Summary Basis of Decision for Zolgensma

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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

Recent Activity for Zolgensma

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.

 

The following table describes post-authorization activity for Zolgensma, a product which contains the medicinal ingredient onasemnogene abeparvovec. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

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

 

Updated: 2024-05-13

 

Drug Identification Number (DIN):

DIN 02509695 - 2 x 1013 vector genomes (vg)/mL, onasemnogene abeparvovec, solution, intravenous administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 274469

2023-04-17

Issued NOC 2024-03-19

Submission filed as a Level I – Supplement in response to a Post-Decision Letter dated December 16, 2020, issued by Health Canada for NDS control # 239719 to conduct a study evaluating the potential for germline integration for Zolgensma. The submission provided the final toxicology report for Study 2170026. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 275295

2023-05-15

Issued NOC 2024-01-15

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Clinical Pharmacology sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

SNDS # 273937

2023-03-31

Issued NOC 2023-11-10

Submission filed as a Level I – Supplement for the addition of a new drug product and drug substance manufacturing site and a new manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 268586

2022-10-07

Issued NOC 2023-03-07

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box; Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

NC # 270877

2022-12-20

Issued NOL 2023-01-24

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the shelf life for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 267184

2022-08-19

Issued NOC 2022-12-05

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information related to the risk of fatal acute liver failure. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box; Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

Health Professional Risk Communication

Not applicable

Posted 2022-09-12

Health Professional Risk Communication posted (Zolgensma [onasemnogene abeparvovec] and Fatal Cases of Acute Liver Failure), containing new safety information for healthcare professionals.

NC # 265159

2022-06-14

Issued NOL 2022-08-24

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the auxiliary materials/reagents of biological origin, cell bank/seed bank qualification protocol, drug product release or shelf‐life specifications, and changes affecting the quality control testing of the drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 261251

2022-02-07

Issued NOC 2022-06-06

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Non-clinical Toxicology sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

NC # 260495

2022-01-17

Issued NOL 2022-03-17

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in specification for the materials. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 255655

2021-08-11

Issued NOC 2021-11-02

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

NC # 253868

2021-06-16

Issued NOL 2021-09-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 249683

2021-02-18

Issued NOC 2021-06-09

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

NC # 249190

2021-02-01

Issued NOL 2021-05-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a drug product testing site. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02509695) market notification

Not applicable

Date of first sale: 2021-02-04

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 239719

2020-05-21

Issued NOC 2020-12-15

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Zolgensma

Date SBD issued: 2021-03-10

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

Onasemnogene abeparvovec

Drug Identification Number (DIN):

  • DIN 02509695 - 2 x 1013 vector genomes (vg)/mL, solution, intravenous administration

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 239719

 

On December 15, 2020, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Zolgensma.

The market authorization 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-risk profile of Zolgensma is favourable for the treatment of pediatric patients with 5q spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene and:

  • 3 or fewer copies of the SMN2 gene; or
  • infantile-onset spinal muscular atrophy.

 

1 What was approved?

 

Zolgensma (onasemnogene abeparvovec) is an adeno-associated virus vector-based gene therapy. It was authorized for the treatment of pediatric patients with 5q spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene and:

  • 3 or fewer copies of the SMN2 gene; or
  • infantile-onset spinal muscular atrophy.

The efficacy and safety data supporting the use of Zolgensma in treating pediatric patients with spinal muscular atrophy are derived from completed and ongoing open-label, single-arm clinical trials in patients with:

  • infantile-onset spinal muscular atrophy and 2 copies of the SMN2 gene; and
  • presymptomatic genetically diagnosed spinal muscular atrophy and 2 or 3 copies of the SMN2 gene.

Knowledge of the disease natural history and the use of management strategies that assist the patient in coping with the manifestations of spinal muscular atrophy, which can include decline in motor function, serious respiratory complications, and feeding difficulties, remain necessary for the overall management of the disease. Zolgensma should only be administered by health care professionals who are experienced in the screening, diagnosis, and management of patients with spinal muscular atrophy and who are trained in the delivery of gene therapy.

