ALS researchers worldwide continue to build upon existing work and make new discoveries in the hopes of realizing a world free of ALS. In the January 2025 Research Update, explore new insights into predicting disease onset, new potential therapies and treatment targets, and the use of biomarkers in ALS clinical trials.
We have developed a Research Glossary that contains a list of scientific and medical terms and definitions relevant to ALS. This glossary was created to support knowledge-sharing by clarifying terminology that may be unfamiliar to our readers. Click here to download a copy.
Rozebalamin® Approved in Japan for the Treatment of ALS
In Japan, Eisai Co., Ltd.’s Rozebalamin® for Injection 25 mg (mecobalamin) has been approved as a disease-modifying treatment for ALS. The approval is based on results from the JETALS study conducted in Japan.
Background on Rozebalamin Clinical Trials
A Phase 2/3 clinical trial in Japan, completed in 2014, evaluated two doses of Rozebalamin (mecobalamin, 25 mg or 50 mg) compared to placebo in 373 participants. The doses were administered via intramuscular injections twice per week for 3.5 years. The trial did not show a significant difference in disease progression or survival rates for either dose. However, further analysis indicated that a subgroup of participants with recently diagnosed ALS (within one year of symptom onset) might potentially benefit from the higher dose.
To validate these findings, the JETALS confirmatory Phase 3 study was conducted in 130 participants with recently diagnosed ALS (within one year of symptom onset) and moderate disease progression. Over 16 weeks, participants received either mecobalamin 50 mg or placebo twice per week via intramuscular injection. The study demonstrated that the group treated with a 50 mg dose of mecobalamin had a significantly different ALSFRS-R score at 16-weeks compared to the placebo group. None of the secondary endpoints (survival, respiratory function, muscle and grip strength, and others) reached statistical significance.
ALS clinicians in Canada and other countries are working to assess the evidence to understand how they will approach it for their patients. Of note, there is no evidence that Rozebalamin has any effect in individuals treated beyond a year of symptom onset. Rozebalamin is currently not approved for the treatment of ALS in any country outside of Japan.
Rozebalamin’s Mechanism of Action
Rozebalamin is composed of an ultra-high dose of vitamin B12. The exact mechanism of action of the drug is not known, but it is speculated that the therapy has a neuroprotective effect, reducing oxidative stress and cell death in the lab. It is important to emphasize that Rozebalamin is a very high dose of vitamin B12, injected intramuscularly, which is different from the lower oral doses found over the counter. In Canada, only injections of up to 1 mg may be available.
ALS Canada does not endorse or recommend any specific treatments. Please consult your ALS clinician for information and advice on specific treatments.
For more information on Vitamin B12 in ALS, access ALSUntangled’s review article.
Brainstorming ALS: Predicting Disease Onset in Asymptomatic Gene Variant Carriers
While researchers are still working to understand the exact causes of ALS, it is known that some cases are caused by a genetic variant (mutation). Several genes have been identified that, when altered, can contribute to disease. Pathogenic variants in a gene called C9orf72 are the most common genetic cause of both ALS and frontotemporal dementia (FTD).
Individuals with a variant in the C9orf72 gene who don’t show symptoms of ALS or ALS-FTD are called asymptomatic gene variant carriers. Not all carriers will develop the disease in their lifetime – the reasons why someone with a gene variant may or may not develop the disease are still being investigated by researchers. In a recent study by Dr. van Veenhuijzen et al., researchers studied brain scans of asymptomatic C9orf72 variant carriers to better understand and gain insights into when and how ALS or ALS-FTD develops.
Researchers found that variant carriers who developed the disease showed distinct brain atrophy (shrinkage) patterns up to six years before the onset of symptoms, compared to other asymptomatic carriers. Interestingly, the patterns were consistent among individuals who developed the disease, regardless of their gender, age of onset, or the location of their first ALS symptoms. However, it is important to note that the study sample size among those who developed ALS was very small. Larger studies with more individuals who develop the disease will be required to determine how widely these brain atrophy patterns may predict the underlying disease onset in C9orf72 and other forms of ALS and ALS/FTD.
These findings raise the question of whether it’s possible to predict disease development in gene variant carriers before symptoms even appear, and perhaps someday in individuals without an identifiable genetic risk of ALS or FTD. Additionally, the study supports the growing belief among researchers that initiating therapies earlier – during the presymptomatic phase of the disease – might be beneficial in slowing disease progression. On a similar note, the ATLAS study is investigating a therapy called tofersen in asymptomatic SOD1 gene carriers before they show any clinical symptoms of ALS. The results of this study will also provide greater insights into whether the early initiation of therapies can delay symptom onset or improve disease progression.
The authors suggest next steps for this research could include conducting further studies to correlate other biomarker measurements, such as neurofilament light (NfL) levels, to brain atrophy patterns and disease onset in this population and for other genetic variants. Additionally, further investigation of the specific areas of the brain that showed consistent atrophy patterns among presymptomatic carriers could provide insights into how ALS and ALS-FTD develops.
