Understanding how effective is tofersen? A review of the SOD1-ALS treatment

October 8, 2025 •

4 min read

In a combined analysis of the VALOR trial and its open-label extension, starting tofersen earlier slowed the decline in clinical function, respiratory function, and muscle strength in SOD1-ALS patients compared to delayed initiation. This critical finding helps clarify how effective is tofersen beyond the initial trial results.

Quick Summary

Tofersen is an antisense oligonucleotide for SOD1-ALS that reduces toxic SOD1 protein and neurofilament levels. While its initial trial did not meet the primary endpoint, longer-term and real-world data demonstrate significant slowing of disease progression and functional decline in patients who receive early treatment.

Key Points

Biomarker Efficacy: Tofersen significantly reduces neurofilament light chain (NfL) and toxic SOD1 protein levels, key indicators of neuronal damage and the drug's mechanism of action.
Long-Term Functional Benefits: While the initial trial phase failed to meet its primary clinical endpoint, extended follow-up showed that early initiation of tofersen slowed the decline in clinical function, muscle strength, and respiratory capacity over 12 months.
Accelerated Approval: Tofersen received accelerated FDA approval based on its robust and consistent biomarker effects, with confirmatory studies ongoing.
Patient-Specific Response: The drug's effectiveness can vary depending on the individual's specific SOD1 mutation and their disease stage, with earlier treatment potentially leading to better outcomes.
Targeted Therapy: Tofersen is only indicated for the specific genetic form of ALS caused by an SOD1 mutation and does not benefit patients with other forms of the disease.
Potential for Pre-symptomatic Treatment: A new trial (ATLAS) is investigating whether starting tofersen in pre-symptomatic SOD1 mutation carriers can delay the onset of ALS.
Associated Risks: Common adverse events are often related to the lumbar puncture administration, while serious neurological events like myelitis and aseptic meningitis have also been reported, though less frequently.

The Mechanism Behind Tofersen's Action

Tofersen (brand name Qalsody) is an antisense oligonucleotide (ASO) designed specifically for amyotrophic lateral sclerosis (ALS) caused by a superoxide dismutase 1 (SOD1) gene mutation. This mutation leads to a toxic misfolded SOD1 protein that harms motor neurons. Tofersen is delivered into the cerebrospinal fluid (CSF) via intrathecal injection, reaching the motor neurons. It works by binding to SOD1 mRNA, triggering its degradation and reducing the toxic protein's production. This approach modifies the disease by targeting its genetic cause.

The VALOR Trial: Initial vs. Long-Term Results

The effectiveness of tofersen was evaluated in the Phase 3 VALOR clinical trial. The trial included a placebo-controlled phase followed by an open-label extension (OLE) where all participants received tofersen.

Initial 28-Week Phase

During the initial 28-week phase, tofersen did not meet the primary goal of improving clinical function in faster-progressing patients, as measured by the ALSFRS-R scale. However, it did show significant reductions in CSF SOD1 protein and plasma neurofilament light chain (NfL) levels compared to placebo. NfL is a marker of neuronal damage, suggesting the drug impacts the disease process.

Extended Analysis (52+ Weeks)

A longer-term analysis combining the VALOR trial and OLE over 12 months provided more clarity on tofersen's efficacy. Patients who started tofersen early experienced less decline in functional measures compared to those who started later. This indicates that tofersen's benefits may take time to appear and are greater with earlier treatment.

Real-World and Observational Evidence

Real-world data supports the clinical trial findings. An observational study of seven SOD1-ALS patients treated with tofersen showed sustained reductions in neurofilament biomarkers and apparent disease stabilization or mild functional improvements. Most patients in this study saw improved muscle strength and functional independence. These benefits can be sustained long-term, with one group reporting stability into the third year of treatment.

