Summary Basis of Decision for Qalsody

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Qalsody is located below.

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Qalsody. When the PAAT for Qalsody becomes available, it will be incorporated into this SBD.

Date SBD issued: 2025-05-08

The following information relates to the New Drug Submission for Qalsody.

Tofersen

Drug Identification Number (DIN):

• DIN 02555735 – 100 mg tofersen/15 mL, solution, intrathecal administration

Biogen Canada Inc.

New Drug Submission Control Number: 283158

Submission Type: New Drug Submission (New Active Substance) - Notice of Compliance with Conditions

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): N07 Other nervous system drugs

Date Filed: 2024-01-26

Authorization Date: 2025-02-28

On February 28, 2025, Health Canada issued a Notice of Compliance under the Guidance Document: Notice of Compliance with Conditions (NOC/c) to Biogen Canada Inc. for the drug product Qalsody. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization of Qalsody was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Qalsody is favourable for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

Qalsody, a nervous system drug, was authorized for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

No pediatric data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use (less than18 years of age).

Experience with the use of Qalsody in the geriatric population (65 years of age or older) 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.

Qalsody (100 mg tofersen/15 mL) is presented as a solution. In addition to the medicinal ingredient, the solution contains calcium chloride dihydrate, magnesium chloride hexahydrate, potassium chloride, sodium chloride, sodium phosphate dibasic anhydrous, sodium phosphate monobasic dihydrate, and water for injection.

The use of 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.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Product Monograph for Qalsody is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Health Canada considers that the benefit-harm-uncertainty profile of Qalsody is favourable for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

Qalsody was authorized under the Guidance Document: Notice of Compliance with Conditions (NOC/c) on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Amyotrophic lateral sclerosis is a rapidly progressive, disabling, and fatal disease caused by motor neuron degeneration in the cortex, brainstem, and spinal cord. This leads to progressive weakness and death from respiratory failure within 3 to 5 years of symptom onset. When axons are degenerating, neurofilament light chain (NfL) leaks into the cerebrospinal fluid and blood. The lowering of NfL levels is thought to indicate slowing of neurodegeneration and may be a prognostic indicator for disease progression and provide evidence of treatment effect. Amyotrophic lateral sclerosis due to SOD1 gene mutations (SOD1-ALS) is a genetic subset of ALS in which the accumulation of toxic SOD1 protein leads to the loss of motor neurons, and subsequently the loss of strength, the loss of function, and death. This subset represents 1% to 2% of ALS cases (approximately 80 persons in Canada as of 2025), with many highly variable mutation types.

Tofersen, the medicinal ingredient in Qalsody, is an antisense oligonucleotide designed to target the pathology of SOD1-ALS by binding to and degrading SOD1 messenger ribonucleic acid and reducing the synthesis of toxic SOD1 protein. This leads to a reduction in neurodegeneration, measured by the biomarker NfL (in plasma and cerebrospinal fluid), which is hypothesized to stabilize or delay the progression of the disease.

The clinical safety and efficacy of Qalsody in the treatment of SOD1-ALS are derived from Study 101 Part C, a Phase III, 28-week, double-blind, placebo-controlled study designed to assess if Qalsody plus standard of care was superior to placebo/standard of care alone. The study enrolled 108 patients with a confirmed SOD1 mutation of which 72 were randomized to the Qalsody arm and 36 to the placebo arm. Patients received three loading doses of 100 mg of Qalsody or placebo administered as an intrathecal bolus every 2 weeks, followed by a 100 mg dose or placebo administered as an intrathecal bolus every 4 weeks. Following the completion of Study 101 Part C, patients could enter Study 102, an open-label, extension study, along with patients from the Phase I and II dose-finding Parts A and B of Study 101 (95 patients from Study 101 Part C, and 44 patients from Parts A and B). The primary objective of Study 102 was to evaluate the long-term safety of Qalsody. Data from Study 101 Part C were integrated across Studies 101 and 102 at Week 52 for the intention-to-treat population, to compare the efficacy in patients randomized to Qalsody in Study 101 Part C (early start group) with those randomized to placebo in Study 101 Part C (delayed start group). The efficacy evaluation was exploratory and no formal statistical testing was performed for the integrated efficacy analysis.

