Tofersen is an antisense oligonucleotide.1
Tofersen is used for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene.1,7 Tofersen has been designated an orphan drug for the treatment of ALS.18 The current indication for tofersen is approved under the accelerated approval pathway based on reduction in plasma neurofilament light chain observed in patients treated with the drug; continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s).1,8
The current indication for tofersen is based on the results of a randomized, double-blind, placebo-controlled, phase 3 study conducted in patients with weakness attributable to ALS and a confirmed SOD1 mutation.1,2 Patients were assigned in a 2:1 ratio to receive intrathecal tofersen or placebo for 24 weeks; treatment was administered as 3 doses once every 2 weeks, followed by 5 doses once every 4 weeks.1,2 Concomitant use of riluzole and/or edaravone was permitted during the study.1 The primary efficacy endpoint was the change from baseline to week 28 in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score, a standard scale used to assess fine motor, gross motor, bulbar, and respiratory function in patients with ALS (scores ranging from 0 to 48 with higher scores representing greater functional ability).1,2 The prespecified primary analysis was conducted in the intent-to-treat population of patients who met criteria for rapid disease progression.1 A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).2
A total of 60 patients were included in the rapid disease progression subgroup.1,2 Baseline clinical characteristics were generally similar in the tofersen and placebo groups for use of riluzole, edaravone, or both; time from onset of disease symptoms; baseline ALSFRS-R score; and percentage of predicted slow vital capacity.2 However, patients in the tofersen group had a slightly shorter time from symptom onset and higher plasma neurofilament light chains (NfL) at baseline than those in the placebo group.1,2 The baseline mean ALSFRS-R score was approximately 37 in both groups.1,2 Patients treated with tofersen experienced less decline from baseline in the ALSFRS-R score compared to placebo, but the difference was not significant (change of -6.98 in the tofersen group and -8.14 in the placebo group).2 Tofersen reduced total SOD1 concentration in CSF and concentration of NfL in plasma to a greater extent than placebo, but the differences were also not significant.2
In addition, patients who were initially in the placebo group but were switched to tofersen in the open-label extension study experienced reductions in NfL during an interim analysis at 52 weeks that were similar to the reductions seen in patients treated with tofersen in the original study.1 However, NfL is an established ALS marker of axonal injury and neurodegeneration, and not a clinical endpoint.2 Exploratory analysis of data from the open-label follow-up period found a trend towards improved clinical outcomes with earlier versus delayed initiation of tofersen therapy; however, these findings should be interpreted with caution.1
During an early access program, an observational study followed 24 patients with ALS carrying pathogenic variants of the SOD1 gene who were treated with tofersen for up to 16 doses.6 The study found that median ALSFRS-R decreased from 38 to 35, corresponding to a median progression rate of 0.11 points of ALSFRS-R lost per month.6 Median serum NfL also significantly declined in these patients, corroborating the results from the placebo-controlled, phase 3 study.6
There are ongoing trials evaluating the effects of early versus delayed treatment with tofersen and efficacy of tofersen in presymptomatic adult carriers of SOD1 mutations with elevated neurofilament.2,8
ALS (i.e., Lou Gehrig disease, Charcot's sclerosis) is a fatal, progressive neurodegenerative disease affecting both upper and lower motor neurons; manifestations include gradual weakness and atrophy in limb, thoracic, abdominal, and bulbar muscles with related deficits in activities of daily living.3,9,10,13,14 Typically, the disease is fatal within 2-5 years of clinical onset, often as a result of respiratory failure.3,9,10,11,13 Approximately 2% of all ALS cases and 15% of familial ALS cases are associated with mutations in SOD1 .2,17 Mutated SOD1 proteins aggregate within motor neurons and glial cells, resulting in neuronal degeneration in patients with ALS.2,4,16 There is no cure for ALS and the limited treatment options available (e.g., riluzole, noninvasive ventilation, percutaneous endoscopic gastrostomy [PEG]) have shown only modest benefits in delaying disease progression and death.3,9,10,11,12,14 Disease management requires a multidisciplinary approach to address patients' physical deficits (e.g., loss of mobility, respiratory failure, dysarthria, dysphagia) as well as their social and psychological needs.11,14
