Tofersen: The Antisense Drug for SOD1 Amyotrophic Lateral Sclerosis

Table of Contents

1. Tofersen at a Glance
2. SOD1 Amyotrophic Lateral Sclerosis and How Common It Is
3. How an Antisense Drug Lowers SOD1
4. Getting the Drug Into the Spinal Fluid
5. The First Human Trial
6. VALOR: The 28-Week Placebo-Controlled Trial
7. The Open-Label Extension: Earlier Versus Later Start
8. Accelerated Approval Based on Neurofilament
9. Results Outside the Trials
10. ATLAS: Starting Before Symptoms Appear
11. Label Warnings: Spinal Cord, Nerve Root, Brain Pressure and Meningitis
12. Common Side Effects and Spinal Fluid Changes
13. Pregnancy, Breastfeeding, Children and Older Adults
14. What Is Not Known
15. Key Research Papers
16. Connections
17. Featured Videos

Tofersen at a Glance

• What it is: an antisense oligonucleotide, a short single strand of chemically modified genetic letters. The U.S. label describes it as a 20-letter strand.
• What it is approved for: amyotrophic lateral sclerosis in adults who have a variant in the SOD1 gene. The label states that this approval is an accelerated approval based on a reduction in plasma neurofilament light chain, and that continued approval may depend on confirmatory trials showing clinical benefit.
• U.S. approval: April 2023, as a German study of the drug records; the label lists 2023 as the year of first U.S. approval. The European Medicines Agency has also approved it, as a 2026 multicentre study from Central Eastern Europe and a 2026 review both report.
• How it is given: by lumbar puncture into the spinal fluid. The label gives 100 mg (15 mL) per dose: three starting doses 14 days apart, then one dose every 28 days.
• Label warnings: inflammation of the spinal cord (myelitis) and of the spinal nerve roots (radiculitis), swelling of the optic nerve head (papilledema) and raised pressure inside the skull, and aseptic meningitis. The label lists no contraindications.
• Main evidence: a phase 1–2 dose-finding trial, the phase 3 VALOR trial and its open-label extension, a growing set of reports from clinics in Germany, Italy, France, the United States and Iceland, and an autopsy study of eight people who had been treated.

SOD1 Amyotrophic Lateral Sclerosis and How Common It Is

The SOD1 gene carries the instructions for superoxide dismutase 1, an enzyme that clears a reactive form of oxygen inside cells. Its normal role, and its dependence on copper and zinc, are covered on the Superoxide Dismutase and Copper for Antioxidant Defense pages.

How large a share of amyotrophic lateral sclerosis comes from SOD1 variants depends on who is counted:

• The 2026 long-term VALOR report and a 2026 review in the European Journal of Pharmaceutical Sciences both state that approximately 2% of all amyotrophic lateral sclerosis cases are attributable to a disease-causing variant in the SOD1 gene.
• A 2018 laboratory paper states that SOD1 variants are responsible for 20% of familial (inherited) amyotrophic lateral sclerosis.
• A 2026 study across six Central Eastern European countries found 24 distinct disease-causing SOD1 variants in 67 of 1,200 people with confirmed amyotrophic lateral sclerosis. Of those 67, 65.7% had a family history of the disease and 34.3% did not. A SOD1 variant can therefore turn up in a person with no known affected relatives.
• VALOR itself enrolled people carrying 42 different SOD1 variants.

Researchers describe SOD1 amyotrophic lateral sclerosis as a disease of a harmful new property of the altered protein rather than a simple loss of the enzyme. The 2018 paper puts it this way: given the gain of toxic function in this dominantly inherited disease, lowering SOD1 messenger RNA and protein is predicted to provide benefit. A 2026 review describes the altered protein as prone to misfolding and clumping together (aggregation). That reasoning is the whole basis of the drug: if the harmful protein is the problem, making less of it might slow the damage.

How an Antisense Drug Lowers SOD1

A gene is copied into a working message, messenger RNA, and the cell reads that message to build a protein. An antisense oligonucleotide is a short strand built to match one stretch of one message, the way one side of a zipper matches the other. The U.S. label states that tofersen binds SOD1 messenger RNA and causes it to be broken down, which reduces how much SOD1 protein the cell makes.

