Title:
A Multicenter Phase 2A Study Evaluating Safety, Pharmacokinetics, and Pharmacodynamics of NTRX-07, a Selective Cannabinoid Receptor Type 2 Agonist, in Subjects with Mild Cognitive Impairment or Mild-to-Moderate Alzheimer's Disease

A Phase 2A Study of Safety, PK, and PD of NTRX-07, a Cannabinoid CB2 Agonist, in MCI or Early Alzheimer's Disease

Background:
Neuroinflammation driven by dysregulated microglial activation is a pathological hallmark of Alzheimer's disease (AD). NTRX-07 is an orally administered, brain-permeable, selective cannabinoid receptor type 2 (CB2R) agonist under development for AD. In preclinical models, NTRX-07 mitigated microglial activation, inhibited neuroinflammation, promoted amyloid-beta (Aβ) clearance, and improved long-term potentiation (LTP). In a Phase 1 study, NTRX-07 was well tolerated at 90 mg/day — a dose predicted to be pharmacologically efficacious — with a 7-day cohort of AD subjects demonstrating directional trends toward cognitive improvement and partial qEEG reversal of AD-associated deficits versus healthy aged controls.[^4]

Methods:
A multicenter, randomized, placebo-controlled, 28-day Phase 2A trial enrolled 48 subjects (NTRX-07, n=23; placebo, n=25) with a Clinical Dementia Rating (CDR) of 0.5–2.0, Mini-Mental State Examination (MMSE) score of 12–26, and plasma pTau-217 levels consistent with AD. Exclusion criteria included MRI evidence of non-AD intracranial pathology and anti-amyloid immunotherapy within 3 months prior to dosing. Primary endpoints were safety, tolerability, and plasma pharmacokinetics. Exploratory pharmacodynamic endpoints included free-water MRI (CDM AngleR), cerebrospinal fluid (CSF) biomarkers (Aβ42, Aβ42/Aβ40, NF-Light, GFAP, pTau, IL-8), and quantitative electroencephalography (qEEG).

Results:
NTRX-07 was well-tolerated. Treatment-emergent adverse events (TEAEs) occurred in 26.1% of active and 28.0% of placebo subjects; total TEAEs numbered 13 vs. 15, respectively, with no clinically significant group differences. Plasma pharmacokinetics demonstrated a mean Cmax of 146 ng/mL, Tmax of 1.0 h, and AUC0–12h of 392 ng·h/mL. Free-water MRI showed the NTRX-07 group had a median change from baseline in neuroinflammation-associated cortical disarray (CDM AngleR) just below zero, while the placebo group exhibited a median increase above 1%; the upper interquartile range for treated subjects remained below the placebo median. In CSF biomarkers, active treatment trended favorably vs. placebo for Aβ42, Aβ42/Aβ40, NF-Light, and IL-8. qEEG demonstrated a statistically significant increase in a key frequency domain measure in the NTRX-07 group (Wilcoxon test, p=0.012).

Conclusions:
NTRX-07 was safe and well-tolerated following 28 days of treatment in subjects with MCI or mild-to-moderate AD. Exploratory MRI findings were directionally supportive of the neuroinflammatory hypothesis, with treated subjects trending toward stabilization of cortical microstructural pathology. Directionally favorable trends in CSF biomarkers and a significant qEEG signal provide encouraging pharmacodynamic evidence for CB2R-mediated neuromodulation as a therapeutic strategy in AD.