Setbacks and New Hope in the Fight Against a Devastating Disease
The past few years have been an emotional roller coaster for the ALS community. Just as hope emerged with new drug approvals, devastating setbacks followed—most notably the market withdrawal of Amylyx's Relyvrio after it failed to outperform a placebo in confirmatory trials.
This disappointment came alongside failures of candidates from established players like Sanofi and Denali Therapeutics. Yet, within this cycle of progress and setback, a resilient research community is pushing forward with innovative science. A new wave of therapies, powered by cutting-edge technologies like artificial intelligence and genetic medicine, suggests the field may be on the brink of a renaissance, offering fresh hope for patients facing this relentless disease.
Average survival after diagnosis
Average time to diagnosis
Patients with SOD1 mutation eligible for Qalsody
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the progressive paralysis of voluntarily innervated muscles, typically causing death from respiratory failure within an average of three years. Its causes remain largely unknown, though the misfolded protein TDP-43 is known to spread through the brain and spinal cord, a hallmark of the disease.
Diagnosing ALS is a complex process that can take 10 to 18 months on average. It involves a comprehensive neurological examination to identify signs of both upper and lower motor neuron dysfunction, electromyography (EMG) to assess the integrity of lower motor neurons, and a series of tests to rule out other conditions.
For decades, therapeutic options have been desperately limited. In Europe, riluzole—a glutamate antagonist that marginally prolongs survival by about three months—remains the only approved drug. The recent withdrawal of one of the few marketed therapies, Relyvrio, dealt a heavy blow to patients who have very minimal options.
Despite the setbacks, research is advancing on multiple fronts. Scientists now recognize that ALS, like cancer, is not a single disease but a heterogeneous condition comprising many patient subtypes. This understanding is driving a more personalized approach to treatment.
"We're seeing not only slowing of disease, but in a number of patients we're actually seeing frank reversal of disease," noted Eric Green, CEO of Trace Neuroscience.
A significant bright spot has been the success of Biogen's Qalsody, an antisense oligonucleotide approved for the 2% of ALS patients with a SOD1 gene mutation. This success has become a catalyst for developing similar genomic medicines for the broader ALS population.
| Company/Initiative | Therapeutic Approach | Key Mechanism of Action | Development Stage |
|---|---|---|---|
| Trace Neuroscience | Antisense oligonucleotide (ASO) | Restores RNA splicing of UNC13A gene, a protein lost in nearly all ALS patients 1 9 | Preclinical |
| Coya Therapeutics | Biologic (COYA 302) | Enhances function of regulatory T cells (Tregs) to suppress neuroinflammation 1 8 | Phase II |
| Korro Bio | RNA-editing therapy | Makes a single protein change to keep TDP-43 in the cell nucleus 1 | Discovery |
| Eikonizo Therapeutics | Small molecule (EKZ-102) | Highly selective HDAC6 inhibitor to improve neuronal transport and reduce inflammation 2 | Preclinical |
| Clene Nanomedicine | Nanocrystal suspension (CNM-Au8) | Oral gold nanocrystals that increase cellular energy production 8 | Seeking Approval (2025) |
Targeting specific genetic mutations like SOD1 and developing approaches for broader patient populations with UNC13A restoration.
Developing novel compounds that target neuroinflammation, cellular energy production, and protein aggregation.
To understand the complexities of ALS drug development, it is helpful to examine a specific clinical trial. The RAS-ALS study was a randomized, double-blind, placebo-controlled trial investigating rasagiline—a monoamine oxidase B (MAOB) inhibitor—as an add-on therapy to riluzole in 252 ALS patients.
The 18-month trial, conducted across 15 German specialty centers, was designed with strict inclusion criteria. Participants had to have definite, probable, or possible ALS, with disease progression starting within 36 months and a disease duration of over 6 months but under 3 years. All participants were already on a stable dose of riluzole.
The primary goal was to evaluate the effect of 1 mg of rasagiline per day on survival. Researchers also tracked functional decline using the ALS Functional Rating Scale-Revised (ALSFRS-R), a standard measure of patient function.
The primary endpoint of the trial was negative; rasagiline did not significantly improve survival for the entire study population at 18 months. However, exploratory analysis revealed a crucial finding: the drug appeared to work for a specific subset of patients.