A 2024 review of every antisense drug approved by the FDA groups tofersen with the drugs that work by the first of three known routes: the strand pairs with its target message and a cell enzyme called RNase H then cuts that message. The label describes the chemistry: a 20-letter "gapmer" with five protected letters at each end flanking a central gap of ten. The 2024 review notes that such chemical changes stabilize antisense drugs and make them resistant to enzymes that break down genetic strands.

The label describes tofersen as binding SOD1 messenger RNA and does not describe it as telling the variant copy of the gene apart from the normal copy.

The animal work that led to the drug:

• In a 2018 study, next-generation SOD1 antisense strands extended survival by more than 50 days in rats and by almost 40 days in mice that carry a human disease-causing SOD1 variant.
• In the same study, in mice, an early loss of the electrical response of muscle to nerve stimulation was reversed after a single dose, and a rising blood marker of nerve-fibre damage (phosphorylated neurofilament heavy chain) stopped rising.

These were animal results. The authors concluded that the compound was ready for a human trial.

Getting the Drug Into the Spinal Fluid

Tofersen is placed directly into the cerebrospinal fluid, the clear fluid that bathes the brain and spinal cord. The procedure is called intrathecal injection. The label states that giving the drug this way lets it spread from the spinal fluid into the tissues of the brain and spinal cord.

What the U.S. label gives for the procedure:

• The dose is 100 mg in 15 mL, given by lumbar puncture by, or under the direction of, healthcare professionals experienced in the procedure.
• About 10 mL of spinal fluid is removed first, and the drug is then injected over 1 to 3 minutes.
• Treatment starts with three loading doses 14 days apart, followed by one dose every 28 days.
• The label mentions sedation and imaging guidance as options when a patient's condition calls for them.

How the body handles it, according to the label:

• Some of the drug passes from the spinal fluid into the bloodstream, where levels peak 2 to 6 hours after a dose. The highest pre-dose (trough) level in the spinal fluid was reached at the third loading dose, with little to no build-up from the monthly doses after that.
• The effective half-life in the spinal fluid is estimated at 4 weeks.
• It is expected to be broken down by enzymes that trim genetic strands from their ends. It is not handled by the liver's CYP450 drug-processing enzymes and does not block or switch them on. No clinical drug interaction studies have been done.
• There are no studies in people with kidney or liver impairment.

A 2026 autopsy study gave the first direct look at where the drug goes in people. In 8 people who had lived with SOD1 amyotrophic lateral sclerosis and received tofersen (aged 42 to 66), drug levels in the spinal cord and the motor area of the brain matched what each person's dosing history predicted. In the 3 who had been treated recently, SOD1 messenger RNA and protein in the lower spinal cord were 45% to 84% lower than in untreated donors, even though each had missed 1 to 2 scheduled doses before death. The surviving motor nerve cells had taken up the drug. Clumps of misfolded SOD1 protein were still found in surviving motor nerve cells of both treated and untreated donors.

The First Human Trial

The phase 1–2 trial, published in 2020, tested rising doses in 50 adults with SOD1 amyotrophic lateral sclerosis. In each dose group (20, 40, 60 or 100 mg), participants were assigned 3 to 1 to tofersen or placebo and received five doses into the spinal fluid over 12 weeks. Its main aims were safety and how the drug behaves in the body.

• SOD1 in the spinal fluid: at day 85, compared with placebo, the change was 2 percentage points at 20 mg, −25 at 40 mg, −19 at 60 mg and −33 percentage points at 100 mg. The authors concluded that SOD1 levels fell at the highest dose.
• Side effects: side effects linked to the lumbar puncture were seen in most participants. A raised white-cell count and raised protein in the spinal fluid were reported as side effects in 4 and 5 people on tofersen.
• Deaths: among those on tofersen, one person died of a blood clot in the lung on day 137 and one of breathing failure on day 152. One person on placebo died of breathing failure on day 52.

The 100 mg dose went forward into the phase 3 part of the programme.

