Neurizon's NUZ-001 Reduces Aggregation of Key ALS Disease Target TDP-43 in Preclinical Study

• Positive preclinical results in human in vitro iPSC Motor Neuron models of Amyotrophic Lateral Sclerosis (ALS)
• Neurizon's lead drug NUZ-001 and its major active metabolite significantly and dose-dependently prevented the aggregation of TAR DNA-binding protein 43 (TDP-43) by ~50% and ~55% respectively, in M337V Motor Neurons in response to a stressor
• TDP-43 aggregation is a key hallmark pathological feature of ALS
• Treatment with NUZ-001 and its major metabolite significantly improved electrophysiological dysfunction of TDP-43 mutated M337V Motor Neurons
• Provides valuable insights into the mechanism of action of NUZ-001 in ALS and strengthens promising efficacy results from the Phase 1 MEND study completed earlier this year in patients with ALS

MELBOURNE, Australia, Nov. 19, 2024 /PRNewswire/ -- Neurizon Therapeutics Limited (ASX: NUZ & NUZOA) ("Neurizon" or "the Company"), a clinical-stage biotech company advancing treatments for neurodegenerative diseases, is pleased to announce positive results from a preclinical study of its lead candidate, NUZ-001. These innovative studies reveal NUZ-001's unique mechanism of action in preventing the aggregation of TAR DNA-binding protein 43 (TDP-43), a key pathological feature of ALS, and the ability of NUZ-001 to significantly improve the electrophysiological dysfunction of TDP-43 M337V mutated motor neurons, showcasing the potential for NUZ-001 to be a transformative treatment for ALS. Importantly, these findings reinforce the promising efficacy results seen in Neurizon's Phase 1 MEND study and bolster confidence in NUZ-001 therapeutic capabilities for patients with ALS.

Two separate preclinical studies were conducted in collaboration with Ncardia, a leading human induced pluripotent stem cell (iPSC) technology company. The first study evaluated the ability of NUZ-001 and its major active metabolite (NUZ-001 Sulfone) to reduce TDP-43 aggregation in M337V Motor Neurons co-cultured with astrocytes in response to a stressor. TAR DNA-binding protein 43 (TDP-43) is a known driver of ALS pathology. The results show NUZ-001 and NUZ-001 Sulfone significantly and dose-dependently reduced TDP-43 aggregation in M337V Motor Neurons treated simultaneously with aggregation stressor MG-132 by ~50% and ~55%, respectively.

The second study evaluated the ability of NUZ-001 and NUZ-001 Sulfone to restore the normal electrophysiological function of TDP-43 mutated M337V Motor Neurons. The TDP-43 M337V mutation is associated with the development of ALS and has been shown to impair neuronal electrical activity at multiple levels. NUZ-001 and NUZ-001 Sulfone rescued the electrical activity of TDP-43 M337V Motor Neurons, by increasing bursting and network burst activity, and reducing inter-burst intervals to wild type Motor Neuron activity levels.

Dr. Michael Thurn, Managing Director and Chief Executive Officer of Neurizon, commented: "The positive results from these preclinical studies are a significant milestone, providing validation of our hypothesis that NUZ-001 and its major metabolite prevent the damaging accumulation of TDP-43 in diseased neuronal cells. This finding also highlights the power of NUZ-001 to improve neuronal electrophysiology, an essential step towards providing patients with ALS with a meaningful treatment option."

"This advancement brings us closer to delivering a much-needed therapeutic option for patients with ALS," Dr. Thurn continued. "NUZ-001's positive results present a compelling case for continued development and create exciting opportunities for partnerships as we advance our clinical studies. We are committed to making a significant difference in the lives of patients with ALS and are eager to move forward with our next clinical trial of NUZ-001 in early 2025."

Impact on ALS Therapy and the Market

The ability of NUZ-001 to target TDP-43 aggregation and repair motor neuron function positions it as a promising lead candidate for the treatment of ALS, where effective treatments remain scarce. With its novel mechanism, NUZ-001 has the potential to address ALS pathology at its core, offering hope to patients and caregivers affected by this debilitating disease. The ALS treatment market, projected to grow significantly in the coming years, presents a critical opportunity for NUZ-001 to fill a longstanding therapeutic gap.