Tofersen (Qalsody)
tofersen — antisense oligonucleotide
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| ALS in patients with a SOD1 gene mutation | Adults with confirmed SOD1 mutation | Disease-modifying (gene-targeted); may be used alongside riluzole and/or edaravone | FDA Accelerated Approval |
Tofersen is the first approved treatment targeting a specific genetic cause of ALS. It was granted accelerated approval in April 2023 based on reduction in plasma neurofilament light chain (NfL), a biomarker of axonal injury and neurodegeneration, rather than on a statistically significant change in a clinical functional measure. SOD1 mutations account for approximately 2% of all ALS cases and up to 20% of familial ALS. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials, including the ongoing ATLAS study evaluating tofersen in presymptomatic SOD1 mutation carriers.
Presymptomatic SOD1 mutation carriers: The Phase 3 ATLAS trial (NCT04856982) is evaluating whether tofersen can delay clinical onset of ALS when initiated in presymptomatic individuals with SOD1 mutations and elevated NfL. Results are pending. Evidence quality: Low (ongoing trial, no completed data).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| SOD1-ALS — loading phase | 100 mg IT every 14 days × 3 doses | 100 mg IT every 28 days | 100 mg per administration | Administer as 15 mL intrathecal bolus injection over 1–3 min via lumbar puncture. Remove ~10 mL CSF before injection. Loading: Day 1, Day 15, Day 29. Maintenance begins Day 57. |
| SOD1-ALS — maintenance phase | 100 mg IT every 28 days | 100 mg per administration | Continue indefinitely. Maximal CSF trough concentration reached at third (last loading) dose. No accumulation with monthly maintenance dosing. Administered by or under direction of HCPs experienced in lumbar punctures. | |
| Missed dose — second loading dose | Administer ASAP; give third loading dose 14 days later | Resume the original loading schedule from the missed dose. | ||
| Missed dose — third loading or any maintenance dose | Administer ASAP; next dose 28 days later | Resume maintenance schedule from the missed dose. | ||
Tofersen requires lumbar puncture for each dose. Allow the refrigerated vial to warm to room temperature without external heat. Remove approximately 10 mL of CSF before injecting the full 15 mL (100 mg) as a bolus over 1–3 minutes. Consider sedation and/or imaging guidance based on the patient’s clinical condition. Administer within 4 hours of removing the solution from the vial. The drug contains no preservatives.
Pharmacology
Mechanism of Action
Tofersen is a 20-mer 5-10-5 MOE gapmer antisense oligonucleotide designed to bind to SOD1 messenger RNA (mRNA). This binding triggers RNase H-mediated cleavage and degradation of the mRNA, thereby reducing synthesis of the superoxide dismutase 1 (SOD1) protein. In patients with SOD1-mutated ALS, gain-of-function mutations lead to production of a toxic, misfolded SOD1 protein that drives motor neuron degeneration. By reducing total SOD1 protein levels, tofersen aims to slow the neurodegenerative process at its upstream genetic source. In the pivotal trial, tofersen reduced CSF SOD1 protein by approximately 35% and plasma NfL by approximately 55% at 28 weeks, providing pharmacodynamic evidence of target engagement and reduced neurodegeneration.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption / Distribution | IT administration into CSF; distributes from CSF to CNS tissues (confirmed by autopsy in 3 patients); transfers from CSF to plasma with Tmax 2–6 h | Direct CNS delivery bypasses the blood-brain barrier; systemic exposure is a secondary consequence of CSF clearance, not the therapeutic target |
| CSF Kinetics | Maximum CSF trough at third dose (end of loading); little to no accumulation during monthly maintenance; effective CSF half-life ~4 weeks | Loading phase is critical for achieving steady-state CNS exposure; monthly maintenance maintains trough levels |
| Metabolism | Exonuclease (3′- and 5′)-mediated hydrolysis; not a substrate/inhibitor/inducer of CYP450 enzymes or major transporters | No hepatic CYP metabolism means negligible risk of drug-drug interactions and no need for hepatic dosing adjustments |
| Elimination | Primary route not characterised; no plasma accumulation with monthly dosing | The ~4-week CSF half-life supports the monthly maintenance dosing interval; renal/hepatic impairment studies have not been conducted |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Pain (includes back pain, pain in extremity) | 42% (vs 22% placebo) | Most common AE; largely procedural (lumbar puncture-related). Post-LP pain management with analgesics and hydration; consider lying flat post-procedure |
| Fatigue | 17% (vs 6% placebo) | May overlap with ALS-related fatigue; assess whether temporally related to dosing days |
| Arthralgia | 14% (vs 6% placebo) | Joint pain, often mild; manage with standard analgesics if needed |
| CSF white blood cell increased | 14% (vs 0% placebo) | Pleocytosis; reflects CSF inflammatory response to ASO administration. Usually asymptomatic. Distinguish from infectious meningitis or myelitis |
| Myalgia | 14% (vs 6% placebo) | Muscle pain; may occur systemically post-dose |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| CSF protein increased | 8% (vs 3% placebo) | Reflects intrathecal inflammatory response; monitor in context of clinical symptoms |
| Musculoskeletal stiffness | 6% (vs 0% placebo) | Often mild and self-limiting |
| Neuralgia | 6% (vs 0% placebo) | Nerve pain; evaluate for radiculitis if persistent or severe |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Myelitis and/or radiculitis | ~4% (6/147 patients) | Variable; can occur after any dose | Initiate diagnostic workup (MRI spine, CSF analysis); treat per standard of care; may require interruption or permanent discontinuation. 2 of 6 patients discontinued; remaining 4 resolved without stopping |
| Papilledema / elevated intracranial pressure | ~3% (4/147 patients) | Variable | Fundoscopic exam; standard ICP management. All 4 patients resolved with treatment; none discontinued tofersen |
| Aseptic meningitis (chemical meningitis) | ~1% (2/147 patients) | Hours to days post-dose | CSF analysis to exclude infectious aetiology; supportive care. 1 patient discontinued tofersen; 1 continued treatment |
All three categories of serious neurological adverse reactions (myelitis/radiculitis, elevated ICP/papilledema, aseptic meningitis) are class effects of intrathecal ASO administration. Clinical teams should have protocols in place for MRI spine, fundoscopy, and CSF analysis. Most events resolved with standard-of-care management and did not require permanent discontinuation. Symptoms of myelitis may include new or worsening limb weakness or sensory changes, which require careful differentiation from ALS disease progression.