Study 101 Part C failed to reach statistical significance on the primary efficacy endpoint of change from baseline to Week 28 on the ALS Functional Rating Scale-Revised (ALSFRS-R) score in fast progressors, a modified intention-to-treat subgroup defined by SOD1 mutation and pre-randomization ALSFRS-R slope. However, results showed a non-statistically significant difference of 1.2 points favouring Qalsody (n = 39) over placebo (n = 21) (p = 0.97). Additionally, consistent trends in favour of Qalsody were observed at Week 28 in reductions of cerebrospinal fluid SOD1 protein (an indirect measure of target engagement in SOD1-ALS) and in plasma NfL (a biomarker of neurodegeneration).

The efficacy analyses supporting the benefit of Qalsody are based on plasma NfL levels, a surrogate endpoint which has not yet been validated for predicting clinical benefit but has been accepted as a neurodegeneration biomarker. However, the assessment of plasma NfL includes mechanistic evidence and biological plausibility of the effect of Qalsody based on its pharmacology and the pathophysiology of SOD1-ALS. The relationship between Qalsody-driven reductions in cerebrospinal fluid SOD1 protein and plasma NfL and the delayed changes in functional decline in ALSFRS-R score also suggests slowing or stabilization of neurodegeneration. As such, reductions in plasma NfL are considered reasonably likely to predict clinical benefit in patients with SOD1-ALS.

After unblinding the results of Study 101 Part C, post hoc exploratory analyses were conducted for the integrated data from Study 101 and Study 102 at Week 52, adjusting for baseline plasma NfL as a covariate and predefined alternative faster-progressing subgroups based on the median baseline NfL. These results showed a greater treatment difference favouring earlier Qalsody initiation. The treatment effect of Qalsody on NfL was also most apparent in faster-progressing disease, defined by higher baseline NfL levels. Although none of the results could be analysed for statistical significance due to failure to reach significance on the primary efficacy endpoint, longer-term data suggest a treatment effect of Qalsody, with numerical differences in favour of early-start Qalsody (versus [vs] placebo/delayed-start Qalsody) across measures of function, clinical outcomes, and biomarker levels in the integrated analysis of Study 101 Part C and Study 102 at Week 52.

The safety database for Qalsody included the 108 patients from Study 101 Part C and the integrated database of 147 patients treated with 100 mg of Qalsody in either Study 101 or Study 102. In Study 101, adverse events known to be associated with lumbar puncture procedures (headache, procedural pain, and post-lumbar puncture syndrome) occurred in most patients, and equally between treatment arms. Common non-serious adverse drug reactions reported at a greater incidence in patients treated with Qalsody vs placebo included pain (back pain, pain in extremities) (42% vs 22%), fatigue (17% vs 6%), arthralgia (14% vs 6%), myalgia (14% vs 6%), increased cerebrospinal fluid white blood cell count (14% vs 0%), increased cerebrospinal fluid protein (8% vs 3%), headache (8% vs 0), musculoskeletal stiffness (6% vs 0), neuralgia (6% vs 0), pyrexia (4% vs 3%), myelitis (2% vs 0), aseptic meningitis (1% vs 0), and radiculitis (1% vs 0).

The main safety concern associated with Qalsody relates to the serious neuroinflammatory adverse drug reactions of myelitis (4/147), radiculitis (2/147), papilledema/increased intracranial pressure (4/147), and chemical meningitis (2/147), for a total of 12 events in 10 out of 147 patients. These are considered manageable with standard of care diagnostics and treatment. The symptoms of the serious neuroinflammatory reactions were variable, resolving between 2 to 854 days after onset, with an average duration of 159 days. Apart from papilledema, the neuroinflammatory adverse drug reactions were correlated with non-clinical findings, were only reported in Qalsody-treated patients, occurred with a higher-than-expected incidence, shared similar findings with intrathecal administration of other antisense oligonucleotides, and were associated with increased cerebrospinal fluid white blood cell count and cerebrospinal fluid protein. Other potential class effects of antisense oligonucleotides include the risks of nephrotoxicity, thrombocytopenia, and coagulation abnormalities, which cannot be excluded.

