The Evolving Landscape of ALS Treatment
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that attacks nerve cells in the brain and spinal cord, leading to loss of muscle control [1.5.5]. For decades, treatment options were extremely limited. The first drug, Riluzole (Rilutek), was approved in 1995 and works by reducing levels of the chemical messenger glutamate, which is thought to damage nerve cells [1.6.1, 1.6.2]. It wasn't until 2017 that the next drug, Edaravone (Radicava), was approved, which functions as an antioxidant to combat oxidative stress [1.5.1]. The pace of therapeutic development has accelerated recently, bringing new hope and more complex treatment decisions for patients and clinicians.
A New Era of Targeted Therapy: Qalsody (tofersen)
The most significant recent approval in the fight against ALS is Qalsody (tofersen), which received accelerated FDA approval in April 2023 [1.3.2]. This marked a pivotal moment, as Qalsody is the first gene-based therapy available for a specific form of ALS.
Mechanism of Action
Qalsody is an antisense oligonucleotide (ASO) [1.3.1]. ASOs are synthetic strands of genetic material that can alter the expression of messenger RNA (mRNA) [1.3.1]. In the case of Qalsody, it targets the mRNA produced from a mutated superoxide dismutase 1 (SOD1) gene [1.3.2]. This mutation, which accounts for about 2% of all ALS cases, produces a toxic form of the SOD1 protein that damages motor neurons [1.3.1, 1.8.3]. By binding to and causing the degradation of the SOD1 mRNA, Qalsody reduces the production of this harmful protein [1.3.3].
Efficacy and Patient Eligibility
The accelerated approval was based on Qalsody's effect on a biomarker: plasma neurofilament light chain (NfL), which is an indicator of nerve injury and degeneration [1.3.2]. Clinical trials showed that patients treated with Qalsody had significant reductions in NfL levels compared to a placebo group [1.8.3]. While the primary goal of slowing functional decline wasn't met in the initial 28-week trial, a follow-up study showed that earlier initiation of the drug led to a noticeable deceleration in the decline of clinical function, respiratory function, and strength [1.3.1].
Qalsody is specifically indicated only for adult patients with ALS who have a confirmed SOD1 mutation [1.3.4]. It is administered intrathecally—via a lumbar puncture (spinal tap)—by a healthcare professional. The regimen starts with three loading doses at 14-day intervals, followed by a maintenance dose every 28 days [1.3.2].
A Recent Development: The Discontinuation of Relyvrio
Approved by the FDA in September 2022, Relyvrio (sodium phenylbutyrate and taurursodiol) was another promising option for a broader range of ALS patients [1.2.1]. It was an oral powder combination believed to protect nerve cells from death by reducing stress in the endoplasmic reticulum and mitochondria [1.4.1, 1.4.2].
However, in March 2024, the confirmatory Phase 3 PHOENIX trial failed to show a significant benefit over a placebo. Following these results, its developer, Amylyx Pharmaceuticals, announced it was voluntarily withdrawing Relyvrio from the market in the U.S. and Canada [1.4.3]. This was a significant and disappointing development for the ALS community, as the drug had shown promise in earlier trials by slowing functional decline and extending survival [1.4.3].
Comparison of Modern ALS Medications
With the latest changes, the landscape of FDA-approved ALS drugs consists of three primary therapies, each with a unique profile.
| Drug Name (Brand) | FDA Approval (Initial) | Mechanism of Action | Administration | Key Benefit Claimed |
|---|---|---|---|---|
| Riluzole (Rilutek) | 1995 | Reduces glutamate release, preventing nerve damage [1.6.1, 1.6.2]. | Oral tablet, liquid, film [1.6.2] | May extend survival by 2-3 months [1.6.1]. |
| Edaravone (Radicava) | 2017 | Antioxidant that scavenges free radicals to reduce oxidative stress [1.5.1]. | IV infusion, oral liquid [1.5.1] | Slowed decline in daily functioning by 33% in trials [1.5.1]. |
| Tofersen (Qalsody) | 2023 | Antisense oligonucleotide that reduces the production of toxic SOD1 protein in patients with an SOD1 mutation [1.3.2]. | Intrathecal injection [1.3.2] | Reduces biomarker of nerve damage (NfL) [1.3.2]. |
The Future: What's in the Pipeline?
The search for more effective ALS treatments is incredibly active. As of 2025, numerous companies are advancing new therapies through the clinical trial pipeline [1.7.2]. Some promising approaches include:
- Gene Therapies: Beyond SOD1, researchers are developing ASOs and other genetic approaches for different forms of ALS, such as those linked to FUS and C9orf72 gene mutations. Ionis Pharmaceuticals, which co-developed Qalsody, has a drug called ulefnersen for FUS-ALS in Phase 3 trials [1.7.2].
- Stem Cell Therapies: Companies like BrainStorm Cell Therapeutics are in late-stage trials for therapies that use mesenchymal stem cells (NurOwn) to deliver neuroprotective factors to the spinal cord [1.11.2, 1.11.4].
- Targeting New Pathways: Researchers are exploring novel mechanisms like inflammation and cellular waste disposal. For example, Verge Genomics is testing VRG50635, a drug discovered using AI that inhibits a protein called PIKfyve [1.7.2]. NeuroSense Therapeutics' PrimeC, a combination of two existing drugs, is also in a pivotal Phase 3 study [1.7.2, 1.11.3].
Conclusion
While there is still no cure for ALS, the approval of Qalsody (tofersen) represents a landmark achievement in precision medicine for a genetic form of the disease. It underscores a new direction for drug development focused on underlying genetic causes. Although the recent withdrawal of Relyvrio was a setback, the drug development pipeline remains robust and diverse, exploring multiple new mechanisms of action. The progress offers tangible hope that more effective and personalized treatments will continue to emerge, slowing progression and improving the quality of life for all people living with ALS.
For more information on ongoing research, a valuable resource is the ALS Association.