The efficacy and safety of Zolgensma in pediatric patients 8 months of age and older at the time of infusion have not been established in clinical trials.

Zolgensma is not authorized for geriatric use.

The use of Zolgensma 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.

Zolgensma was authorized for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Zolgensma is presented as a sterile solution for infusion (2.0 x 1013 vector genomes [vg]/mL). In addition to the medicinal ingredient, the solution contains hydrochloric acid (for pH adjustment), magnesium chloride, poloxamer 188, sodium chloride, tromethamine, and water for injection.

For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Zolgensma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Zolgensma approved?

 

Health Canada considers that the benefit-risk profile of Zolgensma is favourable for the treatment of pediatric patients with 5q spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene and:

  • 3 or fewer copies of the SMN2 gene; or
  • infantile-onset spinal muscular atrophy.

Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease characterized by progressive degeneration of motor neurons leading to progressive muscle weakness and atrophy. The incidence of SMA is approximately 1:10,000 live births worldwide. An estimated 37 new cases of SMA are diagnosed annually in Canada. Spinal muscular atrophy is the most common genetic cause of infant mortality.

The most common form of SMA results from bi-allelic mutations or deletions to the SMN1 gene located on the long arm of chromosome 5 (chromosomal region 5q11.2-q13.3). Approximately 95% of the 5q SMA cases are due to homozygous deletions of exons 7 and 8 of the SMN1 gene. The remaining cases have hemizygous deletions with a point mutation on the other chromosome. In humans, two forms of the SMN gene exist: SMN1 and SMN2. Transcription of the SMN1 gene produces full-length messenger ribonucleic acid (mRNA) transcripts that encode the SMN protein, which is necessary for motor neuron survival. The SMN2 gene is nearly identical to the SMN1 gene, but contains a single base substitution that results in the preferential exclusion of exon 7 in the transcript and a resultant non-functional truncated SMN protein in 85% to 90% of instances. Therefore, the SMN2 gene is unable to fully compensate for the absence or deficiency of the SMN1 gene in SMA patients. The SMN2 copy numbers can vary between 0 and 4 per chromosome 5 in the general population. Generally, in the 5q SMA patients, a lower number of SMN2 gene copies is correlated with more severe disease.

Spinal muscular atrophy includes a wide range of phenotypes that are classified into clinical groups according to age at disease onset and the developmental motor milestones achieved. More than half of patients have the most severe phenotype of SMA type 1 (also known as infantile-onset SMA or Werdnig-Hoffmann disease) with onset of symptoms within the first 6 months of age and a life expectancy of under 2 years.

Currently, the only drug authorized in Canada for the treatment of patients with 5q SMA is Spinraza (nusinersen). Spinraza is an antisense oligonucleotide drug designed to increase the production of the SMN protein by modulating the splicing of the SMN2 gene, thereby compensating for the underlying genetic defect.

Zolgensma is a gene therapy designed to deliver a functional copy of the SMN1 gene to the motor neuron cells of patients with SMA to address the monogenic root cause of SMA. By providing an alternative source of SMN protein expression in motor neurons, Zolgensma is expected to promote the survival and function of transduced motor neurons.

The market authorization of Zolgensma was based on data derived from several completed or ongoing open-label, single-arm, single-dose clinical trials that assessed the efficacy and safety of a single intravenous infusion of Zolgensma in subjects with infantile-onset symptomatic SMA or genetically diagnosed presymptomatic SMA. All subjects possessed a bi-allelic deletion of the SMN1 gene and either 2 or 3 copies of the SMN2 gene.

In a completed Phase III clinical trial of symptomatic SMA, treatment with Zolgensma resulted in event-free survival (i.e., alive without permanent ventilation) at 14 months of age in approximately 90% of subjects. Approximately 60% of subjects achieved the ability to sit alone for at least 30 seconds, including two subjects who achieved the ability to stand without support and the ability to walk alone. Motor function improvements relative to baseline were also observed as measured by the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). Approximately 95% of subjects achieved a CHOP-INTEND score ≥40, including approximately 25% of subjects who achieved a CHOP-INTEND score ≥60. Based on the natural history of infantile-onset SMA, fewer than 25% of patients are expected to survive past 14 months of age, none are expected to develop the ability to sit without support and none are expected to achieve a CHOP-INTEND score ≥40.

