Qalsody Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Health Professional Information .................................................................................. 5

1. 1.

   Indications .................................................................................................................. 5

   1.1. Pediatrics .............................................................................................................. 5

   1.2. Geriatrics .............................................................................................................. 5

2. 2. Contraindications ........................................................................................................ 5
3. 4.

   Dosage and Administration ......................................................................................... 5

   4.2. Recommended Dose and Dosage Adjustment ..................................................... 5

   4.4. Administration ...................................................................................................... 6

   4.5. Missed Dose ......................................................................................................... 7

4. 5. Overdose..................................................................................................................... 7
5. 6. Dosage Forms, Strengths, Composition, and Packaging ............................................... 7
6. 7.

   Warnings and Precautions ........................................................................................... 7

   General ............................................................................................................................. 7

   Driving and Operating Machinery .................................................................................... 8

   Hematologic ..................................................................................................................... 8

   Neurologic ........................................................................................................................ 8

   Renal ................................................................................................................................ 9

   Reproductive Health ........................................................................................................ 9

   7.1. Special Populations ............................................................................................... 9

   7.1.1. Pregnancy ......................................................................................................... 9

   7.1.2. Breastfeeding ................................................................................................... 9

   7.1.3. Pediatrics .......................................................................................................... 9

   7.1.4. Geriatrics ........................................................................................................ 10

7. 8.

   Adverse Reactions ..................................................................................................... 10

   8.1. Adverse Reaction Overview ................................................................................ 10

   8.2. Clinical Trial Adverse Reactions .......................................................................... 10

   8.3. Less Common Clinical Trial Adverse Reactions ................................................... 11

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ........................................................................................................... 12

8. 9.

   Drug Interactions ...................................................................................................... 12

   9.2. Drug Interactions Overview ................................................................................ 12

   9.3. Drug-Behaviour Interactions .............................................................................. 12

   9.4. Drug-Drug Interactions ....................................................................................... 12

   9.5. Drug-Food Interactions ....................................................................................... 12

   9.6. Drug-Herb Interactions ....................................................................................... 12

   9.7. Drug-Laboratory Test Interactions Overview ...................................................... 12

9. 10.

   Clinical Pharmacology ............................................................................................... 13

   10.1. Mechanism of Action ...................................................................................... 13

   10.2. Pharmacodynamics ........................................................................................ 13

   10.3. Pharmacokinetics ........................................................................................... 13

   10.4. Immunogenicity .............................................................................................. 15

10. 11. Storage, Stability, and Disposal ................................................................................. 15
11. 12. Special Handling Instructions .................................................................................... 15

Part 2: Scientific Information ................................................................................................ 16

1. 13. Pharmaceutical Information ...................................................................................... 16
2. 14.

   Clinical Trials ............................................................................................................. 17

   14.1. Clinical Trials by Indication ............................................................................. 17

   SOD1-ALS ....................................................................................................................... 17

3. 15. Microbiology ............................................................................................................. 18
4. 16. Non-Clinical Toxicology ............................................................................................. 19

Patient Medication Information ........................................................................................... 21

Part 1: Health Professional Information

1. Indications

QALSODY (tofersen injection) is indicated for:

• The treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

The clinical benefit of QALSODY for the indication remains to be confirmed as this indication is issued market authorization with conditions. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

1.1. Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥ 65 years of age): Experience with the use of QALSODY in the geriatric population is limited. Evidence from clinical studies suggests that use in the geriatric population is not associated with differences in safety or effectiveness, however a greater sensitivity in some older individuals cannot be ruled out. (see 7.1.4. Geriatrics).

2. Contraindications

QALSODY is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6. Dosage Forms, Strengths, Composition, and Packaging.

4. Dosage and Administration

4.2. Recommended Dose and Dosage Adjustment

• The recommended dose of QALSODY is 100 mg (15 mL).
• QALSODY treatment should be initiated with three (3) loading doses administered at 14-day intervals (Day 0, Day 14, Day 28).
• A maintenance dose should be administered every 28 days thereafter (Day 56, Day 84, etc.).