VALOR: The 28-Week Placebo-Controlled Trial

VALOR, published in the New England Journal of Medicine in 2022, randomly assigned 108 adults with SOD1 amyotrophic lateral sclerosis 2 to 1 to eight doses of tofersen 100 mg or placebo over 24 weeks. The main result was measured at week 28. The 2026 long-term report adds that VALOR ran at 32 sites in 10 countries. Use of riluzole or edaravone, two other amyotrophic lateral sclerosis drugs, was allowed; the label notes that 62% of patients were taking riluzole and 8% edaravone at the start.

The main measure was the change in the ALS Functional Rating Scale-Revised, a questionnaire scored from 0 to 48 in which higher scores mean better everyday physical function. It was judged in the 60 people predicted to have faster-progressing disease.

• Main result: in the faster-progression group, the score fell by 6.98 points on tofersen and 8.14 points on placebo. The difference was 1.2 points (95% confidence interval −3.2 to 5.5; P = 0.97). This did not reach statistical significance.
• Other clinical measures: breathing capacity (slow vital capacity) and handheld muscle-strength testing in 16 muscles did not differ significantly between the groups.
• SOD1 protein: the label reports that total SOD1 protein in the spinal fluid fell 35% at week 28 on tofersen, against a 2% decrease on placebo.
• Neurofilament light chain: the label calls plasma neurofilament light chain a blood-based marker of injury to nerve fibres (axons) and of nerve degeneration. In the whole trial population, plasma levels fell 55% on tofersen and rose 12% on placebo. The label states that levels declined until about day 113 and then stayed down.

The authors concluded that tofersen reduced SOD1 in the spinal fluid and neurofilament light chain in the blood over 28 weeks but did not improve clinical end points and was associated with adverse events. Neurologic serious adverse events occurred in 7% of people given tofersen.

The Open-Label Extension: Earlier Versus Later Start

After VALOR, 95 of the 108 participants (88%) moved into an open-label extension in which everyone received tofersen. Those who had been on placebo therefore started about 6 months later than those first assigned to the drug. Comparing the two groups is a way to ask whether starting sooner makes a difference.

At 52 weeks (reported in 2022): the function score fell 6.0 points in the early-start group and 9.5 points in the delayed-start group (difference 3.5 points; 95% confidence interval 0.4 to 6.7). The authors noted that other measures also favoured early start, but these comparisons were not adjusted for testing many outcomes at once.

Final results over 148 weeks (reported in 2026), earlier start compared with later start was associated with numerically less decline in:

• the function score: −9.9 versus −13.5 points;
• breathing capacity (slow vital capacity): −13.8% versus −18.1%;
• muscle strength (handheld dynamometry megascore): −0.38 versus −0.43 points;
• quality of life on the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5: 17.0 versus 22.5 points.

46 people completed the extension: 34 (47%) of the early-start group and 12 (33%) of the delayed-start group. Follow-up could reach 3.5 years or more from the start of VALOR. The authors state that tofersen prolonged survival relative to the expected natural history of SOD1 amyotrophic lateral sclerosis, and that all serious neurological adverse events were reversible.

The U.S. label, updated with the same final analysis, describes these results more cautiously:

• The earlier-start advantages in the function score, breathing capacity and strength were trends that were not statistically significant.
• Earlier start was associated with a trend towards lower risk of death or permanent ventilation (hazard ratio 0.64; 95% confidence interval 0.28 to 1.46) and of death (hazard ratio 0.52; 95% confidence interval 0.20 to 1.36), also not statistically significant.
• In a subgroup more likely to progress fast (higher neurofilament at the start), the median time to death or permanent ventilation was 253.6 weeks with early start and 76.0 weeks with delayed start, which the label describes as an approximately 3.4-year extension. The label states that these exploratory analyses are to be interpreted with caution because data collected outside a controlled study may be subject to confounding.
• People who switched from placebo showed the same lasting fall in neurofilament as those treated from the start.