Comparison of Tofersen's Efficacy


Efficacy Metric	VALOR Trial (Initial 28 weeks)	VALOR OLE (Early vs. Delayed)	Real-World & Observational Data
Primary Endpoint (ALSFRS-R)	Failed to show significant clinical improvement versus placebo.	Significant difference favoring early start, with slower functional decline over 52 weeks.	Apparent stabilization or slight functional improvement in some patients.
Biomarkers (NfL)	Significant reduction in NfL vs. placebo.	Sustained reduction in NfL levels over 52 weeks.	Confirms sustained reduction in serum and CSF neurofilaments.
Muscle Strength	No significant difference versus placebo.	Significant difference favoring early start over 52 weeks.	Improvement in muscle strength observed in most patients.
Respiratory Function	No significant difference versus placebo.	Significant difference favoring early start over 52 weeks.	Slower decline or stabilization observed.
FDA Status	Did not meet primary endpoint, but biomarker data led to accelerated approval.	Long-term data supported accelerated approval and ongoing evaluation.	Supports findings from clinical trials.

Addressing Key Clinical Questions

Tofersen's effectiveness can be influenced by factors like the specific SOD1 mutation and the stage of the disease. Neurofilament biomarkers are helpful in assessing the drug's impact on neurodegeneration, even before clinical changes are obvious. The ongoing ATLAS study is investigating if tofersen can delay symptom onset in pre-symptomatic SOD1 carriers. It's crucial to note that tofersen is only for ALS caused by an SOD1 mutation and is not effective for other forms of the disease.

Safety and Side Effects

Tofersen is generally well-tolerated, but carries risks. Many common side effects are related to the intrathecal injection procedure, such as headache, pain during the procedure, and back pain. Less common but more serious adverse events require monitoring:

Myelitis and Radiculitis: Inflammation of the spinal cord or nerve roots, causing symptoms like back pain, numbness, tingling, and weakness.
Papilledema and Increased Intracranial Pressure: Swelling of the optic nerve and elevated pressure in the skull, with potential blurred vision, headache, and vomiting.
Aseptic Meningitis: Inflammation of the brain's protective layers, potentially causing fever, headache, stiff neck, and nausea.

Healthcare providers experienced with lumbar punctures administer tofersen, and patients are monitored for adverse effects.

Conclusion: The Overall Picture of Tofersen's Effectiveness

Tofersen has demonstrated effectiveness in adults with SOD1-ALS. Although the initial trial phase did not show a statistically significant clinical benefit over a short period, longer-term data indicates that early treatment significantly slows disease progression and functional decline. The sustained reduction in neurofilament biomarkers supports this, confirming the drug's mechanism. Early treatment appears crucial for maximum benefit. Ongoing studies, like ATLAS, are exploring its potential to delay disease onset. Tofersen's path to accelerated approval underscores the value of biomarkers and long-term data in evaluating therapies for rare genetic diseases.

For more information on the pivotal clinical trial, you can review the full study published in the New England Journal of Medicine.

Frequently Asked Questions

Tofersen is specifically for adults with amyotrophic lateral sclerosis (ALS) who have a confirmed mutation in the superoxide dismutase 1 (SOD1) gene.

Tofersen is administered via intrathecal injection, a spinal injection performed by healthcare professionals, with three initial doses followed by monthly maintenance doses.

No, the Phase 3 VALOR trial did not meet its primary endpoint of significant clinical improvement over a 28-week period, though positive biomarker results were observed.

The key evidence comes from long-term follow-up data (over 52 weeks) showing that early initiation of tofersen significantly slows the decline in clinical function, respiratory function, and muscle strength compared to delaying treatment.

NfL are biomarkers of neuronal damage. Tofersen consistently reduces plasma NfL levels, and this reduction correlates with slower disease progression, providing a strong biological indicator of the drug's effect.

The most common side effects include pain (back pain, pain in arms or legs), fatigue, arthralgia (joint pain), and myalgia (muscle pain). Many are related to the injection procedure itself.

No, tofersen's mechanism specifically targets the SOD1 gene and is only effective for SOD1-ALS. It will not benefit patients with other forms of ALS.

The FDA's decision was based largely on the significant reduction of NfL biomarkers, which was deemed 'reasonably likely to predict clinical benefit,' with additional studies required to confirm the clinical benefit.

Yes, the ATLAS study is currently evaluating whether early treatment with tofersen in pre-symptomatic SOD1 mutation carriers with elevated NfL levels can delay the onset of clinical symptoms.