Pediatrics (<18 years of age)

Health Canada has not authorized an indication for pediatric use. Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatrics (≥65 years of age)

There is no evidence for special dosage considerations based on age when QALSODY is administered (see 7.1.4. Geriatrics).

Renal Impairment

QALSODY has not been studied in patients with renal impairment.

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Hepatic Impairment

QALSODY has not been studied in patients with hepatic impairment (see 10.3. Pharmacokinetics).

4.4. Administration

QALSODY is administered intrathecally by healthcare professionals experienced in performing lumbar punctures. Aseptic technique must be used when preparing and administering QALSODY intrathecally (see 7. Warnings and Precautions, General).

Vial preparation instructions

• Prior to administration, the refrigerated vial should be allowed to warm to room temperature (25°C) without external heat sources (see 11. Storage, Stability, and Disposal).
• The vial containing QALSODY should not be shaken.
• The solution should be visually inspected prior to removal of QALSODY from the vial. The solution should be free of visible particles. Only clear and colorless to slightly yellow solution should be administered. If not, the vial must not be used.

Procedural preparation instructions

• If indicated by the clinical condition of the patient, sedation can be considered.
• If indicated by the clinical condition of the patient, imaging to guide intrathecal administration of QALSODY can be considered.
• An unopened vial can be returned to the refrigerator for total time permitted (see 11. Storage, Stability, and Disposal).
• Patients should be evaluated prior to and after intrathecal injection for the presence of potential conditions related to lumbar puncture to avoid serious procedural complications.

Administration

• Just prior to administration, the plastic cap should be removed from the vial and a non-spinal anesthesia needle attached to the syringe for the purpose of withdrawing QALSODY from the vial. The syringe needle is inserted into the vial through the center of the over-seal to withdraw the required dose of 15 mL (equivalent to 100 mg) from the vial.

  • QALSODY must not be diluted.
  • External filters are not required.
• It is recommended that approximately 10 mL of cerebrospinal spinal fluid (CSF) is removed using a lumbar puncture needle prior to administration of QALSODY.

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

  • QALSODY contains no preservatives (see 11. Storage, Stability, and Disposal).
• Any unused content of the single-dose vial should be discarded.

Following injection, no additional monitoring procedures are recommended apart from standard post-lumbar-puncture care.

4.5. Missed Dose

If the second loading dose is delayed or missed, QALSODY should be administered as soon as possible, and the third loading dose should be administered 14 days later.

If the third loading dose is delayed or missed, QALSODY should be administered as soon as possible, and the first maintenance dose should be administered 28 days later.

If a maintenance dose is delayed or missed, QALSODY should be administered as soon as possible. Subsequent maintenance doses should be administered every 28 days from the last dose.

5. Overdose

No cases of overdose associated with QALSODY were reported in clinical trials.

In the event of overdose, medical care should be provided including consulting with a healthcare professional and close observation of the clinical status of the patient.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

QALSODY is available in a pack of 1 vial.

Description

QALSODY is a sterile, clear and colorless to slightly yellow solution supplied as a 100 mg/15 mL (6.7 mg/mL) solution in a single-dose glass vial with stopper not made with natural rubber latex, and an aluminum over-seal with flip-off plastic button.

7. Warnings and Precautions

General

QALSODY should be administered by healthcare professionals who are experienced in performing lumbar puncture procedures. Patients should be evaluated for the presence of potential

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contraindications for lumbar puncture (e.g., skin infection near site of lumbar puncture, suspicion of increased intracranial pressure, uncorrected coagulopathy, acute spinal cord trauma), and all necessary precautions should be taken to avoid serious procedural complications.

Adverse reactions associated with the administration of QALSODY by lumbar puncture have been observed, including headache, back pain, post lumbar puncture syndrome, and infection (see 8. Adverse Reactions).

Driving and Operating Machinery

Studies on the effects on the ability to drive or use machines during treatment with QALSODY have not been performed.