Drug Interactions
No clinical drug interaction studies have been performed with tofersen. As an antisense oligonucleotide administered intrathecally, tofersen is metabolised by exonuclease-mediated hydrolysis and is not a substrate, inhibitor, or inducer of CYP450 enzymes or major drug transporters. No clinically significant pharmacokinetic interactions are expected. In the VALOR trial, 62% of patients were taking concomitant riluzole and 8% were taking edaravone, with no apparent interaction signals.
Tofersen has no known clinically significant drug-drug interactions. Its intrathecal route and non-CYP metabolism make pharmacokinetic interactions exceedingly unlikely. The primary procedural concern is the interaction between anticoagulant therapy and the need for repeated lumbar punctures, which is a well-established procedural consideration rather than a drug-drug interaction.
Monitoring
- Neurological AssessmentBefore and after each dose
RoutineEvaluate for new neurological symptoms (limb weakness, sensory changes, vision changes, headache, neck stiffness) before and after each intrathecal injection. Differentiate drug-related myelitis/radiculitis from ALS progression. - Plasma NfLBaseline, then periodically
RoutinePlasma neurofilament light chain is the surrogate biomarker on which accelerated approval was based. Reductions of ~55% were observed at 28 weeks in the pivotal trial. Track to assess treatment response and guide shared decision-making. - ALSFRS-R ScoreBaseline, then every 1–3 months
RoutineStandard ALS functional outcome measure. The pivotal trial did not achieve statistical significance on this endpoint at 28 weeks, but long-term data at 148 weeks showed numerically less decline with earlier tofersen initiation. - Fundoscopic ExamBaseline, then periodically
Trigger-basedPapilledema and elevated intracranial pressure reported in 4 patients. Perform if patient reports visual changes, persistent headache, or nausea/vomiting post-dose. - CSF AnalysisAs clinically indicated
Trigger-basedIf symptoms of myelitis, radiculitis, or meningitis develop, send CSF for cell count, protein, glucose, and culture to exclude infection. CSF pleocytosis and protein elevation are common with tofersen and do not necessarily indicate a serious neurological event. - SOD1 Genetic ConfirmationBefore first dose
RoutineA confirmed SOD1 mutation by a central or certified laboratory is required before initiating treatment. Tofersen is not indicated for ALS without a confirmed SOD1 mutation. - Coagulation StatusBefore each LP
RoutineStandard pre-LP assessment. Evaluate anticoagulant/antiplatelet use and platelet count. Follow institutional LP guidelines for timing of anticoagulant hold.
Contraindications & Cautions
Absolute Contraindications
- None listed in the FDA prescribing information. Tofersen has no formally listed contraindications. However, standard contraindications to lumbar puncture (raised ICP with mass lesion, local infection at puncture site, severe coagulopathy) apply to the administration procedure itself.
Relative Contraindications (Specialist Input Recommended)
- Prior serious neurological event with tofersen: Patients who experienced myelitis, radiculitis, or aseptic meningitis requiring treatment discontinuation should be evaluated by a neurology specialist before considering rechallenge.
- Active CNS infection: Intrathecal injection should be deferred until infection has resolved.
- Significant coagulopathy or active anticoagulation: LP may be contraindicated or require careful timing; discuss with haematology if the patient requires ongoing anticoagulation.
Use with Caution
- Pregnancy: No adverse developmental effects observed in animal studies (mice at 4x and rabbits at 20x human exposure). No adequate human data. Weigh risk-benefit.
- Breastfeeding: Detected in mouse milk; human data unavailable. Consider risk-benefit.
- Paediatric patients: Safety and efficacy not established in children.
- Patients with prior lumbar surgery or spinal abnormalities: May require imaging-guided LP.
