Neurizon’s lead drug crosses blood-brain barrier, reinforcing ALS treatment potential

Neurizon reports encouraging new rodent preclinical pharmacokinetic data for its lead candidate NUZ-001, showing it effectively crosses the blood-brain barrier.

Neurizon’s results from a PK study show NUZ-001 crosses the blood-brain barrier. Pic via Getty Images

Special Report: Clinical-stage biotech Neurizon Therapeutics has reported encouraging new rodent preclinical pharmacokinetic (PK) data for its lead candidate NUZ-001, showing it effectively crosses the blood-brain barrier (BBB). 

• PK study shows strong brain penetration of NUZ-001 and major active metabolite NUZ-001 Sulfone
• Both compounds significantly prevented TDP-43 aggregation in a patient-derived ALS neuron model at all tested concentrations
• Brain concentrations reached matched those needed to reverse TDP-43 aggregation

Neurizon Therapeutics (ASX:NUZ) reported that NUZ-001 and its major active metabolite NUZ-001 Sulfone effectively cross the 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 company said 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).  Neurizon said this is a crucial aspect, in addition to delivering therapeutically relevant amounts to the CNS, is vital for their success. 

The company said the new results highlighted the ability to achieve target-relevant CNS exposure and marked a pivotal moment in validating the potential of NUZ-001 to act directly on disease pathology mechanisms in the brain. 

The results reinforce encouraging efficacy results seen in Neurizon’s phase 1 MEND study in ALS, the most common form of motor neurone disease (MND) with NUZ-001. 

TDP-43 aggregation is a hallmark of ALS and several other neurodegenerative disorders, including frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). 

While Neurizon is currently focused on treating ALS, the company said the results show its potential for broader application across other TDP-43-related neurodegenerative diseases. 

Blood-Brain Barrier Penetration

In the PK study NUZ-001 and its major active metabolite NUZ-001 Sulfone successfully crossed BBB, a key challenge for therapies targeting brain diseases. 

After a single dose, NUZ-001 reached brain concentrations ranging from 285 to 1,300 nM, with an average strong brain-to-plasma ratio of 0.47 across all tested doses.

Its major active metabolite, NUZ-001 Sulfone, also penetrated the brain, reaching levels between 177 and 1,231 nM, with a brain-to-plasma ratio of 0.13.

Neurizon said the results confirmed the drug’s ability to deliver therapeutically relevant concentration levels to the brain, essential for treating conditions like ALS and other neurodegenerative diseases.

TDP-43 Aggregation Assay

In a separate lab-based study, Neurizon repeated its earlier TDP-43 assay using a broader range of doses with the goal to confirm and extend previous findings on the drug’s ability to prevent toxic protein build-up in ALS.

The company said both NUZ-001 and its sulfone metabolite significantly reduced the aggregation of TDP-43.  

The effect was observed across all concentrations tested (270 to 4,400 nM). Neurizon said notably these therapeutic concentrations closely matched the brain levels achieved in the rodent PK study, which were reached through peripheral (non-invasive) administration.

The findings further validate NUZ-001’s potential to act directly within the central nervous system and modify disease progression.

In ALS, cytoplasmic accumulation (abnormal buildup) of TDP-43 disrupts cellular processes, leading to motor neuron dysfunction and degeneration.

By targeting TDP-43 pathology, NUZ-001 offers a new approach to mitigating ALS progression and highlights the potential for expanded applications in other neurodegenerative diseases.

Source: Neurizon

‘Reinforces the potential of NUZ-001’

Managing director and CEO Dr Michael Thurn said the results provided 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,” he said. 

“With these findings, we are more determined than ever to deliver a therapy that precisely targets the underlying pathology driving this devastating disease, supporting the accelerated advancement of NUZ-001.

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Originally published as Neurizon’s lead drug crosses blood-brain barrier, reinforcing ALS treatment potential