Patients who develop visual disturbance during QALSODY use should be cautioned to avoid driving or operating machinery.

Hematologic

Coagulation abnormalities and acute severe thrombocytopenia have been observed after subcutaneously and intravenous administration of antisense oligonucleotides. If clinically indicated, platelet and coagulation laboratory testing is recommended prior to lumbar puncture procedure.

Neurologic

Aseptic or chemical meningitis: Serious adverse reactions of aseptic or chemical meningitis have been reported in patients treated with QALSODY. In clinical trials, two patients treated with QALSODY reported serious adverse event of aseptic or chemical meningitis (1.4%). Both patients were symptomatic and received 5 and 7 doses of QALSODY respectively before the onset of aseptic or chemical meningitis. One patient discontinued QALSODY. If symptoms consistent with aseptic or chemical meningitis develop, diagnostic evaluation and treatment should be initiated according to the standard of care.

Myelitis and/or radiculitis: Serious events of myelitis and radiculitis have been reported in patients treated with QALSODY.

In the clinical studies, six patients receiving QALSODY 100 mg reported serious adverse reactions of myelitis (4.1%). The number of QALSODY doses received before the onset of myelitis ranged from 5 to 58 doses. Four patients were symptomatic. Five patients had abnormal magnetic resonance imaging (MRI) findings related to the event and one patient had a normal MRI. Two patients discontinued treatment, with resolution of the event. Two patients required immunomodulatory treatment.

Two patients receiving QALSODY 100 mg reported serious adverse reactions of radiculitis (1.4%) after receiving 1 dose and 24 doses, respectively. Both adverse reactions were symptomatic. One patient had abnormal MRI findings related to the event. No patients discontinued treatment. One patient had sequelae of bilateral foot sensory loss.

If symptoms consistent with these adverse reactions develop, diagnostic evaluation and treatment should be initiated according to the standard of care.

Increased intracranial pressure (ICP) and/or papilledema: Serious events of elevated intracranial pressure and/or papilledema in clinical studies were reported by four QALSODY-treated patients (2.7%). The number of QALSODY doses received before the onset of increased ICP and/or papilledema ranged from 7 to 18. All four adverse reactions were symptomatic. All patients had an MRI with no findings pertinent to the event. Management included long-term treatment with acetazolamide in several patients, and IV methylprednisolone with tofersen dosing in one patient. One event of ICP led to permanent discontinuation of QALSODY after resolution of the event, and one event of papilledema led to interruption of QALSODY treatment.

If symptoms consistent with these adverse reactions develop, diagnostic evaluation and treatment should be initiated according to the standard of care.

Renal

Renal toxicity, including potentially fatal glomerulonephritis, has been observed after subcutaneous and intravenous administration of antisense oligonucleotides. If clinically indicated, urine protein testing is recommended. For persistent elevated urinary protein, further evaluation should be considered.

Reproductive Health

• Fertility

  There are no data available on the potential effects on fertility in humans. In toxicity studies in animals, no effects on male or female fertility were observed (see 7.1.1 Pregnancy and 16. Non-Clinical Toxicology).

7.1. Special Populations

7.1.1. Pregnancy

There are no data from clinical trials on the use of tofersen during pregnancy. Administration of tofersen in mice and rabbits had no impact on fertility, embryo-fetal development, or pre/postnatal development (see 16. Non-Clinical Toxicology).

QALSODY is not recommended during pregnancy and in patients of childbearing potential not using contraception.

7.1.2. Breastfeeding

There are no data on the use of QALSODY during breastfeeding in humans. It is unknown whether tofersen or its metabolites are excreted in human milk. Precaution should be exercised because many drugs can be excreted in human milk. A risk to the newborn or infants cannot be excluded. QALSODY is not recommended during breastfeeding. In rodent studies, tofersen was detected in milk samples from all tofersen-dosed animals. There were no tofersen-related effects on either the maternal dams or offspring (see 16. Non-Clinical Toxicology).

