20 µg dose shows favorable safety, tolerability and encouraging therapeutic signal on top of standard of care

Novel mechanism of action shown preclinically to promote synaptogenesis

NEW YORK, NY, USA I July 19, 2017 I Neurotrope, Inc. (NASDAQ: NTRP) today 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.”

Table 1:  SIB Results, MMRM Change from Baseline versus Placebo

  SIB Change Score Difference Compared with Placebo
  Week 5 Week 9 Week 13
20 µg mITT







20 µg completer







40 µg mITT







40 µg completer







NS = not statistically significant; pre-specified (per statistical analysis plan) p <0.1, 1-tailed

The prospective analysis defined two primary patient populations: the modified intent-to-treat (mITT) population (135 subjects received study drug and had at least one efficacy/safety evaluation), and the completer population (the 113 subjects in mITT that completed the 13-week assessment).

The full presentation from the oral session is available at: http://www.neurotropebioscience.com/Welcome_to_Neurotrope_BioScience/HomePage-Forms/AAICF.pdf

About Bryostatin

Bryostatin-1 is a protein kinase C epsilon (PKCɛ) activator that works through synaptic growth factors, as well as anti-amyloid and anti-tangle signaling pathways in the brain. It has been shown in preclinical efficacy studies to induce the growth of mature synapses in the brain and prevent neuronal death. Thus, Bryostatin-1 introduces a fundamentally different biological mechanism of action with the potential for longer lasting effects than the other currently available therapies. Bryostatin-1 is the first PKCε modulator to be tested in a phase 2 clinical study for patients suffering from moderate to severe AD — a difficult to treat population.  

The rationale for researching this novel mechanism in AD results from in vitro and in vivo models of AD demonstrating that modulation of PKCε by Bryostatin-1 enhances synaptogenesis and prevents neuronal death. As synaptic loss is tightly correlated with cognitive impairment in AD, this attribute of the molecule made bryostatin an intriguing candidate for additional investigation in dementia. Furthermore, preclinical studies also demonstrated bryostatin reduces toxic Aß levels, prevents plaque formation, inhibits tau phosphorylation, and enhances cognition. Thus, the multimodal effects of this first PKCε modulator offer a potential new mechanism to study in AD with the ultimate goal to slow or prevent the progression of disease.  

The maximum dose chosen for this study, if normalized to a standard body surface area (BSA) of 1.73 m2, is similar to the 25 µg/m2 dose studied in oncology patients and shown to be relatively safe.

About Neurotrope

Neurotrope is at the forefront of developing a new approach to combatting AD and other neurodegenerative diseases. The Company’s world-class science offers the potential to realize a paradigm shift to overcome one of today’s most challenging clinical problems — finding a way to slow or even prevent the progression of AD.

In addition to the Company’s Phase 2 trial of bryostatin-1 in moderate to severe AD, Neurotrope has also conducted preclinical studies of bryostatin as a potential treatment for Fragile X Syndrome, Niemann-Pick Type C disease and Rett Syndrome—three rare genetic diseases for which only symptomatic treatments are currently available. The FDA has granted Orphan Drug Designation to Neurotrope for Bryostatin-1 as a treatment for Fragile X Syndrome. Bryostatin-1 has already undergone testing in more than 1,500 people in cancer studies, thus creating a large safety data base that will further inform clinical trial designs in AD.

SOURCE: Neurotrope