Accelerated Approval Based on Neurofilament

The FDA's accelerated approval pathway allows a drug for a serious disease to be approved on a laboratory or imaging marker that is judged reasonably likely to predict real benefit, on the condition that further trials confirm it. The tofersen label states its basis plainly: the indication is approved under accelerated approval based on reduction in plasma neurofilament light chain observed in patients treated with the drug, and continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

A 2024 German study summarises the timing the same way: tofersen was approved by the FDA in April 2023 after a decrease in neurofilament light chain levels had been shown. A 2026 review notes that VALOR did not meet its main function-score end point at 28 weeks and that the significant drop in neurofilament, read as a sign that the drug was reaching its target, supported accelerated approval.

The reasoning behind using neurofilament comes from research on people who carry disease-causing variants before they fall ill. The ATLAS design paper reports that in the Pre-Symptomatic Familial ALS study, a rise in blood neurofilament light chain came before the onset of clinical disease. A 2023 review describes blood neurofilament as a possible marker that may predict when disease will begin in some carriers.

A 2025 drug review describes tofersen as the first drug approved for amyotrophic lateral sclerosis associated with SOD1 variants. The European Medicines Agency has also approved tofersen; a 2026 review describes the U.S. and European approvals as accelerated regulatory approvals.

Results Outside the Trials

Since approval, clinics in several countries have published what happened to their own patients. None of these studies has a randomized placebo group, so they cannot separate the drug's effect from chance, selection or the natural variety of the disease.

• Germany, 2024 (24 patients, ten centres): over the observation period the median function score went from 38.0 to 35.0, a median loss of 0.11 points per month. Median blood neurofilament light chain fell from 78.0 to 36.0 pg/ml, and a related spinal fluid marker (phosphorylated neurofilament heavy chain) fell from 2226 to 1151 pg/ml. Two drug-related serious adverse events were reported.
• Italy, 2024 (17 patients followed at least 48 weeks): the rate of decline in function score and in muscle strength changed significantly compared with the year before treatment. Nine of the 17 substantially stabilized or slightly improved, four worsened, and in the rest the disease was too slow to judge. Neurofilament fell markedly in nearly all.
• France, 2026 (46 patients, 19 centres, the FORSLA study): the mean rate of decline slowed from 0.53 to 0.22 points per month, and blood neurofilament light chain fell from 89.0 to 29.2 pg/ml at 12 months. In 39 pairs matched with past patients who were not treated, mean survival was 42.6 months with tofersen and 31.8 months without, and an adjusted analysis linked tofersen with a lower risk of death (hazard ratio 0.34; 95% confidence interval 0.12 to 0.91). The month-by-month rate of decline did not differ significantly between the matched groups. The authors list the limits of a look-back design.
• United States, 2025 (7 patients, one centre): blood neurofilament light chain fell by a mean of 57.9% and a spinal fluid neurofilament marker by 67.6%. The function score changed by a mean of 1.1 points, and an independence score for daily activities rose by a mean of 5.13 points. Several patients also had outpatient rehabilitation.
• Iceland, 2026 (4 patients with the same variant): 15 to 26 months after starting, none had significant clinical worsening and three showed some recovery of movement. Spinal fluid neurofilament fell into the normal range. The authors describe this as a chronic non-progressive form of the disease not documented before.

A 2025 pooled analysis of 12 studies covering 195 treated patients (2 randomized trials, 5 cohort studies, 1 case series and 4 case reports) found a significantly slower decline in function score with tofersen than with placebo in the randomized trials (standardized mean difference 0.44; 95% confidence interval 0.05 to 0.83; P = 0.03). Most of the pooled studies were small and uncontrolled.

A 2026 study of blood SOD1 enzyme activity in 18 treated patients found that neurofilament and SOD1 protein fell during treatment while SOD1 enzyme activity in the blood stayed stable. The authors raised the question because people who inherit two faulty copies of the gene, with reduced SOD1 activity, have severe motor nerve problems, so a fall in activity caused by the drug could in theory be harmful. They state that the effect on SOD1 activity in the spinal fluid remains to be studied.

ATLAS: Starting Before Symptoms Appear

Because people with a known SOD1 variant can be identified before they are ill, researchers designed a trial to test whether tofersen started early can hold the disease off. The design of the ATLAS study was published in 2022.