7.1.3. Pediatrics

Pediatrics (< 18 years of age): QALSODY is not indicated for pediatric use. Safety and effectiveness in pediatric patients have not been established.

7.1.4. Geriatrics

Geriatrics (≥ 65 years of age): A total of 13.5% (22/162) SOD1-ALS patients were 65 years of age and older and 1.2% (2/162) patients were 75 years of age and older at initiation of treatment in clinical trials. Evidence from clinical studies suggests that use in the geriatric population is not associated with differences in safety or effectiveness. Data are limited, and a greater sensitivity of some older individuals cannot be ruled out.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The safety of QALSODY 100 mg was evaluated in 147 SOD1-ALS patients. The median patient exposure was 199.7 weeks (range: 4 to 321 weeks). QALSODY was evaluated in the placebo-controlled Study 1 and in the open label extension Study 2.

Very common adverse reactions (≥ 10%) reported in QALSODY-treated patients were pain (68.7%), arthralgia (36.7%), fatigue (30.6%), CSF white blood cell increased (27.9%), CSF protein increased (26.5%), myalgia (22.4%), and pyrexia (20.4%).

A total of 14 serious neuroinflammatory adverse reactions were reported in 12 (8.2%) QALSODY-treated patients in clinical trials. The serious adverse reactions in QALSODY-treated patients were myelitis (4.1%), increased intracranial pressure and/or papilledema (2.7%), radiculitis (1.4%) and aseptic or chemical meningitis (1.4%).

Serious neuroinflammatory reactions that led to discontinuation of tofersen included two cases of myelitis, one case each of aseptic meningitis and intracranial pressure increased (following event resolution).

Serious neuroinflammatory reactions that led to dose interruption included two cases of myelitis, and one case each of papilledema and intracranial pressure increased.

No cases lead to dose reduction, and none were fatal. The symptoms of the serious neuroinflammatory reactions were variable and resolved between 2-854 days after onset. These adverse reactions persisted for an average of 159 days.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Table 2 –Adverse Drug Reactions (ADRs) with an Incidence of ≥ 1% in QALSODY-Treated Patients in Study 1 (placebo-controlled) and Study 2 (open-label extension)

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¹ Pain includes preferred terms of pain, back pain, and pain in extremity.

² CSF white blood cell increased includes preferred terms of CSF white blood cell increased and pleocytosis.

³ Aseptic meningitis includes preferred terms of meningitis chemical and meningitis aseptic.

⁴ Radiculitis includes preferred terms of radiculopathy and lumbar radiculopathy.

⁵ Myelitis includes preferred term of myelitis, myelitis transverse, and neurosarcoidosis.

Note: Table 2 represents cases of serious and non-serious ADRs.

Selected Adverse Events

See 7. Warnings and Precautions for descriptions of the following selected adverse events:

Myelitis and/or radiculitis

Increased intracranial pressure and/or papilledema

Aseptic or chemical meningitis

8.3. Less Common Clinical Trial Adverse Reactions

There are no less common clinical trial adverse reactions, with incidence of < 1%, for QALSODY.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

Elevated cerebrospinal fluid (CSF) white blood cell (WBC) and protein levels were reported commonly both as non-serious adverse drug reactions (ADRs) and as abnormal laboratory findings. The incidence of CSF WBC and CSF protein increased ADRs was higher in the QALSODY-treated vs placebo-treated patients in Study 101 Part C. In addition, data from non-clinical studies, the pro-inflammatory nature of ASOs, and the relation to irritation or inflammation locally or systemically, indicate a likely causal relationship to QALSODY.

These findings were also reported in association with the common neuro inflammatory ADRs associated with QALSODY use. Clinical significance of these findings is unknown.

9. Drug Interactions

9.2. Drug Interactions Overview

Clinical drug interaction studies have not been performed.

The co-administration of other intrathecal medicinal products with tofersen has not been evaluated and the safety of these combinations is not known.