In an ongoing trial of presymptomatic SMA, Zolgensma resulted in event-free survival at about 9.5 months of age in 100% of subjects. In subjects who possessed 2 copies of the SMN2 gene, the developmental motor milestone of sitting alone for at least 30 seconds was achieved by approximately 60% of subjects. Additionally, a CHOP-INTEND score ≥60 was achieved by approximately 85% of subjects. Among subjects with 3 copies of the SMN2 gene, approximately 25% achieved the ability to stand without support, including two subjects who achieved the ability to walk alone. Most subjects who did not meet these developmental motor milestones at the time of data cut-off remained within the window of achievement in which the milestone would commonly be attained.

Based on the clinical trial results and post-market experience, important identified risks of Zolgensma are hepatotoxicity and thrombocytopenia. The risk of hepatotoxicity (acute liver failure, acute liver injury and elevated liver aminotransferases) is highlighted in a Serious Warnings and Precautions box in the Zolgensma Product Monograph along with recommendations to assess and monitor liver function and administer oral prednisolone (or equivalent) to all patients, before and after infusion. Potential risks (identified from non-clinical studies and/or post-market reports) include dorsal root ganglion toxicity, cardiotoxicity, germline integration/transmission, and thrombotic microangiopathy. Uncertainty remains regarding the safety of Zolgensma when used with other 5q SMA agents (e.g., Spinraza [nusinersen]) or when used in patients with baseline anti-adeno-associated virus serotype 9 (anti-AAV9) antibody titers greater than 1:50. These risks and uncertainties, including relevant management and monitoring strategies, are adequately outlined in the Zolgensma Product Monograph.

A Risk Management Plan (RMP) for Zolgensma was submitted by Novartis Pharmaceuticals 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, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market (see What follow-up measures will the company take?).

Apart from the foreign inner labels, the submitted outer labels and package insert for Zolgensma met the necessary regulatory labelling, plain language and design element requirements. Health Canada decided to allow the use of the proposed foreign inner labels with a commitment by the sponsor to create and implement "tag" labels that would be affixed to the foreign inner labels to comply with the Food and Drug Regulations (see What follow-up measures will the company take?).

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Zolgensma was accepted.

Overall, the benefit-risk profile of Zolgensma is considered favourable for the intended patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Zolgensma Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and, therefore, Health Canada has granted 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.

 

3 What steps led to the approval of Zolgensma?

 

The sponsor requested a priority review status for the drug submission for Zolgensma. Following review of the information in the submitted clinical assessment package, Health Canada determined that the sponsor's request fulfilled the criteria set out in the Priority Review Policy. Specifically, sufficient information was provided to conclude that spinal muscular atrophy characterized by bi-allelic deletions or mutations of the survival motor neuron 1 (SMN1) gene in patients two years of age and younger represents a serious, life-threatening and/or severely debilitating disease, and that the overall benefit-risk profile of Zolgensma may be improved over the existing therapies for this disease.

 

Submission Milestones: Zolgensma

Submission Milestone Date
Pre-submission meeting 2019-12-10
Request for priority status  
Filed 2020-03-19
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics 2020-04-17
Submission filed 2020-05-21
Screening  
Screening Acceptance Letter issued 2020-06-18
Review  
Review of Risk Management Plan complete 2020-11-13
Quality Evaluation complete 2020-12-15
Clinical/Medical Evaluation complete 2020-12-15
Biostatistics Evaluation complete 2020-12-15
Labelling Review complete 2020-12-15
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2020-12-15

 

The Canadian regulatory decision on the review of Zolgensma was based on a critical assessment of the data package submitted to Health Canada. Documents with questions posed by foreign regulatory bodies (the European Medicines Agency and the United States Food and Drug Administration) and the sponsor's respective answers were consulted during the review of the submission.