• Who: people with no symptoms who carry SOD1 variants linked to a high or complete chance of developing the disease and to fast progression, and who also show blood evidence of disease activity, a raised neurofilament light chain level.
• The question: whether tofersen can delay the appearance of clinically manifest amyotrophic lateral sclerosis.
• Why it matters: the authors describe it as, to their knowledge, the first interventional trial in presymptomatic amyotrophic lateral sclerosis.

A 2026 review adds that ATLAS used specific SOD1 variants and rises in each person's own neurofilament levels over time to decide who moved into the randomized treatment phase. Another 2026 review describes ATLAS as ongoing. No ATLAS results were found among the PubMed records read for this page.

Label Warnings: Spinal Cord, Nerve Root, Brain Pressure and Meningitis

The U.S. label carries three warnings, each about inflammation or pressure in the nervous system:

• Myelitis and radiculitis (inflammation of the spinal cord or of the spinal nerve roots): eight patients in the clinical studies had one of these. Two stopped the drug and needed treatment for symptoms, with full resolution. In the other six, symptoms resolved without stopping the drug. The label notes that management may require interrupting or stopping treatment.
• Papilledema and elevated intracranial pressure (swelling at the back of the eye from raised pressure inside the skull): four patients developed one or both. All were treated, symptoms resolved, and none stopped the drug.
• Aseptic meningitis (inflammation of the brain's lining without infection): one patient had a serious chemical meningitis that led to stopping the drug, and one had a serious aseptic meningitis that did not.

For each of these, the label states that diagnostic workup and treatment follow the standard of care. It directs prescribers to tell patients and caregivers that the drug could cause these problems and to have them contact their healthcare provider if matching symptoms appear.

A 2025 report from the trial investigators described the serious neurologic events across the tofersen trials in more detail. Ten participants, approximately 7% of those treated with 100 mg, had 12 serious neurologic events: 4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis and 4 of raised intracranial pressure and/or papilledema. All but one resolved, on their own, with a pause or change in dosing, or with other treatment; the remaining one was improving at the last report. Three events led to stopping tofersen. None was life-threatening or fatal. The authors note that aseptic meningitis had been reported with nusinersen, an antisense drug for spinal muscular atrophy, but that myelitis, radiculitis, raised intracranial pressure and papilledema had not been reported with antisense treatment before.

Clinic reports describe the same kind of event. In the German series, two patients had symptoms of combined spinal cord and nerve root inflammation alongside spinal fluid changes, which the authors read as a possible autoimmune reaction. In the Italian series, two patients had an acute pure motor radiculitis that responded to steroid therapy. The Transverse Myelitis page describes spinal cord inflammation in general.

Common Side Effects and Spinal Fluid Changes

The label's safety data cover 147 patients given 100 mg, with a median time on the drug of 199.7 weeks (range 4 to 321 weeks). The most common side effects (at least 10% of patients and more often than on placebo) were pain, fatigue, joint pain, raised white cells in the spinal fluid, and muscle pain.

Side effects in VALOR seen in at least 5% of tofersen patients and more often than on placebo, as the label lists them (tofersen 72 people, placebo 36 people):

• Pain (including back pain and pain in the limbs): 42% versus 22%
• Fatigue: 17% versus 6%
• Joint pain (arthralgia): 14% versus 6%
• Raised white cells in the spinal fluid: 14% versus 0%
• Muscle pain (myalgia): 14% versus 6%
• Raised protein in the spinal fluid: 8% versus 3%
• Musculoskeletal stiffness: 6% versus 0%
• Nerve pain (neuralgia): 6% versus 0%

The label adds that fever (pyrexia), not serious, occurred with repeated doses in the long-term extension.

Antibodies against the drug: 98 of 147 treated patients (66.7%) developed antibodies to tofersen; in 16 (10.9%) they were short-lived and in 82 (55.8%) they persisted. The antibodies lowered the clearance of tofersen from the blood by 37.9%. The label reports no visible effect of the antibodies on the drop in SOD1 protein or neurofilament, or on side effects.

