Research Update, November 2025

Coya Therapeutics has announced that the FDA has accepted its Investigational New Drug (IND) application for COYA 302, a new investigational therapy for ALS. This acceptance enables the initiation of a Phase 2 placebo-controlled trial to evaluate its safety and efficacy in people living with ALS. Canadian sites are still under consideration, and our clinical trials database will be updated once we receive more information.

• COYA 302 is an experimental therapeutic targeting the immune system. It combines low-dose IL-2 and CTLA-4 Ig, designed to enhance regulatory T cell function and reduce inflammation from other immune cells.

AL-S Pharma has reported topline results from the Phase 2 study of AP-101. The study, which included participants living with both sporadic ALS and SOD1-ALS, met its primary endpoint for safety and tolerability. This is the first SOD1-targeted therapeutic being investigated in sporadic ALS cases.

• The press release states that exploratory outcomes showed clinically meaningful changes in outcome measures and stabilization of biomarkers, but did not provide data yet to justify these statements. Data recently presented at an ALS conference has not yet helped to provide clarity. The company has stated their intention to engage with regulatory authorities later in 2025 about next steps.
• AP-101 is a human antibody targeting misfolded SOD1 in ALS, and it is designed to inhibit the spread of misfolded SOD1 in the central nervous system (CNS). It is different from the approved therapy for SOD1-ALS, Qalsody (tofersen), which is an antisense oligonucleotide (ASO) that prevents SOD1 protein from being made in the first place by targeting its mRNA.

Neurizon Therapeutics has reported open-label extension (OLE) results for NUZ-001. The original Phase 1 trial recruited 12 participants living with ALS, with 10 of those continuing to the OLE. Long-term treatment was found to be safe and well-tolerated.

• Despite reports of slower decline in ALSFRS-R score and respiratory function, small Phase 1 trials without a placebo control should be interpreted with high caution, as data can be misleading. Although mentioned as a supportive biomarker trend, stable NfL levels are not suggestive of benefit. A new clinical trial on the HEALEY ALS Platform is planned for Q4 2025.
• NUZ-001 is a repurposed veterinary medication. It is a small oral molecule designed to reduce protein aggregation, regulate cell death (autophagy), and improve neuronal function.

* The ALSFRS-R is a widely used clinical tool to measure disease progression in people living with ALS. It evaluates a patient’s ability to perform everyday tasks and tracks decline over time. Through a structured interview, the clinician or patient assesses bulbar symptoms, fine and gross motor function, respiratory symptoms, and the need for ventilation or feeding tubes. Its use in determining the efficacy of a treatment is common but must be interpreted very carefully as it can sometimes be misleading. You can access the scale here.

MediciNova has announced complete enrollment for the COMBAT-ALS Phase 2b/3 clinical trial of MN-166 (ibudilast). A total of 234 participants were randomized across two treatment arms at sites in the US and Canada. The trial’s primary endpoint is Combined Assessment of Function and Survival (CAFS)*, with secondary measures including ALSFRS-R progression, muscle strength, and quality of life (QoL). Topline results are expected by the end of 2026.

• MN-166 (ibudilast) is thought to reduce the activity of immune cells in the brain, thereby suppressing inflammation. It is also believed to promote the production of neurotrophic factors which play a role in the growth and survival of motor neurons, however, these anti-inflammatory and neurotrophic effects have not been well demonstrated in ALS clinical trials to date.

* The Combined Assessment of Function and Survival (CAFS) is a statistical endpoint used ALS clinical trials that combines survival time and functional status (using the ALSFRS-R score) into a single ranked score.

• On July 24, AB Science announced it received regulatory approval from several European countries to initiate a confirmatory Phase 3 trial of masitinib in ALS. The study will enroll 408 patients with moderate disease progression. Masitinib has already been tested in multiple ALS clinical trials with inconclusive results to date.
• Masitinib is an oral tyrosine kinase inhibitor that targets mast cells and microglia to reduce neuroinflammation.

Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis

In this preprint article, American researchers investigated a therapy targeting TDP-43 function in mice with ALS-like symptoms. TDP-43 is a protein that plays a critical role in cellular health, but in nearly all cases of ALS, its normal levels and behavior are disrupted, even in cases without a variant in the TARDPB (TDP-43) gene.