In in vitro studies, tofersen was not found to be a substrate for, or an inducer or inhibitor of CYP450-mediated oxidative metabolism; therefore, it should not interfere with other medicinal products that interact with these metabolic pathways.

In vitro studies indicated that the likelihood for interactions with tofersen due to competition with or inhibition of transporters is low. Tofersen is not a substrate of BCRP and MDR1 efflux or MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, or OCT2 SLC transporters, nor is it an inhibitor of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2 SLC, BCRP, BSEP, or MDR1 transporters.

9.3. Drug-Behaviour Interactions

The interaction of QALSODY with individual behavioural risks (e.g., cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

Clinical drug interaction studies have not been performed. In vitro studies suggested that tofersen is not expected to interact with CYP450 enzymes or with efflux and uptake transporters (see 9.2. Drug Interactions Overview).

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions Overview

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

The human SOD1 gene encodes an abundant dimeric enzyme, copper/zinc superoxide dismutase (Cu/ZnSOD or SOD1), which catalyzes the transmutation of superoxide (O₂^-) into oxygen (O₂) and hydrogen peroxide (H₂O₂). In SOD1-ALS patients, mutations in the SOD1 gene lead to accumulation of a toxic form of SOD1 protein, resulting in axonal injury and neurodegeneration. Tofersen is an antisense oligonucleotide that is complementary to a portion of the 3′ untranslated region (3′UTR) of the mRNA for human SOD1 and binds to the mRNA by Watson-Crick base pairing (hybridization). This hybridization of tofersen to the cognate mRNA results in RNase-H-mediated degradation of the mRNA for SOD1, which reduces the amount of SOD1 protein synthesis.

10.2. Pharmacodynamics

See 14.1. Clinical Trials for data related to SOD1 proteins (as an indirect measure of target engagement) and neurofilaments (biomarker of axonal injury and neurodegeneration).

Cardiac Electrophysiology

There was no clinical or non-clinical evidence that tofersen would prolong the QTc interval.

No thorough QT (TQT) prolongation study has been conducted but concentration-QTc analyses and electrocardiogram (ECG) monitoring were completed in the clinical trials. ECG measurements and the values for the tofersen 100 mg group (n = 41) were similar to the placebo group (n = 34) in Study 1 part C. The incidence of abnormalities in ECG measurements was higher in the tofersen group compared to the placebo group, with 8 patients (11.3%) displaying a maximum increase from baseline in Fridericia formula (QTcF) > 30 to 60 ms in the tofersen group compared to 2 patients (5.6%) in the placebo group. No patients in the tofersen or placebo group displayed an increase from baseline in QTcF > 60 ms, and no patients displayed maximum postbaseline QTcF > 480 ms.

Tofersen demonstrated a very low potential for cardiac IKR (hERG channel) inhibition (IC₅₀ > 34 μM) and did not produce adverse effects in cardiovascular safety pharmacology endpoints in nonhuman primates at the highest dose tested (35 mg).

10.3. Pharmacokinetics

The single and multidose pharmacokinetics of tofersen, administered via intrathecal injection, were characterized in plasma and CSF of adult ALS patients with a SOD1 mutation and in autopsy tissue from deceased clinical trial patients (n=3).

Table 3 – Summary of Tofersen Plasma Pharmacokinetic Parameters in Adult Patient Population

¹ 100 mg dose

² Median (Range)

³ Population PK model estimates

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Absorption

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 with monthly dosing after the loading phase. Tofersen transferred from the CSF into the systemic circulation, with a median time to maximum concentration (T_max) plasma values ranging from 2 to 6 hours post IT administration. There was no accumulation in plasma exposure measures (C_max and AUC) after monthly maintenance dosing.

Distribution

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

Metabolism

Tofersen is metabolized predominantly through exonuclease (3' and 5')-mediated hydrolysis and is not a substrate for, inhibitor, or inducer of CYP450 enzymes.

