Preclinical studies confirm potential of Neurizon’s lead drug to treat ALS

Positive results of preclinical studies confirm the potential of Neurizon’s lead drug candidate NUZ-001 to be a transformative treatment for Amyotrophic Lateral Sclerosis (ALS).

Neurizon has reported positive preclinical trial results for NUZ-001. Pic: Getty Images

• Preclinical studies confirm potential of Neurizon’s lead drug candidate NUZ-001 to treat ALS

• NUZ-001 shown to significantly reduce aggregation of a key protein that builds up in ALS, contributing to disease progression

• Drug also shown to improve electrical issues in nerve cells that have a common ALS-related TDP-43 mutation

 

Special Report: Clinical-stage biotech Neurizon Therapeutics has released positive results of preclinical studies confirming the potential of its lead drug candidate NUZ-001 to be a transformative treatment for Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases.  

Neurizon Therapeutics (ASX:NUZ) – formerly PharmAust – said the biotech is now inching closer to understanding the exact mode of action for NUZ-001 proven to reduce the aggregation (or clumping) of the TAR DNA-binding protein 43 (TDP-43), a known driver of ALS pathology.

The preclinical studies involved in human in vitro iPSC Motor Neuron models of ALS and were conducted in collaboration with Ncardia, a leading human-induced pluripotent stem cell (iPSC) technology company.

Results showed that NUZ-001 worked in a unique way to stop the aggregation of TDP-43, a protein that builds up in patients with ALS and contributes to disease progression.

Normally TDP-43 is localised to the nucleus of the cell but during times of stress, TDP-43 moves into the cytoplasma of neurons and back again when the stress is removed. However, in diseases such as ALS, TDP-43 can stick together, forming toxic clusters or aggregates with metabolic waste in the neuron causing disruption and damage to the neuron.

The studies showed NUZ-001 also improved electrical issues in neurons damaged with the common ALS-related mutation in the TDP-43 gene, suggesting it could become a powerful treatment for ALS.

Importantly, NUZ said the latest preclinical results build on positive results from NUZ's Phase I MEND study and strengthen confidence in NUZ-001's potential to help patients with ALS.

NUZ reduced TPD-43 aggregation by up to 55%

It’s all very technical but the first study – known as the HTRF TDP-43 Aggregation Assay –tested whether NUZ-001, and its main active metabolite NUZ-001 Sulfone, could reduce aggregation/clumping of the TDP-43 protein in M337V motor neurons.

NUZ said the neurons were grown together with support cells called astrocytes and exposed to a stressor that usually increases TDP-43 aggregation.

The results showed that NUZ-001 and NUZ-001 Sulfone significantly reduced TDP-43 aggregation in these neurons in a dose-dependent way – with the lower doses leading to greater reductions.

Specifically, NUZ-001 at the lowest dose and NUZ-001 Sulfone at the middle dose cut down TDP-43 aggregation by ~50% and ~55% respectively.

NUZ-001 helps damaged neurons recover electrical activity

The second study incorporated a multielectrode array (MEA) – described by NUZ as a powerful tool for evaluating and monitoring the activity of electrically active cells, such as neurons.

The study tested whether NUZ-001 and NUZ-001 Sulfone could restore normal electrical activity in motor neurons with the ALS-related TDP-43 mutated M337V motor neurons.

The mutation disrupts normal electrical signals in the neurons and in turn contributes to the development of ALS symptoms.

The results showed that NUZ-001 and NUZ-001 Sulfone helped the motor neurons with the TDP-43 mutation recover their electrical activity (firing) to be more like a neuron without the mutation.

NUZ said they did this by increasing neuron bursting or short bursts of electrical activity and improving electrical connectivity between neurons.

At certain doses the time between bursts shortened, bringing electrical signaling in these mutated neurons closer to the levels seen in healthy motor neurons.

Significant milestone, validation of hypothesis

Managing director and CEO Dr Michael Thurn said the results were important in the development of NUZ-001.

“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,” he said, adding:

“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.”

The advancement has brought NUZ closer to delivering a much-needed therapeutic option for patients with ALS, Thurn also noted.

“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.”

TDP-43 protein aggregation is common in several other neurodegenerative diseases including frontotemporal dementia, Alzheimer’s disease, and limbic predominant age-related TDP-43 encephalopathy, highlighting NUZ-001’s vast potential.

NUZ presents at ALS Research Symposium

Meanwhile, Dr Thurn presented on Thursday, November 14 (ET) at the 7th Annual ALS Research Symposium hosted by ALS ONE.

This prominent annual event brings together global experts, patients and advocates to share the latest advances in ALS research and treatment development.

The presentation, titled Exploring the Benefits of mTOR Inhibition in Patients with Amyotrophic Lateral Sclerosis, highlighted the preclinical findings on NUZ-001.

This article was developed in collaboration with Neurizon Therapeutics,  a Stockhead advertiser at the time of publishing.

This article does not constitute financial product advice. You should consider obtaining independent advice before making any financial decisions.