Background

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., 2013; Sun 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). Bryostatin promoted survival of motor neurons bearing an SOD1 mutation causative for amyotrophic lateral sclerosis (La Cognata et al., 2023).

Findings

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, the company 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 post hoc 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 (Jan 2020 press release). Analysis of pooled data from this and the previous Phase 2 trial found increased SIB scores in the MMSE 10-14 group with treatment, compared to no improvement with placebo (Thompson et al., 2022).

In August 2020, the company began 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 enrolled 122 patients for two 11-week treatment cycles, with the primary endpoint again being change on SIB. This placebo-controlled study was completed in November 2022. On December 16, the company reported that it had failed to meet the primary endpoint (press release). Results were published after peer review (Alkon et al., 2023). The company claimed effectiveness in the subgroup of moderately severe patients with MMSE 10-14, who showed no decline on the SIB compared to 12.8 points decline in the placebo group. 

Bryostatin completed a clinical trial 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. It has FDA Orphan Drug Designation for treatment of Fragile X syndrome.

For details on bryostatin 1 trials, see clinicaltrials.gov.

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