protein Kinase C)
KW - memantine
KW - neurorestorative
KW - severe Alzheimer's disease
KW - severe impairment battery
KW - synaptic growth factors
KW - synaptogenesis
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U2 - 10.3233/JAD-180759
DO - 10.3233/JAD-180759
M3 - Article
C2 - 30530975
AN - SCOPUS:85060649771
SN - 1387-2877
VL - 67
SP - 555
EP - 570
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 2
ER -