Tracking ALS: NfL as a Key Biomarker in ALS Clinical Trials
ALS is a heterogeneous disease, meaning people living with ALS will experience different symptom onsets and rates of progression. This variability poses significant challenges in ALS clinical trials, making it more difficult to measure whether, and to what extent, a potential therapy is working. To address this, researchers are working to validate standard biomarkers to track disease progression and measure responses to potential therapies. Biomarkers are biological measures that provide real-time insights into processes happening in the body and offer information about a person’s health status. As an example, the level of cholesterol in the blood can serve as a biomarker for the risk of heart disease.
Neurofilament light (NfL) is an essential building block of nerve cells, and elevated NfL levels in bodily fluids (such as blood or cerebrospinal fluid) can indicate damage or death of these cells. NfL is now recognized as one of the most important and useful biomarkers for ALS, and ongoing research is focused on understanding the various ways it can be used as a tool to improve clinical trials.
A recent study led by Dr. Benatar et al. investigated NfL levels as a prognostic biomarker for predicting ALS progression and survival. Researchers collected several biochemical and clinical measurements from people living with ALS who would typically be eligible for most clinical trials. They found that serum NfL (NfL levels in the blood) was the strongest predictor of disease progression. Lower serum NfL levels corresponded to slower declines on the ALS Functional Rating Scale-Revised (ALSFRS-R), a tool widely used for monitoring the progression of functional impairment in people living with ALS.
Notably, NfL levels were better at predicting progression than the ENCALS score, a commonly used tool that incorporates clinical, genetic, and cognitive variables to predict survival in people living with ALS. However, combining NfL levels with ENCALS scores was more accurate at predicting disease progression than using either measurement alone.
These findings support previous studies demonstrating the relevance and importance of including NfL levels in clinical trials. The study recommends incorporating NfL measurements, together with clinical predictors, in all ongoing and future ALS trials to measure the efficacy of potential therapies. Measuring NfL levels at the beginning of a clinical trial may also help to ensure the study is balanced (between fast and slow progressors, for example), leading to more accurate trial results.
Cell-ebrating Progress: Collaborative Data Sharing Is Driving ALS Research Forward
One of the greatest advancements in science over the past decade or so is the development of induced pluripotent stem cells (iPSCs), for which the inventors were awarded the Nobel Prize in Medicine in 2012. These cells make it possible to create essentially any cell type in the body using any other as a starting point. In ALS, iPSCs provide the opportunity to take skin or blood cells from someone living with the disease and turn them into motor neurons and other relevant cell types with the exact genetic makeup of the person donating them, so researchers can study ALS in the lab.
Answer ALS, in collaboration with Cedars-Sinai, recently announced that the largest repository of iPSCs for ALS will be available globally for all researchers to access. The repository also includes biological and clinical data from nearly a thousand people living with ALS. By studying iPSCs in the lab alongside additional clinical data from donors, researchers can gain a more comprehensive and accurate view of the disease. The repository will also provide iPSCs models with the ability to produce motor neurons in just seven to ten days, compared to the approximately 45 days typically needed to generate motor neurons from iPSCs, accelerating ALS therapeutic research.
The availability of this global repository marks a significant step forward in data sharing within the ALS research community. In Canada, ALS Canada has provided essential funding to CAPTURE ALS, a Canadian platform that is also collecting multiple measures of people living with ALS. In early 2025, data from CAPTURE ALS will also be made available to researchers worldwide, pushing forward Canada’s contribution to global ALS research.
These collaborative efforts in data sharing create opportunities to massively accelerate the development of effective treatments for the disease, bringing us closer to a world free of ALS.
UNC13A: Action Potential for ALS Treatment
Pathogenic variants (mutations) in the UNC13A gene have been identified as a significant risk factor for ALS. The UNC13A protein plays a crucial role in synaptic function, which is essential for neurons to communicate with each other and with muscles. Disruptions in the synapse are a hallmark of ALS. Another common pathological feature of most ALS is the dysfunction of the TDP-43 protein, which is critical for RNA processing and regulation. Recent research has shown that the loss of normal TDP-43 function negatively impacts UNC13A protein levels, leading to insufficient UNC13A in the synapse. This deficiency may contribute to disease progression.
In light of these findings, several pharmaceutical companies are currently focusing on therapies targeting UNC13A. Trace Neuroscience, Inc. recently announced a $101 million investment to develop treatments to restore normal UNC13A protein levels. Eli Lilly and Company (“Lilly”) is also investigating a potential UNC13A antisense oligonucleotide (ASO) therapy designed to enhance protein production.
Additionally, AcuraStem is also bringing an UNC13A ASO to clinical trials, supported by a $4 million grant from the California Institute for Regenerative Medicine (CIRM).
Although these potential therapies may take time to progress through clinical trials, restoring normal UNC13A levels could be critical for preserving or improving synaptic function in people living with ALS. The global focus and investment into targeting UNC13A represents a promising step toward developing effective treatments for the disease.
Questions about ALS research? Join us for ALS Research Clinicals Trials 101 Q&A: this monthly Q&A drop-in session is available for people living with ALS, their families, caregivers, and anyone close to someone living with the disease who is seeking information or might have questions about ALS research and/or clinical trials.
Want to learn more about current clinical research in Canada? Join ALS Canada for our next ALS Clinical Trials Unboxed webinar to hear a Canadian or international investigator talking about their clinical trial and research. Watch past Unboxed webinars here.