Neurotrope presented clinical results from its recently completed Phase 2 trial demonstrating that moderate-to-severe Alzheimer’s disease (AD) patients treated with 20 µg bryostatin-1 showed preliminary evidence of sustained improvement in cognition compared to placebo. The data and comprehensive statistical analysis were presented in the Developing Topics: Clinical Trials oral session, “Effect of Bryostatin-1 on Cognition and Daily Living Tasks in Moderate to Severe Alzheimer’s disease Preliminary Report of a Phase 2 Study” at the Alzheimer’s Association International Conference 2017 in London.
“In this exploratory study evaluating a novel mechanism of action, we see an encouraging therapeutic signal in late stage AD patients with the 20 µg group, which was maintained across time points with relatively minimal toxicity and good tolerability,” said Martin R. Farlow, MD, Vice Chairman for Research in the Department of Neurology, Indiana University School of Medicine, Indiana Alzheimer Disease Center, who presented the data. “This study has shown a real and sustained increase in SIB over and above standard of care in a difficult to treat population. It is important now to determine if these effects can be maintained and enhanced over a longer period of time.”
The 13-week, randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and efficacy of bryostatin-1 in 147 moderate-to-severe AD patients across three treatment arms (20 µg, 40 µg, placebo). This is the first placebo-controlled, AD trial of a protein kinase C epsilon (PKCɛ) activator, which in preclinical studies induced the growth of new synapses and prevented neuronal death. This represents a new therapeutic strategy for AD that directly addresses the emerging consensus that synaptic loss has a major impact on cognitive deficits of AD.
The improvements in the primary cognitive endpoint, the Severe Impairment Battery (SIB), were observed in the study’s 20 µg treatment arm as early as week five, and were maintained throughout the 13-week study (Table1). The scores for the secondary functional endpoint, the ADCS-ADL-SIV (Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory Severe Impairment Version) for the 20 µg treatment arm showed improvement at week 13. Unlike the 20 µg dose, there was no therapeutic signal observed with the 40 µg dose. This contrast between the signal observed with the 20 µg dose versus the 40 µg dose was reinforced by the results of a Cohen’s D analysis, part of an in-depth statistical evaluation of the study data that found a consistent signal of benefit in SIB and ADCS-ADL-SIV for the 20 µg dose at the end of the trial.
“Although the study was not powered for statistical significance at a = 0.05, the clinical effects in the 20 µg group compared to placebo were consistent in magnitude for cognition and function, and hold up under multiple sensitivity analyses,” said Suzanne Hendrix, PhD of Pentara Corporation, a leading expert in statistical analysis of AD clinical trial results. “Standardized effect sizes were small for the sensitivity analyses for the 20 µg group. Using a standardized effect size such as Cohen’s D allows comparison of effects between different scales in a way that is independent of the sample size.”
Patients dosed with 20 µg had a dropout rate similar to placebo, while patients dosed at 40 µg experienced poorer safety and tolerability, and had a higher dropout rate. Treatment emergent adverse events (TEAEs) were mostly mild or moderate in severity. TEAEs, including serious adverse events, were more common in the 40 µg group, as compared to the 20 µg and placebo groups. These data reinforce the safety and tolerability of the 20 µg dose.
The lack of signal at the higher 40 µg dose is not entirely unexpected based on the in vitro dose response features of bryostatin-induced PKCɛ activation. As seen with the 40 µg dose, the obligatory downregulation phase appears to override the initial activation phase, thereby mitigating the desired clinical effect.
“The persistent improvement seen in the 20 µg group versus the outcomes seen in the 40 µg treatment arm help define an optimal dosing range to potentially sustain clinical benefit with minimal side effects,” remarked Daniel Alkon, MD, President and Chief Scientific Officer at Neurotrope. “These findings are consistent with preclinical research on bryostatin-1 and affirm the viability of its mechanism of action. We are well positioned to move forward with our clinical development program.”
Filed Under: Drug Discovery