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

 

4 What follow-up measures will the company take?

 

As part of the marketing authorization for Zolgensma, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • The sponsor commits to add the following safety concerns to the Canadian Addendum to the European Risk Management Plan (RMP):
    • "germline integration" as an important potential risk;
    • "use in patients older than 2 years of age" and "interaction with other 5q SMA targeting agents" as missing information.
  • The sponsor commits to consider the inclusion of thrombotic microangiopathy as a safety concern in the RMP upon the completion of the signal evaluation.
  • For the important potential risk of germline integration, the sponsor commits to develop a pharmacovigilance plan, which will include the conduct of non-clinical studies using onasemnogene abeparvovec as the test article, per the International Council for Harmonisation recommendations. The draft protocols for this study will be submitted to Health Canada within 3 months of the authorization of Zolgensma. Approximate timelines for major milestones (e.g., the initiation, completion and submission of the final report of the studies) will accompany the draft protocols. Emergent evidence for germline integration will be monitored and findings will be reported in Periodic Benefit-Risk Evaluation Reports (PBRERs) for Zolgensma. Once the risk of germline integration is better defined, the sponsor commits to update the Canadian Addendum to the European RMP with appropriate risk minimization measures, as applicable.
  • The sponsor commits to establish a data sharing agreement with the Canadian Neuromuscular Disease Registry (CNDR) to generate Canadian real-world evidence and to advocate for the enrollment of patients in the global patient registry (RESTORE) for long-term follow-up and monitoring.
  • The sponsor commits to develop and distribute comprehensive educational materials for Zolgensma to Canadian health care professionals and caregivers/patients.
  • With respect to the inner label of the drug product vials, the sponsor commits to:
    • develop and implement a "tag" label containing Canadian specific information (conforming to the labelling requirements set out in the Food and Drugs Act);
    • develop and distribute a Health Product Risk Communication, with Health Canada's approval and endorsement, to inform health care professionals of the fact that the inner label does not currently reflect Canadian requirements and it is presented in English only.

 

5 What post-authorization activity has taken place for Zolgensma?

 

Summary Basis of Decision documents (SBDs) for eligible drugs 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.

The PAAT for Zolgensma is found above.

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

 

6 What other information is available about drugs?

 

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

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Onasemnogene abeparvovec, the medicinal ingredient in Zolgensma, is a non-replicating recombinant adeno-associated virus (AAV) vector that utilizes AAV9 capsid to deliver a stable, fully functional human survival motor neuron 1 (SMN1) transgene. The transgene present in onasemnogene abeparvovec is designed to reside as episomal deoxyribonucleic acid (DNA) in the nucleus of transduced cells and is expected to be stably expressed for an extended period of time in post-mitotic cells. The transgene is introduced to target cells as a self-complementary double-stranded molecule. Expression of the transgene is driven by a constitutive promoter (cytomegalovirus enhancer/chicken-β-actin hybrid), which is expected to result in continuous and sustained SMN protein expression.

Conventional clinical pharmacokinetic studies are not applicable to gene therapy products. In lieu of conventional pharmacokinetic studies, clearance of onasemnogene abeparvovec was estimated by measuring shed virus in a subset of patients with spinal muscular atrophy (SMA) type 1 treated with the recommended dose (1.1 x 1014 vector genomes/kg) in clinical trials. In addition, biodistribution data were available for a female and a male SMA patient who died 5.7 months and 1.7 months, respectively, after infusion of onasemnogene abeparvovec at the recommended dose.

Onasemnogene abeparvovec vector shedding analysis, which assessed the amount of vector eliminated from the body through saliva, urine, and feces, were performed in five patients in a Phase I study, Study CL-101. Following infusion, onasemnogene abeparvovec was shed in saliva, urine, and feces. Clearance of onasemnogene abeparvovec was primarily via feces and the majority was cleared within 30 days after dose administration. The concentrations of onasemnogene abeparvovec in urine and saliva were highest at day 1 post infusion and dropped thereafter.