Under healthy conditions, TDP-43 resides mostly in the cell nucleus, but in ALS, it mislocalizes to the cytoplasm, where it can form abnormal aggregates and lose its normal, nuclear function. Scientists have long debated which aspect of this dysfunction to target: the loss of TDP-43 in the nucleus, its buildup in the cytoplasm, or both. Here, the researchers focus on restoring a key nuclear function of TDP-43: helping the cell avoid cryptic splicing. Cryptic splicing occurs when the cell’s machinery makes mistakes when reading genetic instructions, adding non-functional segments to the genetic code, which results in defective or loss of proteins.

Using a virus that can cross the blood-brain barrier (BBB)*, the authors delivered a therapeutic molecule (called CTR) to TDP-43-deficient mice. This therapy uses gene expression regulation designed to compensate for the loss of TDP-43, so cryptic splicing is reduced. The researchers reported that systemic delivery of the treatment reached about 80% of the mice’s spinal motor neurons, and attenuated symptoms caused by TDP-43 dysfunction. As a result, the mice showed slower disease progression and avoided limb paralysis.

Importantly, the therapy was safe: healthy mice treated with it showed no negative side effects even after 20 months. These findings offer early evidence that restoring TDP-43 function through gene therapy could be a promising strategy for treating ALS, but more work is needed to reach a place where a clinical trial is possible.

* The blood-brain barrier (BBB) is a protective layer that controls what can pass from the bloodstream into the brain, allowing in essential nutrients while blocking out harmful substances like toxins and bacteria. While this barrier is crucial for keeping the brain safe, it also makes it difficult for most drugs to reach the brain, which is a challenge for treating ALS.

Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset

In this preprint article, UK researchers discovered that signs of ALS can show up in other parts of the body long before any muscle symptoms begin. By examining samples from people who later developed ALS, researchers found abnormal protein activity (specifically involving TDP-43*) in several organs, including muscles, lymph nodes, with particularly high levels in skin. The most affected areas were sweat and oil glands, especially on the back and shoulders. These protein changes in the skin were detected up to 26 years before diagnosis.

This discovery is important because skin is easy to access through a simple biopsy. If these changes can be reliably detected, it could be used as a diagnostic biomarker for ALS and help clinicians diagnose ALS much earlier, possibly even before symptoms start. The authors note that this finding is similar to how skin tests have helped detect Parkinson’s disease. While this is an exciting discovery, more work is needed to confirm the findings, including determining whether TDP-43 is detected in these tissues in people who did not develop ALS.

In 2015, a Canadian researcher, Dr. François Gros-Louis, discovered TDP-43 aggregation in skin models derived from people living with ALS, but it was never explored in individuals before the onset of symptoms.

* TDP-43 is a protein whose normal levels and function are disrupted in most cases of ALS, even in cases without a genetic variant in the TARDPB gene.

A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis

In another recent study, researchers explored the potential of blood proteins as diagnostic biomarkers for ALS. They analyzed over 2,000 proteins in the blood plasma of 231 individuals with ALS, 170 with other neurological conditions, and 214 healthy controls. The study identified 33 plasma proteins with significantly different levels in individuals with ALS. Among these, neurofilament light chain (NfL) showed the most pronounced difference, further reinforcing its growing recognition as a promising biomarker for ALS.

Further analysis of these proteins in independent datasets of people with ALS, including individuals with C9orf72 genetic variants who have ALS and who have not yet experienced any symptoms, resulted in confirmation of 16 new proteins that can be further explored alongside Nfl as potentially important biomarkers to use in the clinical detection and study of the disease.

Using machine learning to analyze this blood sample data, the researchers were able to distinguish people living with ALS from controls with over 98% accuracy. The machine learning model also explored the possibility of estimating the age of ALS clinical onset. Additionally, according to the data, the authors suggest that early dysfunction in energy, muscle, and nerve signaling may occur up to a decade before symptoms.

These findings are important as they offer potential for earlier diagnosis using blood tests, instead of more invasive tests such as cerebrospinal fluid (CSF) collection. Further work is needed to validate these findings, but they provide several new avenues to explore for understanding the biology of ALS prior to symptom onset.

A recent ALS article has been making the news, talking about a potential autoimmune response linked to ALS. While immune responses and neuroinflammation have long been associated with the disease, the novelty is that this research demonstrated potential evidence of an immune response targeting parts of the C9orf72 protein. Pathogenic variants (mutations) in the C9orf72 gene are a known risk factor for ALS and contribute to about 5-10% of all ALS cases. In this paper, this immune response toward the C9orf72 protein was found in blood samples from people living with ALS regardless of a genetic variant, although higher in C9orf72-ALS.