The American Academy of Neurology published an evidence-based review of treatments for ALS in 2009; however, the only disease-modifying drug available at that time was riluzole.14 Additional agents (e.g., edaravone, tofersen) are currently available; however, these drugs have not been shown to provide much, if any, improvement in survival.2,21 Currently, there is no treatment that provides substantial clinical benefit for patients with ALS.21 The mainstay of treatment is timely interventions to manage symptoms.21 Referral to a specialized multidisciplinary clinic should be considered for patients with ALS.14
Dispensing and Administration Precautions
Tofersen is administered intrathecally using a lumbar puncture.1
Administer tofersen using a lumbar puncture needle as an intrathecal bolus injection over 1 to 3 minutes.1
Prior to administration, allow the vial to warm to room temperature (25oC) without using external heat sources.1
Inspect the solution; do not use if it is not clear and colorless to slightly yellow, or contains particulates.1 Do not shake the vial.1
Prior to administration, remove approximately 10 mL of CSF using a lumbar puncture needle.1 Withdraw the required dose of 15 mL (equivalent to 100 mg) from the vial; do not dilute.1 The solution does not contain any preservatives; once drawn into the syringe, the drug should be administered immediately (within 4 hours of removal from vial) at room temperature; otherwise, the solution should be discarded.1 Any unused contents of the single-dose vials should be discarded.1
Unopened vials of tofersen should be stored refrigerated (2-8°C) in the original carton to protect the drug from light; do not freeze.1 If no refrigeration is possible, the drug may be stored in its original carton (≤30°C) for up to 14 days.1 Unopened vials can be removed from and returned to the refrigerator if necessary, for not more than 6 hours a day at temperatures ≤30°C for a maximum of 6 days (36 hours).1
See manufacturer's prescribing information for additional details on preparation and administration of tofersen.1
The recommended adult dose of tofersen for the treatment of amyotrophic lateral sclerosis (ALS) is 100 mg (15 mL) per administration.1 Initiate tofersen treatment with 3 loading doses administered at 14-day intervals.1 A maintenance dose of 100 mg should be administered once every 28 days thereafter.1
If the second loading dose is missed, administer tofersen as soon as possible, and administer the third loading dose 14 days after.1 If the third loading dose or a maintenance dose is missed, administer tofersen as soon as possible, and administer the next dose 28 days later.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
Dosage adjustments are not needed in geriatric patients; however, greater sensitivity to the drug for some older individuals cannot be ruled out.1
Serious adverse reactions of myelitis and radiculitis have been reported in patients treated with tofersen.1,6 In clinical studies, 6 patients treated with tofersen experienced myelitis or radiculitis.1,6 If symptoms consistent with myelitis or radiculitis develop, diagnostic workup and treatment should be initiated according to the standard of care.1 Management may require interruption or discontinuation of tofersen.1
Papilledema and Elevated Intracranial Pressure
Serious adverse reactions of papilledema and elevated intracranial pressure have been reported in patients treated with tofersen.1 In clinical studies, 4 patients developed elevated intracranial pressure and/or papilledema.1 All patients received treatment with standard of care with resolution of symptoms, and no events led to discontinuation of tofersen.1 If symptoms consistent with papilledema or elevated intracranial pressure develop, diagnostic workup and treatment should be initiated according to the standard of care.1
Serious adverse reactions of aseptic meningitis (also called chemical meningitis or drug-induced aseptic meningitis) have been reported in patients treated with tofersen.1 One patient experienced a serious adverse reaction of chemical meningitis, which led to discontinuation of tofersen.1 One patient experienced a serious adverse reaction of aseptic meningitis, which did not lead to discontinuation of the drug.1 Nonserious increases in CSF white blood cell and CSF protein have also been reported with tofersen.1 If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care.1
In controlled studies, anti-drug antibodies (ADAs) were detected in 97 of 166 (58.4%) tofersen-treated patients, of which 14 were transient and 83 were persistent.1 The presence of ADAs decreased plasma tofersen clearance by 32%; however, antibody development did not appear to affect efficacy or safety of the drug.1
There are no adequate data on developmental risks associated with the use of tofersen in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.1 Subcutaneous administration of tofersen in rabbits and mice resulted in no adverse effects on embryofetal development and pre- or postnatal development.1
It is not known whether tofersen is distributed into human milk; the drug is distributed into milk in mice following subcutaneous administration.1 The effects of tofersen on nursing infants or on milk production are not known.1 Consider the benefits of breast-feeding along with the importance of tofersen to the woman and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.1