The rapid clearance of onasemnogene abeparvovec following dosing combined with the fact that onasemnogene abeparvovec is a non-replicating recombinant AAV vector suggests that there is minimal risk of exposure from patient feces, saliva, and urine.

Biodistribution data showed that the highest levels of vector DNA were found in the liver. Vector DNA was also detected in the spleen, heart, pancreas, inguinal lymph nodes, skeletal muscles, peripheral nerves, kidney, lung, intestines, gonads (male and female), spinal cord, brain, and thymus. Immunostaining for SMN protein showed generalized SMN expression in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver, skeletal muscles, and other tissues evaluated.

As the available data suggest systemic distribution of onasemnogene abeparvovec, treated patients should not donate blood, organs, tissues or cells for transplantation. This advice has been included in the Warnings and Precautions section of the Zolgensma Product Monograph. The biodistribution data further demonstrated that onasemnogene abeparvovec transduces male and female gonads, which raises a concern of potential onasemnogene abeparvovec germline integration, which has not been investigated in non-clinical studies. This potential risk is included in the Warnings and Precautions section of the Zolgensma Product Monograph. Moreover, the sponsor is requested to further characterize this risk through conducting additional non-clinical studies to analyze vector levels in germline cells and gonadal non-germline cells as a post-market commitment (see What follow-up measures will the company take?).

For further details, please refer to the Zolgensma Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Zolgensma was evaluated in open-label, single-arm, single-dose clinical trials in symptomatic infants with infantile-onset SMA and 2 copies of the SMN2 gene (Studies CL-303, CL-101, and CL-302) and in presymptomatic infants with genetically diagnosed SMA and 2 or 3 copies of the SMN2 gene (Study CL-304). All trial subjects possessed bi-allelic deletion of the SMN1 gene. Subjects were required to have anti-AAV9 antibody titers at or below 1:50 to be enrolled in the trials.

Symptomatic infants with infantile-onset SMA and 2 copies of the SMN2 gene

Study CL-303

Study CL-303 was a Phase III, open-label, single-arm, single-dose, multicentre trial that enrolled 22 subjects with symptomatic SMA type 1 with a bi-allelic deletion of the survival motor neuron 1 (SMN1) gene and 2 copies of the SMN2 gene without the SMN2 gene modifier mutation (c.859G>C; this mutation correlates with reduced severity of disease). All subjects received a single, intravenous dose of Zolgensma (1.1 x 1014 vector genomes [vg]/kg). At the time of administration, the age and weight of subjects varied from 0.5 to 5.9 months and from 3.9 to 7.5 kg, respectively.

Three subjects did not complete the study: one subject died at the age of 7.8 months due to disease progression; one subject required permanent ventilation at the age of 11.9 months; and one subject discontinued participation in the study at the age of 18 months due to an adverse event.

Co-primary efficacy endpoints were survival at 14 months of age and the proportion of patients who achieve functional independent sitting for at least 30 seconds at the 18 months of age study visit.

Twenty subjects (90.9%) demonstrated event-free survival (i.e., alive without permanent ventilation) at 14 months of age. Thirteen subjects (59.1%) achieved the milestone of independent sitting for at least 30 seconds at the 18 months of age study visit. Additionally, one subject (4.5%) walked with assistance at 12.9 months of age. Based on the natural history of the disease, subjects who met the study entry criteria would not be expected to attain the ability to sit without support. Furthermore, only approximately 25% of these subjects would be expected to survive (i.e., being alive without permanent ventilation) beyond 14 months of age.

Motor function improvements relative to baseline were also observed, as measured by the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). Twenty-one subjects (95.5%) achieved a CHOP-INTEND score ≥40. Subjects with untreated SMA type 1 do not typically achieve a CHOP-INTEND score ≥40. Among treated subjects in this study, 14 (64%) achieved a CHOP-INTEND score ≥50, including five (23%) who achieved a CHOP-INTEND score ≥60.

