Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a challenging and progressive condition that affects nerve cells in the brain and spinal cord (Hardiman et al., 2017). These nerve cells, called motor neurons, control voluntary muscles. As motor neurons degenerate, muscles weaken, leading to difficulty with speaking, swallowing, breathing, and movement.

For many years, there were limited treatment options for ALS. However, thanks to dedicated research, there is renewed hope on the horizon. While we still lack a cure, scientists are making progress in developing therapies that can help slow the disease's progression. These are known as disease-modifying therapies.

What are Disease-Modifying Therapies?

Unlike treatments that only help manage symptoms (like muscle cramps or difficulty sleeping), disease-modifying therapies aim to impact the underlying processes causing the disease. In ALS, this means trying to protect motor neurons or slow their degeneration. These therapies don't stop the disease entirely, but they can potentially extend survival or slow the loss of function, offering valuable time and improved quality of life.

Currently Approved Disease-Modifying Therapies for ALS

As of late 2023 and early 2024, there are a few disease-modifying therapies approved by regulatory bodies like the U.S. Food and Drug Administration (FDA) and in other countries (Tzeplaeff et al., 2023; Jiang et al., 2022; Izenberg, 2023). These include:

Riluzole (brand names include Rilutek, Tiglutik, Exservan)
Edaravone (brand names include Radicava, Radicava ORS)
Sodium Phenylbutyrate and Taurursodiol (brand name Relyvrio, formerly known as AMX0035)
Tofersen (brand name Qalsody, specifically for ALS with a SOD1 gene mutation)

Let's look at each of these in more detail.

Riluzole

Riluzole was the first drug approved for ALS, decades ago.

How it works: It's thought to work by reducing damage to motor neurons caused by excess glutamate, a chemical messenger in the brain and spinal cord (Jaiswal, 2019).
What the studies show: Riluzole has been shown to modestly extend survival. Population studies suggest a survival benefit of 6–19 months, while clinical trials indicated it could prolong median survival by about two to three months and increase the probability of surviving one year by about 9% (Miller et al., 2012; Supporting Info). The benefit can be influenced by factors like the location of symptom onset (e.g., limbs vs. bulbar) and when treatment is started relative to diagnosis (Fávero et al., 2017).
How it's administered: Riluzole is typically taken by mouth as a pill or liquid suspension.
Side effects: Common side effects can include liver enzyme elevation, dizziness, and gastrointestinal issues. Regular monitoring of liver function is important.

Riluzole offers a modest but meaningful benefit and remains a standard part of ALS care for many patients.

Edaravone (Radicava, Radicava ORS)

Edaravone is a newer therapy, first approved in 2015 in some regions and later in the U.S. in 2017.

How it works: Edaravone is a potent antioxidant. It's believed to reduce oxidative stress, a process that can damage cells, including motor neurons. It may also play a role in preventing a type of cell death called ferroptosis (Jaiswal, 2019; Spasić et al., 2020).
What the studies show: Clinical trials showed that edaravone could slow the decline in physical function (measured by the ALS Functional Rating Scale-Revised or ALSFRS-R score) in certain patients, particularly those in earlier stages of the disease (Jaiswal, 2019; Johnson et al., 2022). However, a large real-world study published in 2022 did not find a significant disease-modifying benefit compared to standard therapy alone (Witzel et al., 2022).
How it's administered: Edaravone was initially only available as an intravenous (IV) infusion, given in treatment cycles over several weeks. More recently, an oral suspension (Radicava ORS) has become available, offering a more convenient option (Izenberg, 2023).
Side effects: Potential side effects include bruising, gait disturbance, headache, and allergic reactions.

Edaravone represents a different approach to targeting ALS pathology and may offer benefits for some patients, particularly when started early.

Sodium Phenylbutyrate and Taurursodiol (Relyvrio, AMX0035)

This combination therapy received approval in Canada in 2022 and accelerated approval in the U.S. in September 2022.

