tofersen (Rx)

>10%

Pain (42%)

Fatigue (17%)

Arthralgia (14%)

Cerebrospinal fluid (CSF) WBCs increased (14%)

Myalgia (14%)

1-10%

CSF protein increased (8%)

Musculoskeletal stiffness (6%)

Neuralgia (6%)

Frequency Not Defined

Myelitis

Radiculitis

Papilledema

Elevated intracranial pressure (ICP)

Aseptic meningitis

Pyrexia

Contraindications

None

Cautions

Myelitis and radiculitis reported; initiate workup and treatment according to standard of care if symptoms consistent with myelitis or radiculitis occur; management may require dosage interruption or discontinuation

Papilledema and elevated intracranial pressure reported; if symptoms develop, initiate diagnostic workup and treatment according to standard of care

Aseptic meningitis (ie, chemical meningitis, drug-induced aseptic meningitis) reported; additionally, nonserious adverse drug reactions of increased CSF white blood cells and CSF protein have also been reported; if symptoms consistent with aseptic meningitis develop, initiate diagnostic workup and treatment according to standard of care

Pregnancy

There are no adequate data on developmental risks associated with use in pregnant females to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

Animal studies

• SC administration (0, 3, 10, 30 mg/kg) every other day to pregnant mice during organogenesis resulted in no adverse effects on embryofetal development; plasma exposure at highest dose tested (30 mg/kg) was ~4 times that in humans at the recommended human dose (RHD) of 100 mg
• Similarly, SC administration to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development; plasma exposure at the highest dose tested (30 mg/kg) was ~20 times that in humans at the RHD

Lactation

Data are not available on presence of tofersen or its metabolites in human milk, effects on breastfed infants, or effects on milk production

Detected in milk of lactating mice following SC administration

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Antisense oligonucleotide that causes degradation of superoxide dismutase 1 (SOD1), which is the second most common and best understood genetic cause of amyotrophic lateral sclerosis (ALS)

Tofersen binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production

Absorption

Maximum CSF trough concentration occurred at 3rd (last) loading dose

Little to no accumulation for CSF tofersen with monthly dosing after loading phase

Tofersen is transferred from CSF into the systemic circulation, with median time to maximum concentration plasma values ranging from 2-6 hr

No accumulation in plasma tofersen exposure following monthly maintenance dosing

Distribution

Intrathecal administration allows for distribution within CNS tissues

Metabolism

Expected to be metabolized through exonuclease (3'- and 5')-mediated hydrolysis

Not a substrate for, or inhibitor or inducer of CYP450 enzymes

Elimination

CSF half-life (estimated): 4 weeks

Primary route of elimination has not been characterized

Intrathecal Preparation

Vial preparation

• Allow refrigerated vial to warm to room temperature (25ºC/77ºF) before administration without using external heat sources
• Inspect solution before administering; discard if particles observed or solution is not clear and colorless to slightly yellow
• Do NOT shake vial
• Do NOT dilute solution
• No external filters are required for administration
• Use aseptic technique when preparing
• Before administration, remove ~10 mL of cerebrospinal spinal fluid (CSF) using lumbar puncture needle
• Remove plastic cap and attach needle to syringe, for purpose of withdrawing tofersen from vial
• Insert needle into vial through center of overseal and withdraw required dose of 15 mL (100 mg) from vial

Procedural preparation instructions

• Consider sedation if indicated by patient’s clinical condition
• Consider imaging to guide intrathecal administration if indicated by patient’s clinical condition
• Before removing vial’s cap on aluminum overseal, confirm readiness of patient
• An unopened vial can be returned to refrigerator
• Evaluate patient before and after intrathecal injection for presence of potential conditions related to lumbar puncture, to avoid serious procedural complications

Intrathecal Administration

Administer intrathecally using a lumbar puncture by, or under the direction of, healthcare professionals experienced in performing lumbar punctures

Administer using lumbar puncture needle as an intrathecal bolus injection over 1-3 minutes

Contains no preservatives; once drawn into syringe, use immediately (within 4 hr of removal from vial) at room temperature; otherwise, discard

Discard any unused contents

Missed dose

• If 2nd loading dose missed, administer as soon as possible, and administer 3rd loading dose 14 days later
• If third loading dose or maintenance dose missed, administer as soon as possible, and administer next dose 28 days later

Storage

Upopened vials

• Refrigerate between 2-8ºC (36-46ºF) in original carton to protect from light
• Do not freeze
• If no refrigeration is available, may store in its original carton to protect from light at or below 30ºC (86ºF) for up to 14 days
• If removed from original carton, unopened vials can be returned to refrigerator, if necessary, for not more than 6 hr/day ≤30ºC (86ºF) for maximum of 6 days (36 hr)

Prepared syringes

• Once drawn into syringe, use immediately (within 4 hr of removal from vial) at room temperature