Cognitive Function Sustained With Alzheimer Agent Bryostatin-1

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In a cohort of moderately severe Alzheimer disease, patients on placebo demonstrated cognitive decline while those on active treatment showed no significant decline.

Alan Tuchman, chief executive officer, Synaptogenix

Alan Tuchman

Published in the Journal of Alzheimer’s Disease, new findings from a phase 2 trial showed that treatment with bryostatin-1 (Synaptogenix), an investigational agent, resulted in no cognitive decline over a 10-month period in patients with moderately severe Alzheimer disease (AD). In contrast, those on placebo continued to show expected progressive cognitive deterioration, reaching a deficit of –12.8 Severe Impairment Battery (SIB) points by week 42.1,2

A total of 221 patients were enrolled in the study, of whom 122 were randomly assigned 1:1 to either 20 μg of placebo (n = 61) or byrostatin-1 (n = 61). Measurement of patient performance on the SIB psychometric was assessed at 2-week intervals throughout 2 dosing cycles and, in addition, atother weeks over a 4-month period without any further dosing, ultimately reaching a 42-week SIB assessment. Using the Mini-Mental State Examination (MMSE), patients were grouped as either moderately severe (MMSE, 10-14) or moderate (MMSE, 15-18).

The primary end point was the total SIB score assessment obtained at week 28, following completion of 2 courses of treatment. In a post-hoc analysis, investigators observed a significant downward slope trend, equivalent to cognitive decline, for the placebo arm (P <.001), but no significant decline for the moderately severe byrostatin-1-treated group (P = .40). Using all prespecified points from the clinical protocol, the difference in slopes between the 2 treatment groups was highly significant (P <.007).

"There is a huge unmet need in the AD population for drugs oriented specifically to advanced and severe patients,” Alan Tuchman, chief executive officer, Synaptogenix, said in a statement.1 "Approved drugs do exist for slowing decline in non-demented, patients with Mild Cognitive Impairment (MCI) and possible early AD, but Bryostatin-1-treated Severe Cohort patients, in contrast, showed no significant cognitive decline across a 10-month span in our study. We believe that Bryostatin-1 for later-stage patients would be complementary to the early-stage AD drugs in providing a full range of treatment options for the more than six million Americans living with Alzheimer disease."

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Of the 2 cohorts of patients, only the moderately severe cohort showed significant benefit for the bryostatin-1-treatment vs placebo. The effects of bryostatin-1 persisted in patients after the last dose was administered, sometime between weeks 24-28. At each measurement point from week 13 on, the treatment group was significantly greater than the placebo group as determined by a 2-sided alpha <.05 level. In the absence of significant benefit for the moderate cohort, statistics for the combination of both cohorts were not significant.

In terms of safety, the overall treatment emergent adverse event (TEAE) profiles between the bryostatin-1 and placebo groups were similar (13.8% vs 16.9%), with most considered not treatment-related. There were no obvious treatment-related TEAEs and no fatal TEAEs, including no cases of myalgia, which have been previously reported in trials assessing bryostatin-1 in cancer. There were 4 events of COVID-19 in 4 patients in the active treatment group and 1 event of SARS-CoV-2 test positive in 1 individual on placebo; however, both events were considered mild and unlikely related to the study drug.

"We appreciate the acknowledgement from such an esteemed independent Alzheimer's journal. Persistence of real benefit at least 16 weeks beyond the final bryostatin dosing is an extremely important outcome for patients with Alzheimer disease in the more advanced stages of the disease," Daniel Alkon, president and chief scientific officer, Synaptogenix, said in a statement.1

REFERENCES
1. Synaptogenix announces peer-reviewed publication of NIH-sponsored phase 2 clinical trial results demonstrating safe, significant, and persistent benefits of bryostatin-1 in advanced Alzheimer’s disease. News release. Synaptogenix. September 26, 2023. Accessed October 3, 2023. https://www.prnewswire.com/news-releases/synaptogenix-announces-peer-reviewed-publication-of-nih-sponsored-phase-2-clinical-trial-results-demonstrating-safe-significant-and-persistent-benefits-of-bryostatin-1-in-advanced-alzheimers-disease-301938588.html
2. Alkon DL, Miao-Kun S, Tuchman AJ, Thompson RE. Advanced Alzheimer’s disease patients show safe, significant, and persistent benefit in 6-month bryostatin trial. J Alzheimers Dis. Published online September 19, 2023. doi:10.3233/JAD-230868
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