Tofersen is an intrathecal, antisense oligonucleotide indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. Tofersen approval was based on a reduction in plasma neurofilament light chain (NfL) and continued approval may be contingent upon verification of clinical benefit. NfL is a biomarker of axonal injury and neurodegeneration that is measured in both the cerebrospinal fluid (CSF) and plasma. The efficacy of tofersen for the treatment of ALS with SOD1 gene mutation was assessed in a randomized, double-blind, placebo-controlled trial over 28 weeks. Subjects treated with tofersen (n = 72) experienced a 55% reduction in plasma NfL compared to a 12% increase in plasma NfL in subjects given placebo (n = 36) (difference in geometric mean ratios for tofersen to placebo, 60%; nominal p < 0.0001). Concentrations of SOD1 proteins in CSF decreased 35% with tofersen compared to 2% with placebo (difference in geometric mean ratios for tofersen to placebo, 34%; nominal p < 0.0001). Subjects treated with tofersen experienced less decline from baseline according to the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) compared to subjects given placebo; however, the results were not statistically significant (tofersen to placebo adjusted mean difference, 1.2 [95% CI -3.2 to 5.5]). Myelitis, radiculitis, papilledema, elevated intracranial pressure, and aseptic meningitis have been reported with tofersen use.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Tofersen is a clear and colorless to slightly yellow solution. Do not use tofersen if discoloration, cloudiness, or particles are present.
-Allow the refrigerated solution to come to room temperature before use; do not use external heat sources.
-Do not shake the tofersen vial.
-Storage: Vials contain no preservatives. Discard any unused contents of the single-dose vial. An unopened vial can be removed from and returned to the refrigerator if it has been at or below 30 degrees C (86 degrees F) for no more than 6 hours/day, for a maximum of 6 days (36 hours). Store tofersen in its original carton at or below 30 degrees C (86 degrees F) for up to 14 days if no refrigeration is available. Protect from light.
Intrathecal Administration
Preparation
-Evaluate the patient for readiness for injection and, if indicated, consider sedation of the patient and/or imaging to guide intrathecal administration.
-Use aseptic technique when preparing and administering tofersen.
-Prior to administration, remove approximately 10 mL of cerebrospinal fluid (CSF) using a lumbar puncture needle.
-Withdraw 15 mL (equivalent to 100 mg) of tofersen from the vial into a syringe. External filters are not required. Do not dilute.
-Storage: Once drawn into the syringe, administer the solution within 4 hours of removal from the vial.
Intrathecal Injection
-Administer using a lumbar puncture needle as an intrathecal bolus injection over 1 to 3 minutes.
-Evaluate patients for presence of potential conditions related to lumbar puncture.
-Missed Dose: If the second loading dose is missed, administer tofersen as soon as possible, and administer the third loading dose 14 days later. 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.
Myelitis and radiculitis have been reported in patients receiving tofersen. During clinical studies of patients treated with tofersen, 6 patients experienced myelitis or radiculitis with 2 patients discontinuing tofersen treatment and requiring symptomatic management with full resolution of symptoms. In the remaining 4 patients, symptoms resolved without treatment discontinuation. Treat patients who develop myelitis or radiculitis as clinically appropriate. Interruption or discontinuation of tofersen may be required.
Papilledema and increased intracranial pressure have been reported in patients receiving tofersen. During clinical studies of patients treated with tofersen, 4 patients developed elevated intracranial pressure and/or papilledema. All patients received treatment with standard of care with resolution of symptoms and without discontinuation of tofersen. Treat patients who develop papilledema or increased intracranial pressure as clinically appropriate.
Aseptic meningitis has been reported in patients receiving tofersen. During clinical studies of patients treated with tofersen, 2 patients experienced aseptic meningitis with 1 patient discontinuing tofersen treatment. Cerebrospinal fluid (CSF) leukocytosis (14% vs. 0% placebo) and increased CSF protein (8% vs. 3% placebo) have also been reported in patients receiving tofersen. Treat patients who develop aseptic meningitis as clinically appropriate.