Researchers discovered that the placebo group included patients with very slow disease progression (losing ≤0.328 points per month on the ALSFRS-R before randomization). This subgroup had such a high survival probability (0.85 after 24 months) that it was difficult for any drug to show a statistical benefit. When the analysis focused on the larger group of intermediate-to-fast progressors, the results changed dramatically.
| Outcome Measure | Time Point | Result (Rasagiline vs. Placebo) | P-value |
|---|---|---|---|
| Survival | 6 months | Prolonged survival | 0.02 |
| Survival | 12 months | Prolonged survival | 0.04 |
| ALSFRS-R Decline | 18 months | Reduced functional decline | 0.049 |
This data underscores a critical lesson for future ALS studies: very slow progressors can compromise the statistical power of trials, and patient stratification is essential. The genetic analysis, while not conclusive, suggested a potential benefit for patients with a specific DRD2 genotype (Rs2283265, CC), pointing toward a future of precision medicine for ALS.
The fight against ALS relies on a suite of sophisticated research tools and collaborative resources that enable scientists to study the disease and test new therapies.
| Tool/Resource | Function in ALS Research | Example/Source |
|---|---|---|
| Induced Pluripotent Stem Cells (iPSCs) | Generate patient-specific motor neurons and other brain cells from skin or blood cells to study disease mechanisms and test drugs 7 . | Target ALS Stem Cell Core 7 |
| Multi-omics Datasets | Integrate genomics, transcriptomics, and proteomics data to find disease patterns and drivers across diverse patient subtypes 1 2 . | Answer ALS database 1 |
| Artificial Intelligence (AI) | Analyzes massive, complex datasets to identify new therapeutic targets and biomarkers at unprecedented speed 1 2 . | GATC Health, Longitude Prize 1 2 |
| Lipid Nanoparticles (LNPs) | Safely and efficiently deliver therapeutic mRNA to the brain, a major hurdle for treating neurodegenerative diseases 2 . | Research from University of Pennsylvania 2 |
| Biobanks & Real-World Data | Large collections of biological samples and clinical data (voice, wearables, blood) that provide a holistic picture of ALS progression 2 . | ALS TDI's ARC Study 2 |
Collaboration is the cornerstone of this toolkit. Initiatives like the Target ALS Stem Cell Core provide iPSCs to researchers worldwide with no intellectual property restrictions, while the Longitude Prize on ALS is an £8 million global competition using AI to find new targets. "By sharing insights openly... ALS TDI is helping the entire research community use these data," notes one report, highlighting the field's commitment to open science 2 .
Shared databases accelerate discovery across research institutions
Patient-derived cells enable personalized drug testing
Machine learning identifies patterns invisible to human analysis
While new treatments are vital, a parallel breakthrough could transform the entire fight against ALS: early detection. A landmark study published in Nature Medicine in August 2025 revealed that signals associated with ALS can be detected in the blood years, even a decade, before symptoms appear.
Using advanced proteomics to analyze thousands of proteins at once, an international team including scientists from the Uniformed Services University identified a distinct molecular signature in people who would later develop ALS. Their machine-learning model distinguished ALS patients from healthy individuals and those with other neurological conditions with over 98% accuracy 5 .
"If clinicians can identify ALS long before symptoms appear, they may one day intervene earlier, slow disease progression, and extend lives," said Dr. Clifton L. Dalgard, a senior author on the paper 5 .
This discovery promises a future where a simple blood test could allow diagnosis long before significant motor neuron loss occurs. Such a test would also be invaluable for enrolling at-risk individuals in preventive clinical trials.
Accuracy of predictive model
10-18 month delay from symptom onset to confirmed diagnosis through clinical examination and elimination of other conditions.
Identification of biomarkers in cerebrospinal fluid and blood that may shorten diagnostic time to 6-12 months.
Pre-symptomatic detection through blood tests years before symptoms appear, enabling early intervention.
The path to defeating ALS is undeniably difficult, marked by both "another blow" and inspiring resilience. The withdrawal of a promising drug is a painful reminder of the disease's complexity. Yet, the current research landscape is more vibrant and collaborative than ever before.
The field is moving away from a one-size-fits-all approach and toward precision medicine, developing targeted therapies for specific patient subtypes. The tools of AI, multi-omics, and stem cell technology are breaking down old barriers. As one researcher put it, the ability to generate and analyze complex data is like "going from the cart and buggy to a rocket" 1 .
For patients and their families, this evolving story is not just about scientific progress—it's about the tangible hope for more effective treatments and a future where ALS can be detected early and managed effectively. The journey is far from over, but the collective effort of scientists, patients, and advocates continues to push forward, turning setbacks into stepping stones toward a cure.
References will be added here manually in the future.