Elimination

The primary route of elimination is expected via urinary excretion of unchanged tofersen and its metabolites. Although CNS tissue half-life cannot be measured in humans, the mean terminal elimination half-life was measured in the CNS tissue of cynomolgus monkeys and found to be 31 to 40 days.

Special Populations and Conditions

• Pediatrics: The pharmacokinetics of tofersen in pediatric patients has not been studied.
• Geriatrics: Of the 166 patients who received tofersen in clinical trials, a total of 22 patients were 65 years of age and older, including 2 patients 75 years of age and older. No overall differences in clinical PK were observed between these patients, however data are limited.
• Sex: Population pharmacokinetic analysis identified sex as a covariate on plasma central volume of distribution. The observed differences were not associated with clinically meaningful differences in overall exposure, and no dose adjustment is required based on sex.
• Ethnic Origin: Most patients were Caucasian (61% of total), undisclosed (30% of total) or Japanese (6.5% of total). A total of 7 Japanese patients were enrolled in Study 1 part C and 3 of these patients received tofersen 100 mg. The mean (min, max) of AUC_0-24 and C_max in Japanese patients after the first dose of tofersen 100 mg were 6992.0 (4242, 15040) h*ng/mL and 462.3 (227, 1435) ng/mL, respectively. These values were within the ranges of overall population.
• Hepatic Insufficiency: The pharmacokinetics of tofersen in patients with hepatic impairment has not been studied. Tofersen is not expected to undergo metabolism by hepatic enzymes.

• Renal Insufficiency: The pharmacokinetics of tofersen in patients with renal impairment has not been studied.

  Tofersen is highly bound to human plasma proteins (≥ 98% bound) at clinically relevant or higher plasma concentrations (0.1 and 3 mcg/mL), which limits glomerular filtration and reduces urinary excretion of the drug. The likelihood of drug-drug interactions due to competition with plasma protein binding is very low.

• Body Weight: Population pharmacokinetic analysis showed that body weight and body surface area (BSA) do not have a clinically meaningful effect on tofersen plasma pharmacokinetics.

10.4. Immunogenicity

The immunogenic response to tofersen 100 mg was evaluated in 147 patients with post-baseline plasma samples for anti-drug antibodies (ADAs). Overall, 98 tofersen-treated patients (66.7%) developed treatment-emergent ADAs, of which 16 (10.9%) patients had a transient ADA response and 82 (55.8%) patients had a persistent ADA response. Though data are limited, no discernible effects of ADAs on efficacy or safety (incidence of AEs including hypersensitivity, anaphylactic reaction, and angioedema) have been observed. Medical review of individual cases of serious neurological events also showed no association with ADA status.

The presence of ADAs decreased tofersen plasma clearance by 37.9%. The clinical significance of the associated increase in plasma exposure is unknown. ADA status was not identified as a significant covariate in the SOD1 and NfL PK/PD models and had no impact on CSF SOD1 and plasma NfL levels.

1. 11. Storage, Stability, and Disposal

Store refrigerated at 2°C to 8°C in the original package to protect from light. Do not freeze.

The vial of QALSODY, in its original carton to protect from light, can be stored for up to 14 days at room temperature (not to exceed 30°C).

If removed from the original carton, the unopened vial of QALSODY can be removed from and returned to the refrigerator, if necessary, for not more than 6 hours per day at room temperature (not to exceed 30°C) for a maximum of 6 days (36 hours).

Once drawn from the vial, the solution is physically and chemically stable in syringes with polypropylene barrel at room temperature (15°C to 30°C) for up to 4 hours before administration; otherwise, it must be discarded.

12. Special Handling Instructions

For single dose only.

