Finding new treatments for ALS patients: a look at the late-stage pipeline

Last weekend I attended a photo exhibition in Málaga, Spain, (sponsored by Cinfra), of portraits of individuals living with different chronic diseases. I was particularly drawn to the photo of the Spanish journalist, author, and footballer Carlos Matallanas, who was diagnosed with the rare disease, amyotrophic lateral sclerosis (ALS) in 2013, and passed away in 2021. He wrote extensively about his experiences living with ALS in the Spanish newspaper El Confidencial and was an inspiring advocate for the Spanish ALS community. In his photo he is shown receiving physiotherapy, his breathing aide rests by his side, and he radiates confidence and energetic positivity. For me this was a powerful reminder of the strength of ALS patients as they deal with their condition. And without question, it drew my attention to how much further we need to go in bringing new treatments to those affected. Inspired by his story, this article examines the late-stage drug pipeline for ALS to see what approaches are being investigated. (1,2)

Disease complexity drives the challenge of finding effective treatments

Before looking at the emerging therapies, we need to reflect on why ALS has proven so difficult to treat. Whilst much work is still ongoing to understand the causes of the disease, the prevailing view is that multiple factors are at play: 

Excitotoxicity caused by excessive glutamate overstimulation of neurons

Oxidative stress driven by an imbalance in reactive oxygen species 

Dysfunctional mitochondria 

Protein aggregation, particularly of TDP-43 

Chronic neuroinflammation mediated by activated microglia and astrocytes

Genetic mutations e.g., in C9orf72, SOD1, FUS and TARDBP

Environmental triggers e.g., exposure to toxins, physical trauma

These different mechanisms suggest that in the future, treatment of the disease may require multiple therapies targeting different causes and manifestations of the disease. 

Late-Stage Pipeline Overview

In preparing this article I reviewed the late-stage pipeline of treatments with information from Clinical Trials.gov as well as review papers. From my analysis, the pipeline breaks down as follows:

Table: Number of investigational drugs in the late stage pipeline for ALS. (Sources: 3, 4, 5)

My top level observations are:

A lot of activity underway to establish clinical proof of concept: As we can see from the table, there are many trials currently in Ph2, which for a rare disease is extremely promising. Notwithstanding, this places great pressure on drug developers to find enough patients to participate in these trials.

A wide variety of drug targets and mechanisms of action: which aligns well to the need to have multiple therapies that can address different aspects of the disease. Examples include cell therapies, immunotherapies, anti-protein aggregation and neuroprotective agents.

Early Access Programs (EAPs) available: Many drug developers have established EAPs alongside their formal clinical trials to enable patients access to the treatment if they have not been able to register in the study. This is a very welcome option for patients who are subject to this rapidly evolving disease.

Continued high rate of failure in late-stage trials: Frustratingly many late-stage candidates are continuing to fail in their clinical studies. For example, just two weeks ago it was announced that both Fosigotifator and DNL343 (both of which are eIF2B activators) failed to meet key end points on slowing disease progression and survival in the Ph2/3 HEALEY study. (6)

 A closer look ...

Given the large number of candidates in the pipeline, it is not possible to explore them all here. Therefore, below I cover some of the most advanced drugs across different classes to get a feel of what each may be able to offer as well as upcoming milestones to watch out for:

Macitinib

• Mechanism of Action: Macitinib is a tyrosine kinase inhibitor that targets microglia, macrophage, and mast cell activity, in the central and peripheral nervous systems, reducing neuroinflammation and oxidative stress
• Developer: AB Science
• Stage: Phase III 
• Next milestone: Potential launch 2027 
• Clinical Data: From its Ph2/3 study, masitinib in combination with riluzole demonstrated a significant delay (-27%) in disease progression. For patients with mild or moderate disease severity at baseline, with masitinib as an add-on to riluzole survival was observed to be 25 months greater relative to those treated with riluzole alone, with a 44% reduced risk of death (7)

