our science
Role of Microglia in Neuroinflammation and Neurodegenerative Diseases
The role of microglia is particularly evident in AD, where M2 microglia help in clearing amyloid β, while M1 microglia contribute to neuroinflammation and synaptic damage. In AD and other neurodegenerative disorders, the M1 phenotype is increased. As microglia transition from the M2 to M1 state, cannabinoid type 2 (CB2) receptor expression is induced.
The activation of immune cells, known as microglia, in the central nervous system (CNS) promotes an inflammatory response that serves as a hallmark for a range of neurologic disorders such as Alzheimer’s Disease (AD), amyotrophic lateral sclerosis, neuropathic pain, multiple sclerosis, and Parkinson’s Disease. Microglia play a critical role in CNS immune responsiveness. There are two states of microglia, an M1 phenotype that is predominantly neurotoxic and a neuroprotective M2 phenotype.
Our lead program, NTRX-07, a novel CB2 agonist, activates this receptor and promotes M1 microglia to transition from the pro-inflammatory phenotype to the neuroprotective, M2 phenotype. This results in reduced neuronal damage, increased clearance of amyloid β and inhibited neuroinflammation.
lead
program
NTRX-07 as a Treatment for Alzheimer’s Disease (AD)
NTRX-07 is a potent, highly selective, oral, CB2 receptor agonist in development for the treatment of Alzheimer’s Disease (AD).
Phase 1a (single-ascending dose), Phase 1b (multiple ascending dose) and Phase 2a (28-days of dosing) clinical studies have demonstrated a favorable safety profile and a pharmacokinetic (PK) profile consistent with preclinical studies expected to drive clinical activity. In the recently completed randomized, double-blind Phase 2a study, in addition to demonstrating safety, several endpoints associated with neuroinflammation and neuronal function moved in the same broad direction suggesting treatment benefits in both reducing neuroinflammation and improving neuronal function.
Read more here.
Phase 2a Study met its core objectives and produced a multi-domain signal across safety, PK, biomarkers, MRI, EEG and clinical outcomes that supports confidence in further development.
Safety
Favorable overall tolerability profile; no excess overall TEAE burden on active and no active-arm serious TEAE signal.
PK
Primary PK objective achieved with rapid absorption, measurable exposure, and a coherent dose-exposure profile.
Biomarkers
Directionally favorable trends on selected markers, especially NF-Light, IL8, AB42, and AB42/AB40 ratio.
MRI
Exploratory MRI findings were directionally supportive of the neuroinflammation hypothesis, with changes trending toward stabilization on active treatment.
EEG
EEG provided an additional exploratory CNS signal, although interpretation is limited by baseline imbalance and weak P300.
Clinical / functional
Clinical endpoints were mostly stable over a short window, with several nominal signals emerging despite limited study duration.
potential as a combination therapy
Based on its safety profile, NTRX-07 has strong potential to be used in combination with approved antibody treatments. In preclinical studies we have shown that NTRX-07 reduces microglial activity, leading to reductions in neuroinflammation, while also helping promote clearance of amyloid β. NeuroTherapia plans to test this potential synergy with currently approved antibody treatments.