Discard any unused solution left in a vial. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): tofersen

Chemical name: Tofersen is a 20-base residue (20-mer) 5-10-5 methoxyethyl (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. 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:

2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’-O→5’-O) -2’-O-(2-methoxyethyl)-adenylyl-(3’-O→5’-O)-2’-O-(2-methoxyethyl)-P-thioguanylyl-(3’-O→5’-O) -2’-O-(2-methoxyethyl)-guanylyl-(3’-O→5’-O)-2’-O-(2-methoxyethyl)-P-thioadenylyl-(3′-O→5′-O)-2′-deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thioadenylyl-(3′-O→5′-O) -2′-deoxy-5-methyl-P-thiocytidylyl-(3′-O→5′-O)-2′-deoxy-P-thioadenylyl-(3′-O→5′-O) -2′-deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′-O→5′-O)-2′-deoxy-P-thiothymidylyl-(3′-O→5′-O)-2′-deoxy-P-thioadenylyl-(3′-O→5′-O) -2’-O-(2-methoxyethyl)-5-methylcytidylyl-(3’-O→5’-O)-2’-O-(2-methoxyethyl)-P-thioadenylyl-(3’-O→5’-O) -2’-O-(2-methoxyethyl)-guanylyl-(3′-O→5′-O)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’-O→5’-O) -2’-O-(2-methoxyethyl)-5-methyluridine

Molecular formula and molecular mass: C₂₃₀ H₃₁₇ N₇₂ O₁₂₃ P₁₉ S₁₅ (free acid form),

molecular mass: 7127.86 atomic mass units (amu)

Structural formula:

Physicochemical properties: pH of tofersen is approximately 7.2 in a buffered aqueous solution

14. Clinical Trials

14.1. Clinical Trials by Indication

SOD1-ALS

Table 4 – Summary of Patient Demographics for Clinical Trials in SOD1-ALS

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The efficacy of QALSODY was assessed in a 28-week randomized, double-blind, placebo-controlled clinical trial (Study 1 Part C) in patients aged 23 to 78 years with weakness attributable to ALS and a SOD1 mutation confirmed by central laboratory. One hundred eight (108) patients were randomized 2:1 to receive treatment with either QALSODY 100 mg or placebo for 24 weeks (3 loading doses followed by 5 maintenance doses). Forty-two (42) unique SOD1 mutations were evaluated, with the most common being p.Ile114Thr (n = 20), p.Ala5Val (n = 17), p.Gly94Cys (n = 6), and p.His47Arg (n = 5). Concomitant riluzole and/or edaravone use was permitted for patients who were on a stable dose for at least 30 or 60 days prior to trial baseline, respectively.

At the end of Study 1 Part C, 95/108 patients (tofersen 100 mg: n = 63; placebo: n = 32) enrolled in Study 2, an open-label extension trial to assess long-term safety of QALSODY. In Study 2, all patients received QALSODY 100 mg.

Baseline disease characteristics in the overall intent to treat (ITT) population were generally similar in the QALSODY-treated patients and placebo-treated patients. At baseline, 62% of patients were taking riluzole, and 8% of patients were taking edaravone. Mean (SD) baseline ALSFRS-R score was 36.9 (5.9) in the QALSODY treatment group and 37.3 (5.8) in the placebo group. Median time from symptom onset was 11.4 months in the QALSODY treatment group and 14.6 months in the placebo group. Mean (SD) baseline plasma NfL levels were 100.4 (82.8) pg/mL in the QALSODY treatment group and 89.7 (86.5) pg/mL in the placebo group.

The prespecified primary analysis population (n = 60, modified intent to treat [mITT]) had a slow vital capacity (SVC) ≥ 65% of predicted value as adjusted for sex, age, and height (from the sitting position) at screening and met prognostic enrichment criteria for rapid disease progression, defined based on their pre-randomization ALS Functional Rating Scale-Revised (ALSFRS-R) decline slope and SOD1 mutation type. The non-mITT population (n = 48) had a SVC ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position) at screening and did not meet the enrichment criteria for rapid disease progression.

Study Results

Study 1 Part C: The primary efficacy analysis was the change from baseline to Week 28 in the ALSFRS-R total score in the mITT population, analyzed using the joint rank test to account for mortality in conjunction with multiple imputation (MI) to account for missing data for withdrawals other than death. The results numerically favored QALSODY, however were not statistically significant (QALSODY-placebo adjusted mean difference [95% CI]: 1.2 [-3.2, 5.5]).

