• High levels of NUZ-001 and its major active metabolite NUZ-001 Sulfone cross the blood-brain barrier
• Both compounds significantly prevented the aggregation of TDP-43 in a patient-derived iPSC neuronal model of ALS
• CNS concentrations achieved overlapped with the concentrations shown to reverse TDP-43 aggregation

Neurizon Therapeutics Limited (ASX: NUZ & NUZOA) has announced new rodent preclinical pharmacokinetic (PK) data demonstrating that NUZ-001 and its major active metabolite, NUZ-001 Sulfone, effectively cross the blood-brain barrier (BBB) and achieve brain concentrations consistent with those shown to reverse pathological TAR DNA-binding protein 43 (TDP-43) aggregation in patient-derived induced pluripotent stem cells (iPSC). The ability of therapeutics to access the central nervous system (CNS) remains a major barrier in the treatment of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). These new results highlight the ability to achieve target-relevant CNS exposure and validate the potential of NUZ-001 to act directly on disease-driving mechanisms within the brain. In a rodent PK study, a single administration of NUZ-001 resulted in brain concentrations ranging from 285 to 1,300 nM, while NUZ-001 Sulfone reached brain levels of 177 to 1,231 nM. The ability of NUZ-001 and NUZ-001 Sulfone to reduce TDP-43 aggregation in M337V Motor Neurons co-cultured with astrocytes was evaluated in response to a proteasomal stressor (MG-132). The results show that both compounds significantly prevented the aggregation of TDP-43 in M337V Motor Neurons at all concentrations tested (270-4,400 nM), with the effective concentration (270 nM) overlapping with the concentrations achieved in the rodent PK study.

These excellent results provide compelling evidence that NUZ-001 and its Sulfone metabolite not only effectively penetrate the BBB but do so at concentrations that are proven to reverse pathological TDP-43 aggregation in vitro. This new data provides strong translational validation for our mechanism and reinforces the potential of NUZ-001 as a transformative disease-modifying therapy for ALS.