ION363

• Mechanism of Action: ION363 is an antisense oligonucleotide (ASO) therapy designed to silence the FUS gene mutation and reduce the loss of motor neurons, a driver of familial ALS. In this sense, ION363 has the potential to target the root cause of the disease. FUS mutations account for 4.0–6.0% of familial ALS cases and 0.7–1.8% of sporadic cases
• Developer: Ionis Pharmaceuticals, Otsuka
• Stage: Phase III 
• Next milestone: Primary completion in Jun 2026
• Clinical Data: Data comes from studying ION363 in a single patient, in which there were no severe side effects. However, the patient died after one year from having initiated ION363. Post mortem data showed significant reduction in FUS protein aggregates in neurons and penetration of ION363 penetration into the CNS (5, 8)

PrimeC 

• Mechanism of Action: PrimeC is a fixed dose combination of ciprofloxacin and celecoxib. Ciprofloxacin is a widely used fluoroquinolone antibiotic that can also regulate microRNA and gene expression. Celecoxib is a selective COX-2 inhibitor and a nonsteroidal anti-inflammatory drug. Collectively the drug is expected to target multiple pathways reducing oxidative stress, impair toxic protein aggregation, and reduction of neuroinflammation
• Developer: Neurosense Pharmaceuticals
• Stage: Phase IIb complete
• Next milestone: PhIII expected to begin mid-25
• Clinical Data: From the Ph2B study, 12 months of treatment with PrimeC was associated with a significant, 36% slowing of disease progression compared with those who started on a placebo (as per ALSFRS-R score). The patients on PrimeC for a year also showed a 43% survival benefit relative to those first on a placebo (9)

Ibudiliast (MN-166)

• Mechanism of action: MN-166 a glial attenuator that suppresses pro-inflammatory cytokines IL-1ß, TNF-a, and IL-6, and may upregulate the anti-inflammatory cytokine IL-10. It has additionally been shown to be a toll-like receptor 4 (TLR4) functional antagonist that may contribute to its attenuation of neuroinflammation 
• Developer: Medicinova
• Stage: Ph II/III
• Next milestone: Primary completion Dec 2025
• Clinical data: appears to slow disease progression over up to one year of use based on interim results from Ph III study (assessed by correlations at 6 and 12 months on Combined Assessment of Function and Survival scores) (10)

Back to the Patient

Returning to Carlos Matallanas, the journalist mentioned at the beginning of this article, who lived with and wrote extensively about ALS. He was a passionate believer in the power of science and the role of clinical trials to fundamentally address ALS. Knowing full well that his participation in a trial may not necessarily save him or others, he wrote:  

“[…] my profound conviction that what is really important is that the clinical trials are completed and that the scientists can draw conclusions and find solutions. This is the only relevant thing and that can truly save lives (those of everyone, not just my own).” (2)

Taking heart from these words, we must continue the search and press on.  

Contact

If you are interested in discussing any of the issues above for your company/drug development program, please contact me through my email address dniven@nivenbiopharma.com. Feel free to also visit my website at www.nivenbiopharma.com for more information. I have no conflicts of interest in the production of this article.

Sources:

1. La Mirada del Paciente, Cinfa, www.cinfa.com
2. Mi batalla contra la ELA, Matallanas, El Confidencial
3. Clinical Trials.Gov, accessed Jan 25
4. Drug developer websites, accessed Jan 25
5. Evaluating emerging drugs in phase II & III for the treatment of amyotrophic lateral sclerosis Li et al, Expert Opinion on Emerging Drugs 2024
6. DNL343, fosigotifator fail HEALEY platform trial’s main goal in ALS, ALS News Today, Shapiro, 2025
7. AB Science (investor report), Loza, Inexos, Mar 24 
8. FUS mutation is probably the most common pathogenic gene for JALS, especially sporadic JALS, Chen, Revue Neurologique, 2021
9. PrimeC continues to slow ALS disease progression: One-year trial data, Shapiro, ALS News Today, Jul 24
10. MN-166 may slow ALS progression over year, trial data suggest, Maia, ALS News Today, Dec 24