TOFERSEN: 366 Adverse Event Reports & Safety Profile

Tofersen, an antisense oligonucleotide, is a 20-base residue (20-mer) 5-10-5 MOE gapmer mixed backbone oligonucleotide. Of the nineteen internucleotide linkages, fifteen are 3′-O to 5′-O phosphorothioate diesters, and four are 3′-O to 5′-O phosphate diesters. Ten of the twenty sugar residues are 2-deoxy-D-ribose and the remainder are 2′-O-(2-methoxyethyl)-D-ribose (MOE). The residues are arranged so that there are five MOE nucleosides at the 5′ and 3′-ends of the molecule flanking a gap of ten 2′-deoxynucleosides. The cytosine and uridine bases are methylated at the 5-position. The structural formula is: Figure 1: Structural Formula for Tofersen The molecular formula is C 230 H 317 N 72 O 123 P 19 S 15 and the molecular weight is 7127.86 atomic mass units (amu). QALSODY is supplied as a sterile, preservative-free, clear, and colorless to slightly yellow solution in a Type I glass vial to be administered by intrathecal administration. Each vial of drug product contains a single dose of 100 mg tofersen at a concentration of 6.7 mg/mL in a formulation containing 0.21 mg/mL calcium chloride dihydrate, 0.11 mg/mL dibasic sodium phosphate, 0.16 mg/mL magnesium chloride hexahydrate, 0.03 mg/mL monobasic sodium phosphate, 0.22 mg/mL potassium chloride, 8.77 mg/mL sodium chloride, and water for injection. The pH of QALSODY is approximately 7.2 (range 6.7 to 7.7).

Figure

1

AND USAGE QALSODY is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 ( SOD1 ) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). QALSODY is an antisense oligonucleotide indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 ( SOD1 ) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). ( 1 )

AND ADMINISTRATION QALSODY is administered intrathecally ( 2.1 )

Dosing

Information ( 2.1 ) Recommended dose: 100 milligrams (15 mL) per administration Initiate QALSODY treatment with 3 loading doses administered at 14day intervals. A maintenance dose should be administered once every 28 days thereafter. Preparation and Administration Instructions ( 2.2 ) Allow to warm to room temperature prior to administration Administer within 4 hours of removal from vial Prior to administration, remove approximately 10 mL of cerebrospinal fluid Administer as an intrathecal bolus injection over 1 to 3 minutes 2.1.

Dosing Information 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. 2.2. Preparation and Administration Instructions Use aseptic technique when preparing and administering QALSODY intrathecally. Prepare and administer QALSODY according to the following steps: 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.

None. None ( 4 )

REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Myelitis and/or Radiculitis [see Warnings and Precautions ( 5.1 )] Papilledema and Elevated Intracranial Pressure [see Warnings and Precautions ( 5.2 )]

Aseptic

Meningitis [see Warnings and Precautions ( 5.3 )] The most common adverse reactions ( ≥ 10% of patients treated with QALSODY and greater than placebo) were pain, fatigue, arthralgia, cerebrospinal fluid white blood cell increased, and myalgia. (Section 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-877-725-7639 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of QALSODY cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. The safety of QALSODY 100 mg was evaluated in 147 patients with SOD1-ALS. The median patient exposure was 119.4 weeks (range from 4 to 212 weeks). QALSODY was evaluated in the placebo-controlled Study 1 and in the open label extension Study 2.

In Study

1 Part C, approximately 43% were female; 57% were male; 64% were White and 8% were Asian. The mean age at entry in Study 1 Part C was 49.8 years (range from 23 to 78 years). The most common adverse reactions (≥ 10% of patients treated with QALSODY and greater than placebo) were pain, fatigue, arthralgia, CSF white blood cell increased, and myalgia.

Table

1 shows the common adverse reactions that occurred in at least 5% of patients treated with QALSODY and at a 5% or higher frequency than placebo.

Table

1: Adverse Drug Reactions That Occurred in At Least 5% of Patients Treated with QALSODY and at >5% Higher Frequency Than Placebo ‡‡ Pain includes preferred terms of pain, back pain, and pain in extremity. * CSF white blood cell increased includes preferred terms of CSF white blood cell increased and pleocytosis.

Adverse Reaction Study

1 Part C QALSODY 100 mg (n = 72) % Placebo (n = 36) % Pain ‡‡ 42 22 Fatigue 17 6 Arthralgia 14 6 CSF white blood cell increased * 14 0 Myalgia 14 6 CSF protein increased 8 3 Musculoskeletal stiffness 6 0 Neuralgia 6 0 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.

AND PRECAUTIONS Myelitis and/ or Radiculitis: Serious events of myelitis and radiculitis have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to the standard of care. ( 5.1 ) Papilledema and Elevated Intracranial Pressure: Serious events of papilledema and elevated intracranial pressure have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to standard of care. ( 5.2 )

Aseptic

Meningitis: Serious events of aseptic meningitis have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to standard of care. ( 5.3 ) 5.1. Myelitis and/or Radiculitis Serious adverse reactions of myelitis and radiculitis have been reported in patients treated with QALSODY. Six patients treated with QALSODY experienced myelitis or radiculitis in the clinical studies. Two patients discontinued treatment with QALSODY and required symptomatic management with full resolution of symptoms. In the remaining 4 patients, symptoms resolved without discontinuation of QALSODY. If symptoms consistent with myelitis or radiculitis develop, diagnostic workup and treatment should be initiated according to the standard of care. Management may require interruption or discontinuation of QALSODY. 5.2. Papilledema and Elevated Intracranial Pressure Serious adverse reactions of papilledema and elevated intracranial pressure have been reported in patients treated with QALSODY. Four patients developed elevated intracranial pressure and/or papilledema. All patients received treatment with standard of care with resolution of symptoms, and no events led to discontinuation of QALSODY. If symptoms consistent with papilledema or elevated intracranial pressure develop, diagnostic workup and treatment should be initiated according to the standard of care. 5.3.

Aseptic Meningitis

Serious adverse reactions of aseptic meningitis (also called chemical meningitis or drug-induced aseptic meningitis) have been reported in patients treated with QALSODY. One patient experienced a serious adverse reaction of chemical meningitis, which led to discontinuation of QALSODY. One patient experienced a serious adverse reaction of aseptic meningitis, which did not lead to discontinuation of QALSODY. In addition, nonserious adverse drug reactions of CSF white blood cell increased, and CSF protein increased have also been reported with QALSODY [see Adverse Reactions ( 6.1 )]. If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care.