Signs of immune activity in the spinal fluid:

• The German series found a raised white-cell count in the spinal fluid in 73% of patients tested (11 of 15) and antibody production inside the nervous system in 9 of 10.
• The Italian series found raised white cells and protein in the spinal fluid in 60% of patients, without symptoms in all but two.
• A 2025 Italian study of 18 patients found that two spinal fluid markers of inflammation (SerpinA1 and CHI3L1) rose over time, most clearly after six and twelve months of treatment, while neurofilament fell. The authors raise the possibility of an immune response triggered by the drug.
• The 2026 autopsy study found clusters of immune cells (lymphocytes) in the brain's lining and around blood vessels in 5 recently treated donors, but not in donors whose last dose was long before death.

Pooled safety data: a 2026 meta-analysis of 6 studies (179 treated patients and 48 on placebo) found that 98.0% had at least one adverse event and 10.0% a serious one. Procedure-related pain (56.2%), headache (54.1%), back pain (38.4%) and limb pain (35.9%) were the most common. A raised spinal fluid white-cell count was reported in 44.1%, and breathing failure in 9.2%. The 2026 long-term VALOR report states that most adverse events were consistent with progression of the disease or with known effects of the procedure.

Pregnancy, Breastfeeding, Children and Older Adults

• Pregnancy: the label states that there are no adequate data in pregnant women. In pregnant mice and rabbits given the drug under the skin during organ formation, at blood levels about 4 times (mice) and 20 times (rabbits) those in people, there were no harmful effects on the developing young.
• Breastfeeding: there are no data on tofersen in human milk. The drug was found in the milk of nursing mice.
• Fertility: in male mice, the highest dose caused changes in the testes and lower sperm in the epididymis, without effects on fertility itself; this is a mouse finding. No cancer studies have been done.
• Children: safety and effectiveness have not been established.
• Older adults: 13.5% (22 of 162) of trial patients were 65 or older and 1.2% (2 of 162) were 75 or older. The label reports no overall differences in safety or effectiveness, while noting that greater sensitivity in some older people cannot be ruled out.
• Heart rhythm: the label states that the drug does not prolong the QTc interval to any clinically relevant extent.

Decisions about medicines in pregnancy, breastfeeding and serious neurological disease belong with a clinician.

What Is Not Known

• Clinical benefit in a randomized comparison: the only placebo-controlled period lasted 28 weeks and did not show a significant difference in function. The longer-term advantages come from comparing early with delayed start in an open-label extension, and the label calls them trends that were not statistically significant. The label states that continued approval may depend on confirmatory trials.
• How well neurofilament stands in for function and survival: the approval rests on neurofilament falling. Whether that fall reliably predicts that a person keeps strength, speech, swallowing and breathing for longer is the question the confirmatory evidence has to answer.
• Prevention: whether starting before symptoms delays the disease is the question ATLAS was designed to answer; no results were found among the records read for this page.
• Which variants respond: VALOR included 42 different variants, and clinic reports describe mixed responses, from recovery of movement in some people to continued worsening in others.
• Lowering the normal enzyme: the label does not describe the drug as telling the variant copy of the gene apart from the normal one. A 2026 study found blood SOD1 activity stable during treatment, and its authors state that the effect on SOD1 activity in the spinal fluid is still to be studied.
• Long-term inflammation: spinal fluid changes and markers of immune activity are common, and serious inflammatory events occurred in a minority. What years of repeated injections mean for the nervous system is still being followed.
• Misfolded protein already present: the autopsy study found that clumps of misfolded SOD1 were still present in surviving motor nerve cells of treated donors.
• Sporadic amyotrophic lateral sclerosis without a SOD1 variant: the approval covers only people with a SOD1 variant.