How it works: The drug, formerly known as AMX0035, is a combination of two compounds: sodium phenylbutyrate and taurursodiol. It is designed to target stress signals within the endoplasmic reticulum (ER) and mitochondria, which are essential parts of cells involved in energy production and protein handling. By reducing stress in these cellular components, it aims to protect motor neurons (Supporting Info; Paganoni et al., 2020).
What the studies show: A clinical trial (CENTAUR) involving patients with recent ALS onset demonstrated that the drug slowed the rate of functional decline as measured by the ALSFRS-R score over a 24-week period compared to placebo (Paganoni et al., 2020). Analysis combining trial data suggested a longer survival time for patients who received the drug (Johnson et al., 2022).
How it's administered: It is taken orally as a powder mixed with water or administered via feeding tube.
Side effects: The most common side effects are gastrointestinal, such as diarrhea, abdominal pain, and nausea.

Relyvrio offers another potential option to slow functional decline and potentially extend survival, targeting different cellular pathways than previous therapies.

Tofersen (Qalsody)

Approved in the U.S. under accelerated approval in April 2023, Tofersen is a significant development as it targets a specific genetic cause of ALS.

How it works: Tofersen is an antisense oligonucleotide. This means it's designed to interfere with the genetic instructions that cells use to make a specific protein. In this case, Tofersen lowers the amount of superoxide dismutase 1 (SOD1) protein, which is produced in excess or in a faulty form in people with SOD1 gene mutations (Everett & Bucelli, 2024).
What the studies show: While the initial Phase 3 trial didn't meet its primary endpoint for functional improvement over a specific timeframe, it showed significant reductions in SOD1 protein levels and a marker of nerve damage (neurofilament light chain). Data from an open-label extension study suggested that starting Tofersen earlier slowed the decline in function and strength (Everett & Bucelli, 2024).
Who it's for: Tofersen is specifically for people with ALS who have a confirmed mutation in the SOD1 gene. Genetic testing is necessary to determine eligibility.
How it's administered: It is given via intrathecal injection (into the fluid surrounding the spinal cord) by a healthcare professional.
Side effects: Common side effects include pain (including back pain), fatigue, joint pain, and increased white blood cell count in the spinal fluid.

Tofersen is a groundbreaking step towards personalized medicine in ALS, offering a targeted therapy for a specific genetic form of the disease.

What Families Should Know

These therapies offer hope, not a cure: It's important to have realistic expectations. While these drugs can slow progression and potentially extend survival, they do not reverse the damage already done or stop the disease entirely.
Comprehensive care is key: Disease-modifying therapies are just one part of managing ALS. A comprehensive care team, including neurologists, physical therapists, occupational therapists, speech-language pathologists, respiratory therapists, dietitians, and social workers, is vital for managing symptoms and maintaining quality of life (Hardiman et al., 2017; Lynch, 2023). Symptomatic treatments for issues like spasticity, pain, difficulty swallowing, or breathing are crucial.
Discuss options with your doctor: Choosing the right therapy depends on individual circumstances, including the stage of the disease, overall health, potential side effects, and specific genetic factors (like with Tofersen). Your neurologist is the best resource to discuss which treatment options might be appropriate for you or your loved one.
Research is ongoing: The field of ALS research is rapidly evolving. Scientists are exploring many other potential therapies targeting various mechanisms thought to contribute to ALS, including gene therapies and other novel approaches (Amado & Davidson, 2021; Lynch, 2023; Jiang et al., 2022). Clinical trials are continuously evaluating new treatments.

The Path Forward

The existence of multiple approved disease-modifying therapies represents significant progress in the fight against ALS. While challenges remain, including the heterogeneity of the disease and the need for more effective treatments, the expanding understanding of ALS biology and the development of targeted therapies like Tofersen offer genuine reasons for optimism. The active research pipeline and the commitment of the ALS community fuel the hope that even more impactful treatments will emerge in the future.

References

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Everett, W. H., & Bucelli, R. C. (2024). Tofersen for SOD1 ALS. Current Opinion in Neurology, 37(1), 105–110.

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Spasić, S., Nikolić-Kokić, A., Miletić, S., Oreščanin-Dušić, Z., Spasić, M. B., Blagojević, D., & Stević, Z. (2020). Edaravone May Prevent Ferroptosis in ALS. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration, 21(sup1), 66–69.

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Hope on the Horizon: New Disease-Modifying Treatments for ALS