Numerically larger differences were observed between QALSODY and placebo over 28 weeks in patients with baseline NfL values above the median [mean difference (95% CI) 3.9, (-1.0;8.9)] compared to patients with baseline NfL values below the median [0.6, (-1.3,4.2)]. Clinical secondary outcomes did not reach statistical significance.

Secondary endpoints of change from baseline at Week 28 in plasma NfL, a biomarker of axonal injury and neurodegeneration, and CSF SOD1 protein, an indirect measure of target engagement, favored QALSODY.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General Toxicology

In a repeat-dose toxicology study (9 months), intrathecal (IT) administration of tofersen to adult cynomolgus monkeys was generally well-tolerated. The exception was a female in the high dose group (35 mg; equivalent to 350 mg per IT injection in humans) that had behavior described as muscle cramping, head/neck dorsiflexion, and opisthotonos-like-back-arching posture after IT dosing. Electroencephalogram (EEG) indicated the absence of seizure. The no observed adverse effect levels (NOAELs) in the repeat dose chronic toxicology studies were 150 mg/kg subcutaneous administration in the mouse and 12 mg intrathecal administration in the 9-month nonhuman primate.

Using the nonhuman primate as the most sensitive species, a dose of 12 mg converts to the HED of 120 mg, based on monkey to human CSF volume scaling (approximately 10-fold between human and monkeys), which provides a 1.2-fold safety margin to the MRHD of 100 mg. Based on plasma exposure (AUC_0-24) in nonhuman primates at 12 mg and humans at 100 mg, the exposure-based safety margin is approximately 2.2 times the MRHD of 100 mg.

Evidence of myelitis was not observed in the nonclinical toxicology studies for tofersen. However, vacuolation of neurons in brain and spinal cord as well as mononuclear cell infiltrates in spinal cord/nerve roots were seen with tofersen as well as with other antisense oligonucleotides (ASOs). None of these findings were associated with degenerative changes in the brain or spinal cord.

Genotoxicity

Tofersen demonstrated no evidence of mutagenicity based on nonclinical genotoxicity studies (in vitro Ames bacterial mutagenicity, in vitro chromosome aberration, and in vivo mouse micronucleus assays).

Carcinogenicity

Carcinogenicity studies with tofersen have not been performed.

Reproductive and Developmental Toxicology

Reproductive toxicology studies were conducted using subcutaneous administration of tofersen in mice and rabbits. No impact on fertility, embryo-fetal development, or pre/postnatal development was observed. Male mice in the high dose group of 30 mg/kg (> 50 times the human exposure [AUC] following 100 mg tofersen) had minimal to mild seminiferous tubular degeneration, seminiferous tubule dilatation, spermatid retention, apoptosis of epithelial cells, increased cellular debris in the testes, and hypospermia in the epididymis. In addition, an increase in prostate weight was also noted however, there were no tofersen-related adverse effects on mating and fertility or sperm parameters. In female mice, there was no tofersen-related mortality or early delivery and there were no effects on mating or fertility. In a perinatal/postnatal reproduction study in mice, there were no adverse effects on the F0 females or on the growth and development of the F1 pups at the highest dose evaluated (30 mg/kg). Translation of mouse fertility data to humans is limited based on the lack of cross-reactivity of tofersen to SOD1 in rodents.

Microscopic evaluation of reproductive tissues from both males and females in the 13-week and 39-week non-human primates (NHP) toxicology studies revealed no effects on the reproductive tissues.

There were no effects on embryo-fetal development in mice or rabbits. Female general toxicity and reproductive / developmental NOAEL for tofersen was 30 mg / kg / dose, the highest dose tested in mice and rabbits.

Tofersen was detected in mouse milk samples from all tofersen-dosed animals. There were no tofersen-related effects on either the maternal dams or offspring.