Study CL-101

Study CL-101 was a Phase I, open-label, single-arm, ascending dose, single-centre trial that enrolled 15 subjects (three subjects in a low-dose cohort and 12 subjects in a therapeutic-dose cohort), who had symptomatic SMA type 1 with a bi-allelic deletion of the SMN1 gene and 2 copies of the SMN2 gene without the SMN2 gene modifier mutation (c.859G>C). At the time of administration of Zolgensma, the mean age of subjects was 3.4 (minimum 0.9, maximum 7.9) months.

In the therapeutic-dose (1.1 x1014 vg/kg) cohort, all subjects demonstrated event-free survival at 14 months of age. At the end of the trial (24 months post dose), all subjects continued to demonstrate event-free survival. Ten subjects (83.3%) were able to sit without support for ≥10 seconds, nine subjects (75.0%) were able to sit without support for ≥30 seconds, and two subjects (16.7%) were able to stand and walk without assistance.

Study CL-302

Study CL-302 is an ongoing, Phase III, open-label, single-arm, single-dose multicentre trial that enrolled 33 subjects younger than 6 months of age with symptomatic SMA type 1 with a bi-allelic deletion of the survival motor neuron 1 (SMN1) gene and 2 copies of the SMN2 gene without the SMN2 gene modifier mutation (c.859G>C). The study design and study population are similar to those of Study CL-303.

The interim results of the ongoing Study CL-302 were consistent with the results of Study CL-303. Approximately 90% of subjects survived without need for permanent ventilation to ≥10.5 months of age; two patients were alive but had not yet reached 10.5 months of age (the time for primary analysis). Approximately 20% of the subjects achieved the motor milestone of sitting without support within the window of achievement for this milestone in healthy children. Improvements from baseline in CHOP-INTEND scores were demonstrated relative to the expected outcomes based on the natural history of the disease.

Presymptomatic infants with genetically diagnosed SMA and 2 or 3 copies of the SMN2 gene

Study CL-304

Study CL-304 is an ongoing, Phase III, open-label, single-arm, single-dose multicentre trial in presymptomatic newborn subjects up to 6 weeks of age who are expected to develop infantile-onset SMA. All subjects have a bi-allelic deletion of the SMN1 gene and either 2 copies (14 subjects; cohort 1) or 3 copies (15 subjects; cohort 2) of the SMN2 gene.

As of the data cut-off, all subjects demonstrated event-free survival (i.e., alive without permanent ventilation). In cohort 1, eight subjects (57.1%) achieved the motor milestone of sitting for at least 30 seconds. This milestone was achieved between 6.4 and 11.8 months of age. Six subjects (42.9%) who had not achieved this milestone as of the data cut-off were younger than 9.2 months of age (and thus were still within the normal window of achievement for this motor milestone). Additionally, 13 subjects (92.9%) had achieved a CHOP-INTEND score ≥58.

In cohort 2, four subjects (26.7%) had achieved the motor milestone of standing without support for at least 3 seconds. This milestone was achieved between 9.5 and 12.4 months of age. Eleven subjects (73.3%) who had not achieved this motor milestone at the data cut-off were younger than 12.5 months of age. Additionally, two subjects (13.3%) achieved the motor milestone of walking at least five steps independently, whereas 13 subjects (86.7%; age range of 3.3 to 12.5 months) had not yet achieved this motor milestone.

Indication

The New Drug Submission for Zolgensma was filed by the sponsor with the following indication:

  • Zolgensma (onasemnogene abeparvovec) is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.
     
  • Knowledge of the disease natural history and the use of management strategies that assist the patient in coping with the manifestations of SMA, which may include decline in motor function, serious respiratory complications, and feeding difficulties remain necessary for the overall management of the disease. Treatment with Zolgensma should only be initiated by healthcare professionals who are experienced in the management of SMA.
     