Overall, the clinical efficacy data are considered promising rather than substantial. The pivotal clinical trial did not adequately demonstrate the benefit of Qalsody for the treatment of SOD1-ALS given the primary endpoint did not reach statistical significance. However, the data showed a favourable trend, suggestive of a potential treatment benefit with Qalsody, which could lead to slowing of the disease.

A Risk Management Plan (RMP) for Qalsody was submitted by Biogen Canada Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Product Monograph for Qalsody met the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Qalsody was accepted.

A Notice of Compliance with Conditions-Qualifying Notice (NOC/c-QN) was issued due to a favourable benefit-risk assessment of Qalsody, with promising evidence of clinical effectiveness, despite its limitations, and an acceptable safety profile for a serious, life-threatening, and severely debilitating condition. The identified safety issues can be managed through labelling and monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Qalsody. Further evidence is needed to verify the clinical benefit and to further characterize the benefit-harm-uncertainly profile of Qalsody. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Qalsody will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

The sponsor filed a request for Advance Consideration under the Guidance Document: Notice of Compliance with Conditions (NOC/c) for the review of the New Drug Submission (NDS) for Qalsody. An assessment was conducted to determine if there was promising evidence of clinical effectiveness that the drug has the potential to provide effective treatment, prevention, or diagnosis of a serious, life-threatening or severely debilitating disease or condition for which no drug is presently marketed in Canada or a significant increase in efficacy and/or significant decrease in risk such that the overall benefit-risk profile is improved over existing therapies, preventatives, or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.

The efficacy results obtained from the pivotal studies did not provide promising evidence of a significant increase in efficacy over existing therapies. In addition, from the safety data provided, it was not possible to judge what safety advantage, if any, is achieved by the use of Qalsody as opposed to other existing therapeutic options. For these reasons, the informal adjudicator committee determined that the submission did not meet the criteria for advance consideration under the NOC/c Guidance and therefore the request was denied. The submission was subsequently filed and reviewed as a regular NDS.

The review of the NDS for Qalsody was based on a critical assessment of the data package submitted to Health Canada. As per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference for the review of the non-clinical component, while the reviews completed by the European Medicines Agency (EMA) were used as an added reference for the quality component. and the FDA and EMA were used as added references for the clinical component. The Canadian regulatory decision on the Qalsody NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Qalsody

Requirements for post-market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations and in the Guidance Document: Notice of Compliance with Conditions (NOC/c). Notably, the sponsor has agreed to carry out confirmatory Studies 102 and 303, to submit progress reports of confirmatory trials, and to conduct (and provide) post-marketing safety monitoring, including a re-assessment of the risk-benefit profile of the drug on an annual basis.

Confirmatory Studies

Study 102 (Study 233AS102)

To further investigate the long-term efficacy and safety of Qalsody in the treatment of SOD1-ALS, submit the final clinical study report for the long-term extension Study 102 and the summary of integrated analyses of Study 101 (Study 233AS101) and Study 102.

Study 303 (Study 233AS303)

A Phase III randomized, placebo-controlled study with a longitudinal natural history run-in and open-label extension to evaluate Qalsody initiated in clinically presymptomatic adults with a confirmed SOD1 mutation.

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Qalsody. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

Up-to-date information on drug products can be found at the following links:

• See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.

• See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.

• See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.

• See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Guidance Document: Notice of Compliance with Conditions (NOC/c), if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.

• See the Patent Register for patents associated with medicinal ingredients, if applicable.

• See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.

Refer to the What steps led to the approval of Qalsody? section for more information about the review process for this submission.