Trace Neuroscience Launches First-in-Human Trials of UNC13A-Targeting ASO for ALS, While EXPERTS-ALS Platform Demonstrates Rapid Drug Screening Capability
核心洞察
Trace Neuroscience (搜索)'s TRCN-1023 (搜索), an antisense oligonucleotide targeting UNC13A (搜索) protein dysfunction present in ~97% of ALS patients, enters clinical trials across UK, Europe, North America, and China.
The FUNCTION ALS study will enroll approximately 30 participants to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of TRCN-1023 (搜索) over 24 weeks.
The EXPERTS-ALS platform trial demonstrated that Bayesian modeling enables rapid drug screening with small sample sizes, though metformin and nifedipine failed to lower neurofilament light chain (搜索) levels.
A new antisense oligonucleotide therapy targeting one of the most significant genetic drivers of amyotrophic lateral sclerosis (搜索) (ALS) has entered first-in-human clinical trials, marking a major milestone in the pursuit of disease-modifying treatments for the devastating neurodegenerative condition.
TRCN-1023 (搜索), developed by UCL spinout Trace Neuroscience (搜索), is designed to restore normal function of the UNC13A (搜索) protein, which plays a critical role in communication between nerves and muscles. Loss of UNC13A function is believed to contribute to disease progression in approximately 97% of people with ALS, also known as motor neuron disease (MND), making it one of the most relevant therapeutic targets identified to date.
UNC13A (搜索): A Genetically Validated Target
UNC13A (搜索) has emerged as among the most compelling drug targets in ALS research, grounded firmly in human genetics and disease biology. The protein is critical for neurons to communicate with each other and with muscles, and its loss is observed in nearly all ALS cases.
"UNC13A (搜索) is among the most promising targets in ALS research today, with a strong grounding in human genetics and disease biology," said Dame Pamela Shaw, Professor of Neurology at the University of Sheffield and Chief Investigator for the FUNCTION ALS study. "Restoring its function could benefit the vast majority of patients."
Professor Pietro Fratta, MRC Senior Clinical Fellow at the UCL Queen Square Institute of Neurology and co-founder of Trace Neuroscience (搜索), added: "UNC13A (搜索) is critical for neurons to communicate amongst each other and with muscles and is lost in nearly all MND/ALS cases. Seeing this discovery translated into a clinical trial is a major milestone. It brings us a step closer to a therapy that could make a meaningful difference for the vast majority of people living with MND/ALS."
TRCN-1023 (搜索): Mechanism and Trial Design
TRCN-1023 (搜索) is an antisense oligonucleotide (ASO) — a short, synthetic strand of nucleic acid that binds to RNA inside cells to influence how specific proteins are made. The drug is designed to correct the processing of UNC13A (搜索) RNA, enabling the body to produce a functional version of the protein.
The therapy is administered via intrathecal injection, delivering the drug directly into the fluid surrounding the spinal cord. This route is commonly used for ASO therapies because it allows treatment to reach the central nervous system where ALS causes damage.
The FUNCTION ALS study will enroll approximately 30 participants across sites in the UK, Europe, and North America. In the UK, trial sites will be located at Sheffield Teaching Hospitals NHS Foundation Trust and University College London Hospitals. Participants will receive either TRCN-1023 (搜索) or placebo, with 24 weeks of follow-up. The trial is designed to assess safety and tolerability, pharmacokinetics, and pharmacodynamics, and incorporates biomarker analysis and digital assessments of movement and speech aimed at reducing patient burden.
A parallel study, LAUNCH ALS, is being conducted in China in partnership with Tenacia Biopharmaceutical and led by Dr. Yilong Wang at Beijing Tiantan Hospital. This trial is expected to enroll approximately 25 participants with similar eligibility criteria.
"People with ALS urgently need innovative treatments beyond today's limited options," said Dr. Wang. "TRCN-1023 (搜索)'s biological rationale, potency and durability make it an exciting candidate to bring into the clinic."
The Broader Context: ALS Drug Development
ALS is a devastating and ultimately fatal disease that causes progressive muscle weakness due to degeneration of motor neurons in the brain and spinal cord. As the disease advances, patients gradually lose the ability to move, speak, swallow, and breathe. It is estimated to affect one in 300 people in their lifetime, and there are currently no disease-modifying drugs available to treat the condition.
Trace Neuroscience (搜索) launched in 2024 with a milestone Series A funding round of over $100 million. Eric Green, co-founder and CEO of Trace Neuroscience, stated: "Our team helped establish UNC13A (搜索) as one of the most compelling genetically validated targets in ALS, and we built Trace Neuroscience to translate that biology into a medicine. We're now excited to advance TRCN-1023 (搜索) into the clinic through a global strategy designed to generate robust data with the urgency this disease demands."
EXPERTS-ALS: A Novel Platform for Rapid Drug Screening
In parallel developments, the first results from the EXPERTS-ALS platform trial have demonstrated that promising drugs can be evaluated in ALS patients quickly and at a fraction of the size and cost of conventional drug trials. The platform, a "pre-trial" screening system, uses a revolutionary statistical approach called Bayesian modeling, pioneered at the University of Oxford, to look for early signals of disease-slowing such as lowering of blood levels of neurofilament light chain (搜索) (NFL), a biomarker associated with nerve cell damage.
The first drugs tested on the platform — metformin and nifedipine — were not able to lower NFL levels. Approximately 30 participants were involved, each taking one of the drugs for 18-24 weeks. Despite the small number of participants and some dropouts, there were no overall changes in NFL levels.
Professor Chris McDermott, Professor of Translational Neurology at the University of Sheffield's School of Medicine and Population Health and one of EXPERT-ALS's Chief Investigators, said: "We share the disappointment that neither metformin or nifedipine were able to lower neurofilament light chain (搜索) levels in EXPERTS-ALS. However, EXPERTS-ALS is the first platform of its kind and this result, at this stage of the study, has exceeded our expectations of how it might perform. These results mark a very important advance in speeding up clinical trials that improves the prospects for finding effective drugs for ALS."
The platform's ability to rapidly distinguish between promising and ineffective drugs could save years of research, allowing ineffective treatments to be rejected sooner while those showing efficacy are fast-tracked to larger trials. For people living with ALS, where time is critical, this acceleration represents a significant advance.
The EXPERTS-ALS project was funded by the National Institute for Health and Care Research (NIHR), with support from the Motor Neurone Disease Association, My Name's Doddie Foundation, Life Arc, and the Darby Rimmer Foundation. The work comes from a major collaboration coordinated by the Sheffield Clinical Trials Unit, Sheffield Teaching Hospitals NHS Foundation Trust, and the Sheffield Biomedical Research Centre.