Tofersen does not carry an FDA Boxed Warning. However, the Warnings and Precautions section highlights three categories of serious neurological events: (1) myelitis and/or radiculitis (6 patients; 2 required discontinuation); (2) papilledema and elevated intracranial pressure (4 patients; none discontinued); and (3) aseptic meningitis (2 patients; 1 discontinued). All events were reversible. Clinicians should monitor for new neurological symptoms and initiate diagnostic workup promptly. Management may require dose interruption or discontinuation.
Additionally, tofersen was approved under accelerated approval based on a surrogate biomarker (plasma NfL reduction). The primary clinical endpoint (ALSFRS-R change) did not reach statistical significance in the 28-week pivotal trial. Continued approval may be contingent upon confirmatory trial results.
Patient Counselling
Purpose of Therapy
Tofersen is designed to target the specific genetic cause of SOD1-mutated ALS by reducing the production of the toxic SOD1 protein. It was approved based on its ability to lower neurofilament light chain, a blood marker of nerve damage, rather than on a traditional clinical endpoint. Long-term data over approximately three years suggest that patients treated earlier may experience slower functional decline and prolonged survival compared to what is expected from the natural course of SOD1-ALS. However, tofersen does not cure ALS or restore lost motor function.
How Treatment Is Given
Tofersen is given as an injection into the spinal fluid (intrathecal injection) through a lumbar puncture, performed by a healthcare provider experienced in this procedure. Treatment begins with three loading doses given two weeks apart, followed by one dose every four weeks indefinitely. Each visit requires a lumbar puncture, which may cause temporary discomfort, headache, or back pain.
Sources
- Biogen MA Inc. QALSODY (tofersen) injection, for intrathecal use: US Prescribing Information. NDA 215887. Revised 04/2023. FDA LabelPrimary source for all dosing, pharmacokinetic, safety, and indication data in this monograph.
- US FDA. Approval letter and review documents for QALSODY (tofersen). NDA 215887. April 25, 2023. FDA Approval LetterRegulatory approval documentation under accelerated approval pathway; outlines postmarketing requirements including confirmatory trial.
- Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099–1110. doi:10.1056/NEJMoa2204705Pivotal Phase 3 VALOR trial + OLE 12-month combined analysis. Primary endpoint (ALSFRS-R) not statistically significant; NfL reduction and SOD1 lowering achieved; early-start vs delayed-start analysis supported clinical benefit.
- Miller TM, Cudkowicz ME, Shaw PJ, et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109–119. doi:10.1056/NEJMoa2003715Dose-escalation Phase 1-2 study establishing safety, PK, and dose-dependent CSF SOD1 reduction; 100 mg dose selected for Phase 3.
- Miller TM, Cudkowicz ME, Shaw PJ, et al. Long-term tofersen in SOD1 amyotrophic lateral sclerosis. JAMA Neurol. Published online December 22, 2025. doi:10.1001/jamaneurol.2025.4946Final VALOR/OLE results over ~148 weeks (3.5 years) demonstrating sustained NfL reductions, numerically less functional decline with early-start tofersen, prolonged survival vs natural history, and ~25% of participants showing functional improvement.
- Benatar M, Wuu J, Andersen PM, et al. 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. doi:10.1007/s13311-022-01286-7Design paper for the ATLAS confirmatory study evaluating tofersen in presymptomatic SOD1 carriers with elevated NfL; key for continued approval pathway.
- Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment. Neurology. 2009;73(15):1227–1233. doi:10.1212/WNL.0b013e3181bc01a4AAN guideline for ALS care; predates tofersen but provides the multidisciplinary framework within which genetically targeted ALS therapies are managed.
- Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62. doi:10.1038/362059a0Landmark discovery of SOD1 mutations as a cause of familial ALS; foundational for the development of SOD1-targeted therapies including tofersen.
- Kiernan MC, Vucic S, Talbot K, et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol. 2021;17(2):104–118. doi:10.1038/s41582-020-00434-zComprehensive review of ALS trial design challenges, including discussion of biomarker-driven endpoints and genetic subtyping strategies relevant to tofersen’s approval pathway.
- Akcimen F, Lopez ER, Landers JE, et al. Amyotrophic lateral sclerosis: translating genetic discoveries into therapies. Nat Rev Genet. 2023;24(9):642–658. doi:10.1038/s41576-023-00592-yReview of genetic ALS therapies including ASOs; provides context for tofersen within the broader landscape of genetically targeted ALS drug development.
- Blair HA. Tofersen: first approval. Drugs. 2023;83(11):1039–1043. doi:10.1007/s40265-023-01904-6Concise drug approval summary covering pharmacology, clinical trial results, and regulatory context for tofersen.
- Benatar M, Wuu J, Andersen PM, Lombardi V, Malaspina A. Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Ann Neurol. 2018;84(1):130–139. doi:10.1002/ana.25276Seminal Pre-fALS study demonstrating that serum NfL elevation precedes phenoconversion by ~12 months; foundational evidence for using NfL as a presymptomatic biomarker and informing the ATLAS trial design.