Arthralgia (14% vs. 6% placebo), fatigue (17% vs. 6% placebo), musculoskeletal stiffness (6% vs. 0% placebo), myalgia (14% vs. 6% placebo), neuropathic pain (6% vs. 0% placebo), and pain, including back pain and pain in extremity (42% vs 22% placebo), have been reported during clinical studies of patients treated with tofersen. Fever occurred with repeated administration of tofersen.
During clinical studies of patients treated with tofersen, 97 of 166 patients (58.4%) who were treated with tofersen developed treatment-emergent anti-drug antibodies (ADAs); the treatment-emergent ADAs were transient in 14 patients and persistent in 83 patients. Antibody formation did not affect the safety or efficacy of tofersen.
There are no available data on the use of tofersen in human pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies of pregnant mice and rabbits, subcutaneous administration of tofersen during the period of organogenesis resulted in no adverse effects on embryo-fetal development or pre- and postnatal development. Plasma exposures in the pregnant mice and rabbits were 4 and 20 times, respectively, that in humans at the recommended human dose of 100 mg.
There are no data on the presence of tofersen or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production. Tofersen was detected in the milk of lactating mice after subcutaneous administration. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tofersen and any potential adverse effects on the breast-fed infant from tofersen or the underlying maternal condition.
For the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene:
Intrathecal dosage:
Adults: 100 mg intrathecally every 14 days for 3 doses, followed by 100 mg intrathecally every 28 days.
Maximum Dosage Limits:
-Adults
100 mg/dose intrathecally.
-Geriatric
100 mg/dose intrathecally.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Tofersen products.
Tofersen is an antisense oligonucleotide. It works by binding to and degrading superoxide dismutase 1 (SOD1) mRNA, which results in a reduction of SOD1 protein synthesis. Mutations of SOD1 gene can cause a toxic accumulation of SOD1 proteins in neuronal cytoplasm. Mutant SOD1 proteins may contribute to mitochondrial dysfunction, excitotoxicity, oxidative stress, and impaired axonal transport.
Tofersen is administered intrathecally. After intrathecal administration, tofersen is distributed within the central nervous system tissues. Tofersen is metabolized through exonuclease (3'-and 5')-mediated hydrolysis. The primary route of elimination of tofersen has not been identified. The effective half-life of tofersen in cerebrospinal fluid (CSF) is estimated to be 4 weeks.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: none
In vitro, tofersen is not a substrate, inhibitor, or inducer of major CYP450 enzymes or a substrate or inhibitor of major transporters. Clinical studies evaluating tofersen drug-drug interactions have not been conducted.
-Route-Specific Pharmacokinetics
Other Route(s)
Intrathecal Route
After intrathecal administration, tofersen is distributed from the CSF to central nervous system tissues. The maximum CSF trough concentration occurred at the third loading dose. Little to no accumulation of tofersen in the CSF occurred with monthly maintenance dosing. The median time to maximum plasma concentration (Tmax) ranged from 2 to 6 hours. Tofersen did not accumulate in plasma with monthly maintenance dosing.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of tofersen has not been studied. Tofersen is not expected to undergo metabolism by hepatic enzymes.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of tofersen has not been studied.
Geriatric
The effect of age on tofersen exposure in CSF is unknown. The effect of age on tofersen plasma exposure was not clinically significant.
Gender Differences
The effect of sex on tofersen exposure in CSF is unknown. The effect of sex on tofersen plasma exposure was not clinically significant.
Ethnic Differences
The effect of race on tofersen exposure in CSF is unknown. The effect of race on tofersen plasma exposure was not clinically significant.
Obesity
The effect of body weight on tofersen exposure in CSF is unknown. The effect of body weight on tofersen plasma exposure was not clinically significant.
Other
Immunogenicity
The presence of treatment emergent anti-drug antibodies (ADAs) appeared to decrease the plasma clearance of tofersen by 32%. Total superoxide dismutase 1 (SOD1) protein reduction and plasma neurofilament light chain (NfL) reduction was not affected by the presence of ADAs.