Bryostatin found to slow cognitive decline in advanced Alzheimer’s

New data from Phase 2 trial show positive long-term effects of therapy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Six months of treatment with bryostatin slowed cognitive decline in adults with moderately severe Alzheimer’s disease, according to new data from a Phase 2 clinical trial.

These bryostatin-associated cognitive benefits over a placebo were maintained even four months after stopping treatment, the researchers noted — highlighting the long-term effects of the Synaptogenix experimental therapy.

“There is a huge unmet need in the [Alzheimer’s] population for drugs oriented specifically to advanced and severe patients,” Alan Tuchman, MD, CEO of Synaptogenix, said in a company press release, adding that “approved drugs do exist for slowing decline in non-demented, mild cognitive impairment (MCI) patients and possible early [Alzheimer’s] patients.”

Here, in contrast, a bryostatin-treated group of patients with severe Alzheimer’s “showed no significant cognitive decline across a 10-month span,” Tuchman said.

Results from the trial were detailed in “Advanced Alzheimer’s Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial,” a paper published in the Journal of Alzheimer’s Disease.

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The published paper noted “persistence in the data,” according to Synaptogenix, which highlighted this statement: “The prolonged absence of any significant cognitive decline in bryostatin-treated patients vs. placebo patients — even 16 weeks after the final dose of bryostatin — suggests a long-lasting positive change in the treated patients’ brains.”

“We appreciate the acknowledgement from such an esteemed independent Alzheimer’s journal,” said Daniel Alkon, MD, president and chief scientific officer of Synaptogenix.

Bryostatin is a molecule that’s thought to boost the health of synapses — the connections between nerve cells — and prevent nerve cell death by increasing the activity of an enzyme called protein kinase.

Pooled data from two previous Phase 2 trials showed that three months of bryostatin treatment significantly improved cognitive function in patients. Such an effect was not seen among those given a placebo in the two trials. The studies, NCT02431468 and NCT03560245, involved a total of 255 adults with moderate to severe Alzheimer’s.

None of the participants were using a standard Alzheimer’s medication called Namenda (memantine), as its mechanism of action is thought to likely affect bryostatin’s impact.

These findings prompted the launch of a Phase 2 trial (NCT04538066) to evaluate the effects of longer-term treatment with bryostatin in people with moderate and moderately severe Alzheimer’s.

Sponsored by Synaptogenix in collaboration with the National Institutes of Health’s National Institute on Aging and National Cancer Institute, the trial enrolled 122 patients in sites across the U.S. Dosing started in 2020.

The mean age of the study’s participants was 73.9 years, and they had been living with an Alzheimer’s diagnosis for a mean of 3.7 years.

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Participants split into 2 groups based on disease severity

The patients were divided into two disease severity groups, based on scores on the Mini-Mental Status Exam, a measure of cognition. Patients with higher scores of 15 to 18 were deemed as having moderate Alzheimer’s, while those with lower scores of 10 to 14 had moderately severe Alzheimer’s.

Participants were randomly assigned to receive intravenous or into-the-vein infusions of either bryostatin or a placebo for two 11-week dosing cycles, separated by a month, over a period of six months.

The study’s main goal was assessing changes in scores on the Severe Impairment Battery (SIB), a standardized measure of cognitive and behavioral problems in advanced Alzheimer’s.

SIB scores were assessed every two weeks throughout the two dosing cycles, and then again for another four months without any further dosing — totaling 42 weeks or nearly 10 months of assessment.

The results showed that, in the group of moderately severe Alzheimer’s patients, SIB scores were largely stable over the course of the study among those treated with bryostatin. By week 42, SIB scores had dropped, or worsened, by only 1.5 points.

By comparison, those given a placebo experienced a 12.8-point reduction in SIB scores at 42 weeks. SIB score changes were significantly different between the two groups at all time points from 13 weeks onward.

Persistence of real benefit at least 16 weeks beyond the final bryostatin dosing is an extremely important outcome for Alzheimer’s patients in the more advanced stages of the disease.

The data “demonstrated that bryostatin-treated patients showed statistically significant improvement of cognitive performance (SIB) over placebo patients in the Moderately Severe [group] for Weeks 13 through 42, with the last dose administered at Week 26,” the researchers wrote.

According to Alkon, “persistence of real benefit at least 16 weeks beyond the final bryostatin dosing is an extremely important outcome for Alzheimer’s patients in the more advanced stages of the disease.”

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Bryostatin could be ‘complementary’ to early-stage Alzheimer’s therapies

Among those with moderate Alzheimer’s, there wasn’t any significant difference in SIB score changes between patients given bryostatin or a placebo. Indeed, in both groups, SIB scores were largely stable over the study.

This was somewhat unexpected, given that moderate Alzheimer’s patients on a placebo would be expected to experience a SIB score worsening over time. The researchers speculated that a longer follow-up time might be needed to detect a significant effect for this subgroup of patients.

Bryostatin was generally safe and well-tolerated, showing an adverse event profile similar to those reported for the placebo group. Adverse events were reported in less than 17% of patients in both groups and there were no obvious treatment-related adverse events and no fatal events.

Overall, these findings support bryostatin as a potential therapy for advanced Alzheimer’s, the researchers noted. While some recent treatments have proven effective for slowing Alzheimer’s when given in early stages, there are no effective options for advanced disease, they added.

“We believe that bryostatin-1 for later-stage patients would be complementary to the early-stage [Alzheimer’s] drugs in providing a full range of treatment options for the more than six million Americans living with Alzheimer’s disease,” Tuchman said.