Recommended Dosage

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

The recommended dosage is 100 mg (15 mL) of QALSODY per administration.

Initiate QALSODY treatment with three (3) loading doses administered at 14-day intervals.

Administer a maintenance dose every 28 days thereafter.

Missed Dose

If the second loading dose is missed, administer QALSODY 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 QALSODY as soon as possible, and administer the next dose 28 days later.

Preparation

Vial preparation instructions

• Allow refrigerated QALSODY vial to warm to room temperature (25°C/77°F) prior to administration without using external heat sources [see Storage and Handling (16.2)].
• Inspect the solution in the QALSODY vial prior to administration. Do not administer if particles are observed or the liquid in the vial is not clear and colorless to slightly yellow.
• Do not shake the QALSODY vial.

Procedural preparation instructions

• If indicated by the clinical condition of the patient, consider sedation.
• If indicated by the clinical condition of the patient, consider imaging to guide intrathecal administration of QALSODY.
• Prior to removing the vial's cap on the aluminum overseal, confirm readiness of the patient. An unopened QALSODY vial can be returned to the refrigerator [see Storage and Handling (16.2)].
• Evaluate patients prior to and after intrathecal injection for the presence of potential conditions related to lumbar puncture, to avoid serious procedural complications.

Administration

Prior to administration, remove approximately 10 mL of cerebrospinal spinal fluid (CSF) using a lumbar puncture needle.

Prior to administration, remove the plastic cap and attach a needle to the syringe, for the purpose of withdrawing QALSODY from the vial. Insert the needle into the vial through the center of the overseal and withdraw the required dose of 15 mL (equivalent to 100 mg) from the vial.

• Do not dilute QALSODY.
• External filters are not required.

Administer QALSODY using a lumbar puncture needle as an intrathecal bolus injection over 1 to 3 minutes.

• QALSODY contains no preservatives. Once drawn into the syringe, the solution should be administered immediately (within 4 hours of removal from the vial) at room temperature; otherwise, it must be discarded.

Any unused contents of the single-dose vial should be discarded.

Less Common Adverse Reactions

Serious adverse reactions of myelitis and radiculitis; papilledema and elevated intracranial pressure; and aseptic meningitis have occurred in patients treated with QALSODY [see Warnings and Precautions (5.1, 5.2, 5.3)].

In the long-term extension study, nonserious adverse reactions of pyrexia have occurred with repeat administration of QALSODY.

Risk Summary

There are no adequate data on developmental risks associated with the use of QALSODY in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Risk Summary

There are no data on the presence of tofersen or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Tofersen was detected in the milk of lactating mice following subcutaneous administration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QALSODY and any potential adverse effects on the breastfed infant from QALSODY or from the underlying maternal condition.

Effect of Tofersen on Total CSF SOD1 Protein

Total CSF SOD1, an indirect measure of target engagement, was evaluated in Study 1 Part C in SOD1-ALS patients [see Clinical Studies (14)].

At Week 28 in Study 1 Part C, a reduction in total CSF SOD1 protein of 35% (geometric mean ratio to baseline) in the tofersen-treated group versus a 2% decrease from baseline in the corresponding placebo subjects in the ITT population was observed (difference in geometric mean ratios for tofersen to placebo: 34%; nominal p<0.0001).

Effect of Tofersen on Neurofilament Proteins

Plasma NfL, a blood-based biomarker of axonal injury and neurodegeneration, was evaluated in Study 1 Part C in SOD1-ALS patients [see Clinical Studies (14)].

At Week 28 in Study 1 Part C, mean plasma NfL was reduced 55% (geometric mean ratio to baseline) in the QALSODY-treated subjects, compared to a 12% increase with placebo in ITT population (difference in geometric mean ratios for QALSODY to placebo: 60%; nominal p<0.0001). Plasma NfL declined until approximately Day 113, after which the reductions were sustained. The reductions in phosphorylated neurofilament heavy chain (pNfH) were similar compared to reductions in NfL, as were reductions in CSF compared to plasma.

Cardiac Electrophysiology

At the maximum approved recommended dosing regimen, QALSODY does not prolong the QTc interval to any clinically relevant extent.

Absorption

Intrathecal administration of QALSODY into the CSF allows tofersen to be distributed from the CSF to central nervous system tissues. The maximum CSF trough concentration occurred at the third dose, which was the last dose of the loading period. There was little to no accumulation for CSF tofersen with monthly dosing after the loading phase. Tofersen is transferred from CSF into the systemic circulation, with median time to maximum concentration (Tmax) plasma values ranging from 2 to 6 hours. There was no accumulation in plasma tofersen exposure following monthly maintenance dosing.

Distribution

Autopsy tissue from patients treated with tofersen (n=3) showed that tofersen administered intrathecally was distributed within the central nervous system tissues.

Elimination

Drug Interaction Studies

No clinical drug interaction studies have been performed. In vitro, QALSODY is not a substrate or inhibitor/inducer of major CYP enzymes or a substrate or inhibitor of major transporters.

Specific Populations

Effect of sex, race, age, and body weight on tofersen exposure in plasma was not clinically significant. The effect of these factors on tofersen exposure in CSF is unknown.

Carcinogenesis

Studies to assess the carcinogenic potential of tofersen have not been conducted.

Mutagenesis

Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

In a study to assess effects on fertility and reproductive function, tofersen (0, 3, 10, 30 mg/kg) was administered every other day to male and female mice prior to and during mating and continuing in females to gestation day (GD) 7. Adverse effects on male reproductive organs (seminiferous tubular degeneration, seminiferous tubule dilatation, spermatid retention, apoptosis of epithelial cells, increased cellular debris in the testes, and hypospermia in the epididymis) were observed at the highest dose tested; however, there were no adverse effects on functional endpoints. Plasma exposure at the no-effect dose (10 mg/kg) for adverse effects on male reproductive organs was approximately 2 times that in humans at the recommended human dose of 100 mg.