Bryostatin 1


Name: Bryostatin 1
Chemical Name: (1S,3S,5Z,7R,8E,11S,12S,13E,15S,17R,20R,23R,25S)-25-Acetoxy-1,11,20-trihydroxy-17-[(1R)-1-hydroxyethyl]-5,13-bis(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[,7.111,15]nonacos-8-en-12-yl (2E,4E)-2,4-oct
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Neurotrope


Bryostatin 1 is a natural product derived from the marine invertebrate Bugula neritina. It has potent and broad antitumor activity. Bryostatin 1 activates protein kinase C family members, with nanomolar potency for PKC1α and ε isotypes.

In the central nervous system, bryostatin 1 activation of PKC boosts synthesis and secretion of the neurotrophic factor BDNF, a synaptic growth factor linked to learning and memory (reviewed in Sun et al., 2015). The compound also activates nonamyloidogenic, α-secretase processing of amyloid precursor protein (Yi et al., 2012).

Preclinical work on bryostatin in nervous system diseases has mainly come from the Alkon lab. In their studies, intraperitoneal administration activated brain PKCε and prevented synaptic loss, Aβ accumulation, and memory decline in Alzheimer’s disease transgenic mice (Etcheberrigaray et al., 2004; Hongpaisan et al., 2011). The drug preserved synapses and improved memory in aged rats, and in rodent models of stroke and Fragile X syndrome (Hongpaisan et al., 2013Sun et al., 2008; Sun et al., 2016). In a different lab, bryostatin given by mouth improved memory and learning in an AD model (Schrott et al., 2015). In a mouse model of multiple sclerosis, bryostatin promoted anti-inflammatory immune responses and improved neurologic deficits (Kornberg et al., 2018).


Published data from a Phase 1/2 trial beginning in June 2014 describe no safety issues in six Alzheimer’s patients given a single intravenous body-surface-area-based dose of 25 μg/m2 compared with three participants who received placebo (Nelson et al., 2017). Blood levels of bryostatin 1 and PKCε activation in peripheral blood cells reportedly peaked one to two hours after dosing. Patients receiving drug showed a transient increase of 1.8 points in their MMSE scores three hours after dosing, compared with no change in those on placebo.

In an expanded access trial, three severely symptomatic AD patients received multiple bryostatin infusions for five to nine months. The authors describe behavior improvements that occurred rapidly after the first dose and were maintained for weeks. Two participants were nonverbal, so no cognitive testing was possible. 

In November 2015, Neurotrope began a double-blind, placebo-controlled Phase 2 study enrolling 147 people with moderate to severe AD dementia. Participants had MMSE scores between 4 and 15, and were randomized to 20 or 40 μg bryostatin or placebo given intravenously seven times over 11 weeks. The primary outcomes were safety and an efficacy measure defined by change on the severe impairment battery (SIB) at week 13, two weeks after the last dose. Secondary endpoints included change from baseline SIB at weeks 5, 9, and 15.

Results are published (Farlow et al., 2019). The 20 μg and placebo groups had similar rates of adverse events, with 20 percent dropping out before the end of the trial. The 40 μg group had more side effects, and twice as many dropouts. Common adverse effects included diarrhea, headache, fatigue, and weight loss. Neither dose showed efficacy in the full study group. When the investigators analyzed only those who completed the entire dosing regimen, they found an increase on the SIB for the 20 μg dose. A prespecified exploratory analysis suggested that the improvement occurred only in people not receiving memantine.

In June 2018, a second Phase 2 trial began in 108 AD patients who were not taking memantine. The group was split in two by MMSE scores 4–9 versus 10–15, then randomized to receive the same 20 μg treatment regimen as the previous trial. In a September 2019 press release, the company announced the drug showed no evidence of efficacy, based on the 13-week SIB scores. The study data revealed a baseline imbalance on SIB between placebo and bryostatin groups. A posthoc analysis of change in individual scores over time suggested that SIB improved in the MMSE 10–15 group on both drug and placebo, with a trend toward more improvement on the drug (January 2020 press release).

In 2020, the company is planning a third Phase 2 trial, in patients with moderate dementia due to AD (MMSE 10–18) who are not taking memantine. Funded partially by the NIH, the study will enroll 100 patients for two 11-week treatment cycles, with primary endpoint again being change on SIB (see company press release).

Bryostatin is also in clinical trials for eradication of HIV/AIDS. It has been studied extensively for antitumor activity against multiple types of cancer in more than 20 Phase 2 trials, but none progressed to Phase 3.

For details on bryostatin 1 trials, see

Last Updated: 05 Jun 2020


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Paper Citations

  1. . Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer's Disease Phase IIa and Expanded Access Trials. J Alzheimers Dis. 2017;58(2):521-535. PubMed.
  2. . 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. 2019;67(2):555-570. PubMed.
  3. . Towards universal therapeutics for memory disorders. Trends Pharmacol Sci. 2015 Jun;36(6):384-94. Epub 2015 May 7 PubMed.
  4. . Bryostatin-1 vs. TPPB: Dose-Dependent APP Processing and PKC-α, -δ, and -ε Isoform Activation in SH-SY5Y Neuronal Cells. J Mol Neurosci. 2012 Sep;48(1):234-44. PubMed.
  5. . Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11141-6. Epub 2004 Jul 19 PubMed.
  6. . PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci. 2011 Jan 12;31(2):630-43. PubMed.
  7. . PKC activation during training restores mushroom spine synapses and memory in the aged rat. Neurobiol Dis. 2013 Jul;55:44-62. Epub 2013 Mar 29 PubMed.
  8. . Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13620-5. PubMed.
  9. . Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice. J Pharmacol Exp Ther. 2016 May;357(2):300-10. Epub 2016 Mar 3 PubMed.
  10. . Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer's disease. Curr Alzheimer Res. 2015;12(1):22-31. PubMed.
  11. . Bryostatin-1 alleviates experimental multiple sclerosis. Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2186-2191. Epub 2018 Feb 12 PubMed.

External Citations

  1. press release
  2. press release
  3. press release

Further Reading


  1. . Bryostatin 1 Promotes Synaptogenesis and Reduces Dendritic Spine Density in Cortical Cultures through a PKC-Dependent Mechanism. ACS Chem Neurosci. 2020 Jun 3;11(11):1545-1554. Epub 2020 May 21 PubMed.
  2. . Neuro-regeneration Therapeutic for Alzheimer's Dementia: Perspectives on Neurotrophic Activity. Trends Pharmacol Sci. 2019 Sep;40(9):655-668. Epub 2019 Aug 8 PubMed.
  3. . Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus. J Alzheimers Dis. 2018;63(3):1173-1189. PubMed.
  4. . PKCε deficits in Alzheimer's disease brains and skin fibroblasts. J Alzheimers Dis. 2015;43(2):491-509. PubMed.
  5. . PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons. Neuroscience. 2014 May 30;268:75-86. Epub 2014 Mar 15 PubMed.
  6. . PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons. Neuroscience. 2014 May 30;268:75-86. Epub 2014 Mar 15 PubMed.