The response was predominantly mediated by a type of immune cells, called regulatory T cells (Tregs), which have been implicated in the disease since the late 2000s. They found that the type of reaction varies, as some of these Tregs release substances that promote inflammation, while others release molecules that help calm the cell down. IL-10 is a molecule (called a cytokine) that helps reduce inflammation. The study stated that people living with ALS who had stronger anti-inflammatory responses and higher IL-10 levels were predicted to live longer. However, IL-10 is not a new player in ALS research, and for over a decade, scientists have explored its potential as a therapeutic target.

Although these findings open new areas of research and insights into how the immune system may be involved in ALS, especially for people living with C9orf72-ALS, it’s important to note that this study alone does not mean ALS should be classified as an autoimmune disease. ALS is a complex and varied condition, likely driven by multiple biological, genetic, and environmental processes.

Many anti-inflammatory treatments have been tested in ALS over the years, but none have successfully changed the course of the disease, including Tregs boosting therapies. Recently, there has been a larger trial targeting Tregs with low dose IL-2, called MIROCALS. Our colleagues at the Motor Neurone Disease Association have written a blog about the results here: MIROCALS: breaking down the trial results. Other Treg immune therapies are being developed  by companies such as Coya, Cellenkos, Revalesio and others. Xalud Therapeutics is working to develop an IL-10 treatment for ALS.

In sum, while it’s clear the immune system plays a role in ALS, more research is still needed to understand how it affects the disease, and how it might be harnessed as a therapeutic target.

In this project supported by ALS Canada, in partnership with Brain Canada, Dr. Paul McKeever (University of Toronto, Janice Robertson lab) and others studied brain cells from people with ALS and ALS/frontotemporal dementia (FTD), focusing on both sporadic cases and those with a C9orf72 genetic variant. They found major changes in how neurons and adjacent cells in the nervous system manage energy, proteins, and gene activity. They also discovered unique patterns in how cells process RNA, especially through a mechanism called alternative polyadenylation (APA). APA allows cells to produce different versions of a gene’s messenger RNA (mRNA). These variations can influence which proteins are made, how stable the mRNA is, and where it travels within the cell. To better understand this, they built a deep learning model called APA-Net, to predict APA changes and map the complex biology behind ALS/FTD. This model provides new tools for future studies.

We previously covered this scientific article on environmental factors in New Brunswick in our August Research Update.

Dysregulated Expression of Inflammasome and Extracellular Matrix Genes in C9orf72-ALS/FTD Microglia

Dr. Stefano Stifani (McGill University) and others studied how the C9orf72 genetic variant in ALS and FTD affects immune cells in the brain called microglia. They found that these microglia become overly active and release harmful substances that can damage nearby motor neurons. This happens through a process called inflammasome activation, which triggers inflammation. The findings suggest that these immune cells play a key role in worsening the disease and targeting them could be a potential treatment strategy.

Of note, Zydus Therapeutics is currently recruiting for a Phase 2 clinical trial to study an inflammasome inhibitor called usnoflast.

Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS

ALS Canada-funded early career researcher Dr. Amélie Poulin-Brière (CERVO Brain Research Center) tested an antibody called E6, which targets a specific part of the TDP-43 protein, in a mouse model of sporadic ALS. The treatment reduced motor and cognitive symptoms, protected neurons, improved muscle connection, and shifted immune cells toward a more protective state. These findings suggest that targeting TDP-43 with immunotherapy could be explored further as a potential treatment for ALS.

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

Dr. Tom Durcan’s lab (McGill University) and others are exploring how variants in the TDP-43 gene (TARDBP) affect motor neurons. They found that pathogenic genetic variants disrupt the normal activity of certain RNAs and microRNAs, especially in a region called 14q32. Using this information, they identified potential drugs that could help restore normal gene activity. One compound, MLN4924, showed promise in cells by improving neuron health and function, suggesting that targeting protein modification processes may be a useful strategy in ALS treatments.

Combination of serum neurofilament light chain and serum cardiac troponin T as biomarkers improves diagnostic accuracy in amyotrophic lateral sclerosis

This study in Germany found that combining two blood-based biomarkers, sNfL and cTnT, improves the accuracy of diagnosing ALS, especially when distinguishing it from other neurodegenerative diseases, and may help identify different subtypes of the condition based on disease progression. More work on the value of cTnT as an ALS biomarker is currently underway across the field.