Key Research Papers

1. Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110. PubMed PMID: 36129998
2. Miller TM, Cudkowicz ME, Shaw PJ, Genge A, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Salachas F, Bruneteau G, Al-Chalabi A, Amorin M, Nestorov I, Graham D, Lin L, Sun P, McNeill M, Malek S, Inra J, Garafalo S, Fradette S. Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis. JAMA Neurol. 2026;83(2):115-125. PubMed PMID: 41661214
3. Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109-119. PubMed PMID: 32640130
4. McCampbell A, Cole T, Wegener AJ, Tomassy GS, Setnicka A, Farley BJ, Schoch KM, Hoye ML, Shabsovich M, Sun L, Luo Y, Zhang M, Comfort N, Wang B, Amacker J, Thankamony S, Salzman DW, Cudkowicz M, Graham DL, Bennett CF, Kordasiewicz HB, Swayze EE, Miller TM. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018;128(8):3558-3567. PubMed PMID: 30010620
5. Guise AJ, Sellon MT, Roemer SF, Monine M, Comfort Harris NT, Bartlett D, David E, Xu S, Jandreski L, Malek S, Garafalo S, Nestorov I, Ireland MD, King A, Bowser RP, Korben VA, Ravits J, Shaw PJ, Highley JR, Ferguson TA, Fradette S, Graham DL, Sorenson EJ, Oskarsson B, Reichard RR, Dickson DW, Paganoni S, Babu S, Oakley DH, Frosch MP, Miller TM, Bucelli RC, Perrin RJ, Ly CV, Plowey ED. Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors. JAMA Neurol. 2026;83(9):884-893. PubMed PMID: 42406382
6. Benatar M, Wuu J, Andersen PM, Bucelli RC, Andrews JA, Otto M, Farahany NA, Harrington EA, Chen W, Mitchell AA, Ferguson T, Chew S, Gedney L, Oakley S, Heo J, Chary S, Fanning L, Graham D, Sun P, Liu Y, Wong J, Fradette S. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022;19(4):1248-1258. PubMed PMID: 35585374 (a correction was published: PMID 36175782)
7. Benatar M, Turner MR, Wuu J. Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention. Curr Opin Neurol. 2023;36(4):360-364. PubMed PMID: 37382103
8. Lovett A, Chary S, Babu S, Bruneteau G, Glass JD, Karlsborg M, Ladha S, Mayl K, McDermott C, Bucelli RC, Chiò A, Ferguson TA, Cochrane T, Fradette S, Smirnakis K, Inra J, Malek S, Fanning L. Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis. Muscle Nerve. 2025;71(6):1006-1015. PubMed PMID: 40017137
9. Wiesenfarth M, Dorst J, Brenner D, Elmas Z, Parlak Ö, Uzelac Z, Kandler K, Mayer K, Weiland U, Herrmann C, Schuster J, Freischmidt A, Müller K, Siebert R, Bachhuber F, Simak T, Günther K, Fröhlich E, Knehr A, Regensburger M, German A, Petri S, Grosskreutz J, Klopstock T, Reilich P, Schöberl F, Hagenacker T, Weyen U, Günther R, Vidovic M, Jentsch M, Haarmeier T, Weydt P, Valkadinov I, Hesebeck-Brinckmann J, Conrad J, Weishaupt JH, Schumann P, Körtvélyessy P, Meyer T, Ruf WP, Witzel S, Senel M, Tumani H, Ludolph AC. Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program. EClinicalMedicine. 2024;69:102495. PubMed PMID: 38384337
10. Sabatelli M, Cerri F, Zuccarino R, Patanella AK, Bernardo D, Bisogni G, Tanel R, Sansone V, Filosto M, Lattante S, Martello F, Doronzio PN, Stano S, Zanfini BA, Coccia M, Costantini EM, Lizio A, Lucioli G, Padovani A, Merlini GP, Conte A. Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients. J Neurol. 2024;271(8):5177-5186. PubMed PMID: 38829431
11. Erazo D, Hesters A, Bruneteau G, De La Cruz E, Bernard E, Grapperon AM, Le Masson G, Cintas P, Soriani MH, Guy N, Cassereau J, Camdessanché JP, Genestet S, Corcia P, Pittion S, Danel V, Filliatre M, Choumert A, Jacquin-Piques A, Salachas F, Esselin F, Bohic A, Lautrette G, Attarian S, Catteau J, Guissart C, Vincent MC, Mouzat K, Temple M, Vourc'h P, Couratier P. Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study). Mayo Clin Proc Innov Qual Outcomes. 2026;10(5):100739. PubMed PMID: 42548788
12. Smith SE, McCoy-Gross K, Malcolm A, Oranski J, Markway JW, Miller TM, Bucelli RC. Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a "real-world" setting. Ann Clin Transl Neurol. 2025;12(2):311-319. PubMed PMID: 39783194
13. Thorarinsson BL, Sveinsson OA, Hilmarsson A, Sigurthorsdottir TB, Andersen PM. Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland. J Neurol. 2026;273(2):140. PubMed PMID: 41670738
14. Simonini C, Zucchi E, Martinelli I, Gianferrari G, Lunetta C, Sorarù G, Trojsi F, Pepe R, Piras R, Giacchino M, Banchelli F, Mandrioli J. Neurodegenerative and neuroinflammatory changes in SOD1-ALS patients receiving tofersen. Sci Rep. 2025;15(1):11034. PubMed PMID: 40169784
15. Goehring K, Abler E, Vavra J, Mayer K, Dorst J, Elmas Z, Wiesenfarth M, Richter L, Petri S, Regensburger M, Reilich P, Bjelica B, Lumi R, Süß P, Tumani H, Otto M, Weishaupt JH, Ludolph AC, Oeckl P. Blood SOD1 Activity in ALS Patients Receiving Tofersen Treatment. Ann Neurol. 2026. PubMed PMID: 42581415
16. Hamad AA, Alkhawaldeh IM, Nashwan AJ, Meshref M, Imam Y. Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci. 2025;46(5):1977-1985. PubMed PMID: 39820998
17. Tarazona-Santabalbina FJ, Belenguer-Varea A, Borrás-Blasco J, García-Tercero E, Martin ML, Prior NP, Mariscal G, Valcuende-Rosique A. Safety profile of tofersen in amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci. 2026;47(3):292. PubMed PMID: 41746412
18. Khazaal M, Stretavská P, Kuźma-Kozakiewicz M, Nieporęcki K, Betík A, Vlčková E, Koprušáková MT, Petrovic R, Cetin H, Keritam O, Löscher W, Eggers C, Iglseder S, Orenčák R, Molnár MJ, Grosz Z, Szlepák T, Koritnik B, Koszewicz MA, Baumgartner D, Slachtova L. SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy. Eur J Neurol. 2026;33(8):e70717. PubMed PMID: 42615765
19. Braza AJ, Viñas-Bastart M, Sureda-Rosich M, García-Parra B, Guiu-Segura JM, Modamio P. Tofersen in SOD1-associated amyotrophic lateral sclerosis: From molecular mechanisms to regulatory milestones. Eur J Pharm Sci. 2026;223:107563. PubMed PMID: 42173382
20. Chen M, Li H, Jin Q. Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction. Diagnostics (Basel). 2026;16(17). PubMed PMID: 42739287
21. Sang A, Zhuo S, Bochanis A, Manautou JE, Bahal R, Zhong XB, Rasmussen TP. Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. BioDrugs. 2024;38(4):511-526. PubMed PMID: 38914784
22. McGuigan A, Blair HA. Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations. CNS Drugs. 2025;39(9):903-912. PubMed PMID: 40640528

