Neurotrope’s investigational compound Bryostatin-1 showed evidence of sustained improvement in cognition compared to placebo in patients with moderate-to-severe Alzheimer’s disease, according to additional results from a Phase 2 clinical trial.
This beneficial effect was sustained for at least four weeks upon ending treatment and was even more pronounced in the absence of the therapy memantine (sold in the U.S. as Namenda and Namzaric). The company now has begun recruiting for a new Phase 2 trial to confirm these results.
These results were discussed recently at the 2018 Alzheimer’s Association International Conference (AAIC) in Chicago, Illinois, in a scientific poster presentation titled, “Significant Cognitive Improvement with Bryostatin for Advanced Alzheimer’s Patients in the Absence of Memantine.”
Bryostatin is a small molecule designed to penetrate the blood-brain-barrier and specifically activate the protein kinase C (PKCϵ). Its activity enhances nerve cells’ capacity to communicate with each other, while supporting the repair of damaged communication nodes (synapses).
Preclinical studies have demonstrated that treatment with Bryostatin not only restored synapses, but also triggered the formation of new ones while preventing cell death.
The randomized, double-blind, placebo-controlled Phase 2 trial (NCT02431468) assessed the safety, tolerability, and activity of Bryostatin in moderate-to-severe Alzheimer’s patients.
The study enrolled 147 patients, ages 55-85, who already had manifested cognitive deficits for at least two years, across 27 clinical sites in the U.S. Individuals were randomized to receive bryostatin at 20 or 40 microgram (μg) doses, or placebo, administrated intravenously every other week for a total of 12 weeks.
Overall, treatment was safe with a good tolerability profile. The group treated with the lowest bryostatin dose showed a similar frequency of adverse events (a total of 30 events) as the placebo group (28 events). Those treated with the highest dose had significantly more adverse reactions, with 51 events reported during the study.
At 12 weeks of treatment, evaluation of cognitive function, as determined by changes in Severe Impairment Battery (SIB) scores from baseline, revealed that only patients treated with bryostatin 20 μg experienced sustained improvements compared to the placebo group. SIB is an assessment scale widely used in Alzheimer’s drug trials to evaluate dementia.
By week 13, these patients showed an increase in mean SIB change of 1.51, while placebo-treated patients showed SIB worsening of -1.12 points during the same time period.
The higher dose failed to support any improvement in cognitive activity during the trial duration. According to researchers, this lack of activity could be “due to prolonged down regulation of PKC that typically follows higher and/or longer levels of PKC activation.”
This difference was even more pronounced in a subgroup of patients who were not taking memantine during the trial. These patients showed a mean SIB positive change at week 13 of about 4.1 points and at week 15 of 6.1 point compared to baseline.
The main targets of bryostatin, PKC isozymes, are known to regulate NMDA receptor functions, which are blocked by memantine. NMDA receptors in the brain are very important for nerve cells’ communication and memory function. As such, blocking the NMDA receptor could offset most, if not all, of bryostatin’s treatment effect.
Additional analysis demonstrated that low-dose bryostatin can promote sustained reversal of cognitive decline over time, “even 30 days after all dosing was completed,” Richard Thompson, PhD, said in a press release. Thompson is senior statistician at Bloomberg School of Public Health, Johns Hopkins University.
“Patients not on memantine treatment exhibited significant cognitive improvement, at all time points tested during the trial,” said Thompson. “Various sensitive, comparative analyses were also conducted and resulted in consistent conclusions, including sustainability of the treatment effect over time, even 30 days after all dosing was completed.”
Supported by these results, Neurotrope has launched a new Phase 2 trial (NCT03560245) to confirm the effects of 20 µg dose of bryostatin in comparison to placebo. The trial is expected to enroll about 100 patients with moderate-to-severe and confirmed cognitive deficits present for at least two years, across 16 centers in the U.S.
“We are delighted to have initiated enrollment of the study earlier this month,” said Charles Ryan, JD, PhD, CEO of Neurotrope.