Health Canada revised the proposed indication to further characterize the intended patient population by (i) including the number of copies of the SMN2 gene in pediatric patients with 5q SMA with bi-allelic mutations in the SMN1 gene and (ii) referring to infantile-onset SMA. In addition, the revised indication briefly outlines the patient population that was studied in the clinical trials (either completed or ongoing at the time of the review), including pediatric patients with presymptomatic genetically diagnosed SMA and 2 or 3 copies of the SMN2 gene. Accordingly, Health Canada approved the following indication:

  • Zolgensma (onasemnogene abeparvovec) is indicated for the treatment of pediatric patients with 5q spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene and:
    • 3 or fewer copies of the SMN2 gene; or
    • infantile-onset SMA.
       
  • The efficacy and safety data supporting the use of Zolgensma in treating pediatric patients with SMA are derived from completed and ongoing open-label, single-arm clinical trials in patients with:
    • infantile-onset SMA and 2 copies of the SMN2 gene; and
    • presymptomatic genetically diagnosed SMA and 2 or 3 copies of the SMN2 gene.



















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  • Zolgensma is an adeno-associated virus (AAV) vector-based gene therapy. Knowledge of the disease natural history and the use of management strategies that assist the patient in coping with the manifestations of spinal muscular atrophy, which can include decline in motor function, serious respiratory complications, and feeding difficulties, remain necessary for the overall management of the disease. Administration of Zolgensma should only be performed by healthcare professionals who are experienced in the screening, diagnosis, and management of SMA and trained in the delivery of gene therapy.

For more information, refer to the Zolgensma Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Zolgensma was evaluated in 97 subjects who received Zolgensma at the recommended dose of 1.1 x 1014 vg/kg across four open-label clinical studies (CL-303, CL-101, CL-302, and CL-304; described in the Clinical Efficacy section). All subjects were treated with oral prednisolone (or equivalent) starting on the day before the infusion of Zolgensma. Prednisolone treatment was continued for at least 30 days post infusion. At the time of infusion, subjects were between 0.3 months and 7.9 months of age. The duration of safety follow-up ranged from 1.8 months to 24 months post infusion.

Upper and lower respiratory tract infections, fever, and abnormal increases in liver enzymes were the most frequently reported adverse events in the clinical trials.

Important identified risks of Zolgensma based on the clinical trial data and post-market reports are hepatotoxicity (acute liver failure/liver injury) and thrombocytopenia. Potential risks (identified from non-clinical studies and/or post-market reports) include dorsal root ganglion toxicity, cardiotoxicity, germline integration/transmission, and thrombotic microangiopathy.

Uncertainty remains regarding the safety of Zolgensma when used with other 5q SMA agents (e.g., Spinraza [nusinersen]) or when used in patients with anti-AAV9 antibody titers greater than 1:50.

Appropriate warnings and precautions are in place in the approved Zolgensma Product Monograph to address the identified safety concerns. The risk of hepatotoxicity (acute liver failure, acute liver injury and elevated liver aminotransferases) is highlighted in a Serious Warnings and Precautions box, along with recommendations to assess and monitor liver function and administer oral prednisolone (or equivalent) to all patients, before and after infusion.

For more information, refer to the Zolgensma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Onasemnogene abeparvovec is a non-replicating recombinant adeno-associated virus (AAV) vector that utilizes AAV9 capsid to deliver a stable, fully functional human survival motor neuron 1 (SMN1) transgene.

In mouse models of spinal muscular atrophy disease, treatment with onasemnogene abeparvovec increased SMN protein levels in the brain and spinal cord. These animals exhibited improved survival and motor function.

In monkeys and mice, onasemnogene abeparvovec transduced target tissues such as the neurons of the spinal cord and brain. Many non-target organs were also transduced (as determined by the presence of vector genome and/or SMN messenger ribonucleic acid [mRNA]), including skeletal and cardiac muscles, liver, lungs, spleen, adrenal gland, thymus, and reproductive organs.