Regulatory Document

1. U.S. prescribing information for tofersen injection, for intrathecal use (Structured Product Labeling version 4, published on DailyMed October 26, 2026). DailyMed label

PubMed Topic Searches

1. PubMed: tofersen SOD1 amyotrophic lateral sclerosis
2. PubMed: tofersen myelitis and radiculitis
3. PubMed: tofersen and neurofilament
4. PubMed: ATLAS presymptomatic SOD1 trial

Connections

• Drugs — every drug page on the site
• Amyotrophic Lateral Sclerosis — the disease this drug treats
• Amyotrophic Lateral Sclerosis: History and Discovery — from Charcot to the SOD1 gene and the first gene-targeted drug
• Copper for Antioxidant Defense — the copper enzyme SOD1 and its role in inherited amyotrophic lateral sclerosis
• Superoxide Dismutase — the enzyme family the SOD1 gene belongs to
• Spinal Muscular Atrophy — a motor nerve disease treated with the antisense drug nusinersen
• Transverse Myelitis — spinal cord inflammation, one of the label warnings
• Tauroursodeoxycholic Acid — a bile acid tested in amyotrophic lateral sclerosis
• An Amyotrophic Lateral Sclerosis Drug Approval Later Withdrawn (2022) — another FDA decision in this disease
• Neurology — all nervous system conditions

Featured Videos