Bryostatin 1

The Phase II study will be performed in collaboration with the National Institutes of Health under a $2.7 million grant. New York-based Neurotrope announced a new long-term trial of Bryostatin-1 for Alzheimer’s disease (AD). The Phase II study will be performed in collaboration with the National Institutes of Health (NIH) under a $2.7 million grant. In September 2019, Neurotrope announced the confirmatory Phase II trial of Bryostatin-1 in moderate to severe AD, saying it did not achieve statistical significance on the primary endpoint. The primary endpoint was change from baseline to Week 13 in the Severe Impairment Battery (SIB) total score. On May 18, 2020, Neurotrope and Metuchen Pharmaceuticals announced a deal where the two companies will merge in an all-stock deal that will become Petros Pharmaceuticals. The expectation is that Petros will become a Nasdaq traded company focused on men’s health. The cornerstone product will be Metuchen’s Stendra (avanafil) for erectile dysfunction. The pipeline will include Metuchen’s in-licensed product H-100 for Peyronie’s disease. Once the deal is closed, Neurotrope’s Bryostatin-1 and all of its existing assets will be spun out into a new, separately traded company, NBI. Neurotrope will retain about $14 million, including the $2.7 million NIH grant. Along with the Phase II trial, Neurotrope plans to continue investigation the drug for Multiple Sclerosis and Fragile X syndrome. “The initiation of a new Bryostatin-1 study in AD, and our efforts in advancing a merger with Metuchen, underscore what we believe is a unique opportunity for our investors to participate in two distinct, publicly-listed companies with potentially meaningful value propositions: Petros Pharmaceuticals, Inc. and the spin-out company NBI,” said Charles S. Ryan, Neurotrope’s chief executive officer. The new Phase II trial is expected to enroll 100 patients. It will evaluate Brystatin-1 in the absence of Namenda for six months, which will include two 11-week dosing cycles. The study will concentrate on AD patients with pre-specified moderately severe and moderate disease, including a group that showed the most benefit in the previous study. It will plan to assess sustained cognitive benefit as measured by the Severe Impairment Battery (SIB) score. Namenda (nemantine) is used to treat moderate to severe dementia related to AD. It is marketed by Allergan. Analysis of the study data will be performed in consultation with Richard Thompson, senior scientist from the Bloomberg School of Public Health at Johns Hopkins University. “We are hopeful that this trial can substantiate certain compelling data with Bryostatin from previous trials, which suggests patients could potentially see improvement in their disease which, I believe, would be transformative as an AD treatment,” said George Perry, professor of Biology and Chemistry, Semmes Distinguished University Chair in Neurobiology, University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease . “When I see this in the context of currently available drugs, I believe Bryostatin could chart a new path in how we treat Alzheimer’s disease.” In the previously mentioned study, Brystostatin-1 (20 mcg) was well tolerated and showed early signals of cognitive improvement, including a 5.0 improvement in SIB score compared to baseline in the Moderate Stratum cohort in the non-Namenda group. This score was sustained through the entire treatment period and for four weeks after completion of the study. A second pilot study used the same treatment protocol without for Namenda for 11 weeks showed similar SIB improvement compared to baseline for the Moderate Stratum cohort.

Businessman showing thumbs down. Tero Vesalainen/Getty Images/iStockphoto Yet another Alzheimer’s drug has failed in late-stage clinical trials. vTv Therapeutics’ azeliragon failed to meet either co-primary efficacy endpoint in its Phase III STEADFAST clinical trial. It was being evaluated in patients with mild Alzheimer’s disease. Yet another Alzheimer’s drug has failed in late-stage clinical trials. vTv Therapeutics ’ azeliragon failed to meet either co-primary efficacy endpoint in its Phase III STEADFAST clinical trial. It was being evaluated in patients with mild Alzheimer’s disease. Phase II data in 2016 showed statistically significant benefit in Alzheimer’s patients with mild-to-moderate disease, with secondary endpoints including a statistically significant reduction in psychiatric adverse events. Unfortunately, like many drugs for Alzheimer’s, it failed in the larger, broader Phase III trial. The STEADFAST trial was made up of two independent, but identical double-blind, placebo-controlled trials, Part A and B. The group in Part A that received azeliragon showed a 4.4-point decline from baseline in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and a 1.6-point decline from baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) compared to declines in the placebo groups of 3.3 and 1.6, respectively. These are not clinically significant changes. As a result, the company is halting the current clinical trials of the drug, including the open-label extension trial and Part B of the STEADFAST study. More data analysis will continue. “We will continue to analyze the datasets and trends within subgroups from both Part A and Part B to determine if there are potential benefits or future uses and applications for azeliragon,” said Steve Holcombe, vTv Therapeutics’ chief executive officer, in a statement. “On behalf of vTv Therapeutics, we’d like to extend our most sincere and heartfelt gratitude to study participants, their families, physicians and caregivers for their commitment to this important study.” Azeliragon was an orally active small-molecule antagonist of advanced glycation endproducts (RAGE). RAGE is an immunoglobulin supergene family member that is expressed on multiple brain cell types, specifically on endothelial cells and microglia, which is upregulated in Alzheimer’s disease. RAGE is believed to contribute to Alzheimer’s by promoting vascular leakage, promoting the influx of peripheral beta-amyloid into the brain, mediating beta-amyloid induced oxidative stress, and other mechanisms related to tau proteins and beta-amyloid mediated neuron death. This is yet another recent failure in late-stage Alzheimer’s drug, although just one of over 125. Most recently, Merck & Co.’s verubecestat (MK-8931) failed its APECS Phase III clinical trial. Axovant Sciences ’ intepirdine failed in its MINDSET Phase III trial in September 2017. Eli Lilly ’s solanezumab failed in 2016, and Lundbeck ’s idalopirdine failed in 2016, as well. Recent failures have hinted that the predominant theory, that accumulation of beta-amyloid plaques, is the driver of Alzheimer’s disease, may be incorrect. Many of the drugs being developed attack beta-amyloid or, in the case of BACE inhibitors like verubecestat, prevent the build-up of the plaques. Other drugs prevent or attack tau tangles, which occur much later in the disease. Once again, this failure will focus attention on one of the remaining holdouts, Biogen ’ s aducanumab, an antibody for beta-amyloid. Like many other of these drugs, it’s shown efficacy in early-stage trials, but results for its Phase III trials is about two years down the road. Also of interest is Neurotrope ’s bryostatin, which showed some cognitive improvement in Alzheimer’s patients in a Phase II trial earlier this year. Bryostatin activates Synaptic Growth Factors, but it also activates amyloid-beta degrading enzymes, and activates alpha-secretase, which reduces formation of beta-amyloid. However, the veracity of earlier studies by Neurotrope have been questioned over its data analysis.