NRG, an innovative clinical stage neuroscience company targeting a novel mechanism to restore mitochondrial dysfunction in neurodegenerative diseases, today presented a poster on preclinical and mechanistic data of its lead clinical asset NRG5051 which is being developed as a treatment for amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) and Parkinson’s.
In the poster NRG has disclosed that NRG5051, a first-in-class, orally bioavailable and CNS-penetrant next-generation inhibitor of the mitochondrial permeability transition pore (mPTP), acts through a novel NLRX1-mediated mechanism of action.
The scientists at NRG and their collaborators at WEHI are among the first to demonstrate that NLRX1 is essential for mPTP opening, establishing it as a key component or regulator of pore function. NLRX1 belongs to the NOD-like receptor family, a group of proteins that sense cellular stress and regulate immune responses. NLRX1 is unique within this family in being localised to the mitochondria.
The mPTP is a key inner mitochondrial membrane channel implicated in the toxic effects of misfolded TDP43, which accumulates in mitochondria and triggers energetic failure and a damaging interferon response. Data presented, from research part funded by the ALS Association and Innovate UK, confirmed that NRG5051 displays profound anti-inflammatory and neuroprotective effects in acute NLS-TDP43 ALS mouse models, including reduced plasma neurofilament light (NfL) chain, a translatable fluid biomarker of neuronal damage.
NRG5051 is currently in a Phase 1 randomised, double-blind clinical trial to assess safety, tolerability and pharmacokinetic parameters in healthy volunteers. Dosing in ALS patients is scheduled for later this year which will inform dose selection for future phase 2 proof-of-concept trials in ALS patients planned for 2027.
ALS is a rare, rapidly progressing neurodegenerative disease with high unmet medical need. Despite recent success in treating patients with the very rare SOD-1 genetic form of ALS, the majority (90%) of patients with sporadic disease remain poorly treated by existing medicines.
