Bryostatin Shows Some Effect in Moderate to Severe Alzheimer Disease


Although the therapy did not achieve significance for the primary end point in the full data set, a pre-specified exploratory analysis implemented in a post-hoc framework did provide evidence of significant benefit for the 20-μg dose.

Dr Marwan Sabbagh

Marwan Sabbagh, MD

Newly published data has suggested that 20-µg bryostatin may be a feasible treatment option for cognitive deficits occurring in moderate to severe Alzheimer disease.1

A double-blind, randomized, placebo-controlled phase 2 trial has shown that although the therapy did not achieve significance for the primary end point of the change in Severe Impairment Battery (SIB) scores from baseline at 13 weeks in the full data set (FAS), a pre-specified exploratory analysis implemented in a post-hoc framework did provide evidence of significant benefit for the 20-μg dose.

“Neurotrope’s phase 2 trial of bryostatin for advanced Alzheimer’s patients has shown promising positive signals of improvement,” Marwan Sabbagh, MD, the director of the Cleveland Clinic Lou Ruvo Center for Brain Health, said in a statement.2 “This drug’s observed sustained reversal of cognitive deterioration is consistent with the restorative, synaptogenic findings that Dr. Alkon and his teams have described during the years of pre-clinical research that preceded this potentially breakthrough clinical approach for treating neurodegeneration.”

The study randomized 147 patients with moderate to severe Alzheimer to either 20-µg bryostatin (n = 46), 40-µg bryostatin (47), or placebo (n = 48). By week 13, the FAS showed that those in the 20-μg arm were observed to show an increase in mean SIB of 1.16 points (standard error of the mean [SEM], 1.15) from baseline compared to a change of -0.79 points (SEM, 1.33), for a difference of 1.94 points (80% CI, -0.31 to 4.19; P = .134).

At week 5, there was evidence of benefit in mean SIB scores from baseline among 20-μg bryostatin patients compared to the placebo patients (difference, 4.00; 80% CI, 1.63 to 6.38; P = .016). Statistical analysis did favor the bryostatin 20-µg group compared to placebo at 5 weeks (difference, 2.96; 80% CI, 0.58 to 5.34; P = .056). The 40-µg group was not significantly different at 5 weeks.

“Therapeutic strategies for [Alzheimer] have focused on immunotherapy, and enhancement or blockade of neurotransmitters at synaptic junctions, approaches which may offer some symptomatic efficacy but have not demonstrated the ability to reverse the relentless progression of [Alzheimer],” coauthor Martin R. Farlow, MD, a Professor Emeritus in the Department of Neurology at Indiana University and co-director of the Alzheimer’s Disease Center at Indiana University said in a statement.

Ultimately, the scale of improvement was greater in a pre-specified exploratory analysis of patients who were not on memantine therapy (n = 16). The mean SIB change at the average of week 13 and week 15 time points from baseline was significantly greater in the 20-μg bryostatin arm compared to placebo (difference, 6.1; 95% CI, 1.5 to 10.7; P = .012). That improvement, Farlow and colleagues noted, persisted after controlling for baseline SIB and Mini-Mental State Examination-2 strata at randomization in Analysis of Covariance models.

Individual patient SIB scores over time revealed that 15 out of 16 patients (94%) in the 20-μg bryostatin, non-memantine group showed improvement in SIB at 2-4 weeks post-dosing. For placebo patients and for patients on baseline memantine, no consistent increases were observed.

“Preclinically, Bryostatin-1 has demonstrated the ability to restore synaptic loss, prevent neuronal apoptosis, reduce Aß oligomers, lower hyperphosphorylated tau and reduce oxidative stress,” Farlow added. “These phase 2 results show the early promise of translating this preclinical work, supported by years of research at the NIH and Blanchette Rockefeller Neurosciences Institute, into clinical outcomes. I look forward to seeing them expanded upon in further ongoing studies.”

He and colleagues concluded that the totality of their analyses suggest evidence of bryostatin’s SIB improvement signals in the absence of baseline memantine, “that warrant further trials to evaluate bryostatin’s potential utility to improve cognitive function(s) as well as to provide symptomatic relief and/or to delay cognitive decline of patients with moderately severe to severe AD.”

Neurotrope is currently evaluating Bryostatin-1 (20 µg) in 100 moderate to severe AD patients not on memantine in a confirmatory, placebo-controlled, Phase 2 trial, initiated in July 2018. Enrollment is proceeding as planned, and data from this study are expected during the third quarter of 2019.


1. Farlow MR, Thompson RE, Wei LJ, et al. 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. J Alzheimers Dis. 2018;1-16. doi: 10.3233/JAD-180759

2. Neurotrope Announces Publication of Phase 2 Study of Bryostatin-1 in Moderate to Severe Alzheimer’s Disease in the Journal of Alzheimer’s Disease [press release]. New York, NY: Neurotrope Inc; Published December 17, 2018. Accessed December 18, 2018.

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