The chief medical officer of NeuroTherapia provided insight on promising phase 1b data assessing NTRX-07, a CBR2-targeting agent in development for patients with early-stage Alzheimer disease.
This year’s Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, featured several presentations on promising agents in the Alzheimer disease (AD) pipeline, including NTRX-07 (NeuroTherapia), an orally administered, brain-permeable, selective cannabinoid receptor type 2 (CBR2) agonist. In a phase 1b study, the agent was safety administered for 7 days at doses up to 90 mg/day, with mild transient orthostatic changes in blood pressure, more frequently observed with lower doses.
The trial featured 3 cohorts of volunteers aged 45 to 80 years of age with well-controlled comorbidities and 1 cohort of patients with AD diagnosed with cognitive impairment consistent with prodromal AD or mild AD. Participants received NTRX-07 (10, 30, or 90 mg) or placebo in a double-blinded randomization orally once daily for 7 days, with no dose-limiting or serious adverse events (AEs) observed. No clinically meaningful changes in ECG or safety labs were observed. In addition, no significant changes in cognitive scores were recorded, although there was an interesting trend toward improvement in patients with AD.
Following these results, NeurologyLive® sat down with Joseph Foss, MD, lead investigator of the study and chief medical officer of NeuroTherapia, to provide an overview of the data. He spoke specifically on the mechanism of action of NTRX-07, the previous literature of CBR2-targeting therapies, and why the company believes this agent has therapeutic potential. Additionally, he discussed how the agent could be used in combination with previously approved therapies, whether there’s a certain optimal patient profile to receive treatment, and the next steps in the drug’s clinical development.
Joseph Foss, MD: NeuroTherapia is a company working on developing new small molecules targeted at neuroinflammation, which we believe plays an essential role in Alzheimer's disease. We are studying a compound called NTRX-07. This study completes our Phase One program, which included a multiple ascending dose study designed to provide safety information about the drug in both normal participants and a group of Alzheimer's participants. Additionally, it aimed to gather important data on the drug's plasma levels to ensure therapeutic levels when moving into the next phase. The study progressed smoothly and demonstrated good safety for all participants, yielding some unexpected findings. Surprisingly, there is evidence in the Alzheimer's group suggesting potential efficacy as we move forward. We observed improvements in their reported responses and unanticipated but positive findings on EEG measurements, making it exciting to uncover these results in a relatively short study.
Certainly, the primary focus in Alzheimer's disease has been on removing abnormal proteins like amyloid-ß and tau. However, these proteins in the brain seem to trigger a significant amount of neuroinflammation, which is mediated by microglia, the brain's immune cells. Upon studying this activity, it became apparent that microglia express receptors from the cannabinoid type 2 (CB2) family, distinct from the CB1 receptors related to the marijuana family. These CB2 receptors seem to be a crucial part of the brain's endogenous system for controlling inflammation. Our small orally administered molecule can readily penetrate the brain and modulate microglial activity. In preclinical models, we observed reduced inflammation, improved cognitive function in animals, and signs of improved microglial function in terms of clearing abnormal proteins in the brain.
CB2 has been the focus of study for many years, primarily regarding its potential for treating pain. Initially, we were exploring our compound in this area. However, many earlier compounds were not designed to readily cross into the brain to avoid crossover effects. In contrast, our compound has excellent brain penetration, setting it apart. Furthermore, our molecule activates the CB2 receptor differently, leading to downstream changes that reduce neuroinflammation, which is triggered by microglia.
NTRX-07, on its own, has the potential to make a therapeutic impact by reducing inflammation, which is directly related to the observed neuronal injury in Alzheimer's disease. Nevertheless, we see two areas where synergy might be possible. Firstly, we are interested in its potential effects on amyloid-related imaging abnormalities (ARIA), which appear to have an inflammatory component. Therefore, we will explore combining our compound with antibody compounds to study any potential effects. Secondly, we believe that when you introduce many antibodies into the brain to clear substances, immune cells play a role in helping with that clearance. If we can enhance microglial activity without increasing inflammation, there might be a positive synergistic role.
We obtained very positive safety findings for the compound. We also conducted a small study to investigate the compound's interaction with food, and no significant issues were found. Consequently, we are ready to progress the drug into a Phase Two program. In this study, we will identify Alzheimer's patients, particularly in the mild cognitive impairment (MCI) or early Alzheimer population. They will be randomly assigned to receive our drug or a matching placebo, and their cognitive effects will be evaluated. Furthermore, we observed significant improvements in EEG changes in patients with Alzheimer disease in our initial study, although we initially examined EEG as a safety outcome. These positive EEG changes further support the potential benefits of our drug.
From the Phase 1B study, we do not have sufficient data to draw conclusions about specific patient groups. Improvements were observed across the board. The study included eight patients with Alzheimer's disease, two of whom received a placebo, and six who received the active compound. What caught our attention was the principal investigator's remark during one of our weekly meetings, stating, "these patients are looking pretty good." When we unblinded the data, we found improvements in all six patients who received the active compound, while no changes were observed in the other two. Thus, we are enthusiastic about the drug's potential to help a broad range of patients. The ongoing work on biomarkers, which can aid in patient selection for studies, is an exciting development. We will closely examine the optimal set of biomarkers for our subset of patients when moving forward with the drug study.
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1. Foss J, Giordano T, Kiraly M. A phase 1b double blind multiple ascending dose study of the safety and pharmacokinectics of NTRX-07 in normal volunteers and patients with mild cognitive impairment or early Alzheimer's disease. Presented at: Clinical Trials on Alzheimer's Disease; October 24-27, 2023; Boston, MA. POSTER LP017.