Females and Males of Reproductive Potential
It is not known whether tofersen affects female and male reproductive potential.1 Male mice treated with subcutaneous tofersen experienced adverse effects on reproductive organs; however no adverse effects were observed in functional outcomes.1
Safety and effectiveness of tofersen in pediatric patients have not been established.1
No overall differences in efficacy or safety of tofersen have been observed in geriatric patients compared with younger adults; however, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.1
Tofersen has not been studied in patients with hepatic impairment.1
Tofersen has not been studied in patients with renal impairment.1
The most common adverse reactions (≥10% of patients treated with tofersen and greater than placebo) reported with tofersen in clinical studies were pain, fatigue, arthralgia, increased CSF white blood cells, and myalgia.1,7
No clinical drug interaction studies have been performed with tofersen.1 Tofersen is not a substrate or inhibitor/inducer of major CYP enzymes, or a substrate or inhibitor of major transporters.1
Tofersen is a 20 base residue (20-mer) 5-10-5 MOE gapmer mixed backbone antisense oligonucleotide; the drug binds to SOD1 mRNA, causing its degradation and reduction in SOD1 protein synthesis.1,2,4,16
Approximately 2% of all amyotrophic lateral sclerosis (ALS) cases and 15% of familial ALS cases are associated with mutations in SOD1 , an antioxidant enzyme that protects the cell from reactive oxide species toxicity.2,17 Neuronal degeneration in ALS is thought to be caused by toxic gain of function of the mutant SOD1 protein.2 SOD1 has also been shown to potentially activate the transcription of nuclear genes and act as an RNA-binding protein.4 Mutated SOD1 proteins accumulate within motor neurons and glial cells, leading to protein aggregation and the formation of toxic protein clumps, causing dysfunction in the axonal transport system.4 The exact mechanism of how the intracellular aggregates are toxic to motor neurons is not known.4 Tofersen treatment has been shown to result in a 35% reduction in total CSF SOD1 proteins at 28 weeks.1
Following intrathecal injection, tofersen is distributed from the CSF to CNS tissue.1 The maximum concentration occurs after the third loading dose and there is little to no accumulation.1,4 The median time to peak plasma concentration is 2-6 hours.1,4 The half life of tofersen is 4 weeks.1 The effects of sex, race, age, and body weight on tofersen exposure are not clinically significant.1 No clinical studies have been conducted to evaluate the pharmacokinetics of tofersen in patients with renal or hepatic impairment.1 Tofersen is not expected to undergo metabolism by hepatic enzymes.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for intrathecal use only | 6.7 mg/mL | Qalsody® (supplied in single-dose preservative-free vials) | Biogen |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions February 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Biogen Inc. QALSODY® (tofersen) INTRATHECAL prescribing information. 2023 Apr.
2. 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.
3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209176Orig1s000: Summary Review. From FDA website. [Web]
4. Saini A, Chawla PA. Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis. Eur J Neurol. 2024;31(2):e16140.
6. Wiesenfarth M, Dorst J, Brenner D, et al. 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. Published 2024 Feb 15.
7. Food and Drug Administration. Center for Drug Evaluatin and Research. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. From FDA website. Accessed 2024 Sept 10. [Web]
8. US National Library of Medicine. Clinicaltrials.gov. A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation (ATLAS). NCT04856982. [Web]
9. Bonafede R, Mariotti R. ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles. Front Cell Neurosci. 2017; 11:80
10. Mathis S, Couratier P, Julian A, et al. Current view and perspectives in amyotrophic lateral sclerosis. Neural Regen Res. 2017; 12:181-184
11. Hogden A, Foley G, Henderson RD et al. Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. J Multidiscip Healthc. 2017; 10:205-215
12. Covis. Rilutek® (riluzole) tablets prescribing information. Cary, NC; 2016 April.
13. Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother. 2017; 18:735-738
14. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009; 73:1218-26
15. Biogen. Find a treatment Center. From Biogen website. Accessed 2024 Sept 10. [Web]
16. Bunton-Stasyshyn RK, Saccon RA, Fratta P, et al. SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes. Neuroscientist. 2015;21(5):519-529. doi:10.1177/1073858414561795
17. Abati E, Bresolin N, Comi G, et al. Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS). Expert Opin Ther Targets. 2020;24(4):295-310. doi:10.1080/14728222.2020.1738390
18. Food and Drug Administration. Search Orphan Drug Designations and Approvals. From FDA website. Accessed 2024 Sept 10. [Web]
21. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017 Jul 13;377(2):162-172.