Single-dose toxicity studies in mice tested onasemnogene abeparvovec doses ranging from 7.9 x 1013 to 3.91 x1014 vector genomes [vg]/kg administered by intravenous injection. Onasemnogene abeparvovec-related toxicities occurred in the heart and liver (e.g., degeneration, necrosis), and lungs (edema). Treatment-related mortality from atrial thrombosis and animal stress occurred at doses ≥2.4 x 1014 vg/kg and ≥1.5 x 1014 vg/kg, respectively. Onasemnogene abeparvovec-related findings in cardiac tissues were present at all doses studied and a no-observed-adverse-effect level could not be identified. The liver findings were observed at doses ≥1.5 x 1014 vg/kg (approximately equal to the clinical weight-normalized dose). In monkeys, a single dose of onasemnogene abeparvovec at 3 x 1013 vg/animal resulted in damage to the cerebellum and dorsal root ganglia of the spinal cord two weeks post intrathecal injection. The central nervous system findings included necrosis and neuronal loss. Microscopic changes to the heart and liver were also reported. A no-observed-adverse-effect level could not be determined for this study.

Studies have not been conducted to evaluate the carcinogenic, genotoxic, reproductive or developmental toxicity potential of onasemnogene abeparvovec.

In biodistribution studies, vector sequences were detected in the ovaries and/or testes of mice and monkeys following intravenous or intrathecal injection. Studies evaluating the potential of onasemnogene abeparvovec to integrate into the germline have not been conducted. The sponsor has committed to addressing this data gap by conducting non-clinical studies in the post-market setting (see What follow-up measures will the company take?).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Zolgensma Product Monograph. In view of the intended use of Zolgensma, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Zolgensma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

The drug substance, onasemnogene abeparvovec, is a non-replicating, non-integrating recombinant self-complementary adeno-associated virus serotype 9 (AAV9) capsid shell containing the complementary deoxyribonucleic acid (cDNA) of the human survival motor neuron 1 (SMN1) gene under the control of the cytomegalovirus enhancer/chicken-β-actin hybrid promoter. One of the two inverted terminal repeats of the AAV vector has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Detailed characterization studies were performed to provide assurance that the drug substance exhibits the expected physicochemical properties and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Onasemnogene abeparvovec is produced by transfection of human embryonic kidney cells (HEK293) with three DNA plasmids. The manufacturing of the drug substance involves upstream and downstream manufacturing processes.

The upstream manufacturing process starts with thawing of one vial of the HEK293 working cell bank. Following expansion, the cells are harvested and used to inoculate the bioreactor. The cells are expanded in the bioreactor and transfected with a triple DNA plasmid solution to produce the AAV9 vector containing the SMN1 transgene. After cell culture, the cells are lysed, and the lysed cell solution is subjected to clarification. The clarified lysate is concentrated and diafiltered, and the resulting tangential flow filtration 1 (TFF1) intermediate is frozen and stored at or below -60 °C.

The downstream manufacturing process includes thawing and pooling of the TFF1 intermediate, buffer addition, acidification and clarification, followed by chromatographic, filtration, and centrifugation steps, and subsequent filtration and filling of the bulk drug substance into bottles. The bulk drug substance is frozen and stored at or below -60 °C.

Process validation studies demonstrated that the drug substance manufacturing process is robust, yields material suitable for the next stage of the manufacturing process and consistently produces a drug substance that meets specifications.

The manufacturing process of the drug product involves thawing and mixing of the drug substance, sterile filtration, and concentration adjustment. The sterile bulk drug substance is filled into a 10 mL crystal zenith vial with a nominal fill volume of 5.5 mL or 8.3 mL. After visual inspection and labelling, the vials are stored at or below -60 °C for up to 12 months. Following disposition, the vials are packaged into a patient-specific commercial kit and stored at or below -60 °C until ready for distribution.

Process validation studies demonstrated that the drug product manufacturing process is robust and consistently produces a drug product that meets the acceptance criteria.

Control of the Drug Substance and Drug Product

The drug substance and drug product specifications were established based on batch release data and clinical experience, and are deemed acceptable.

The primary and working reference materials used for the release and stability testing of the drug substance and drug product have been appropriately qualified.

Compendial and non-compendial tests are used as analytical methods for in-process, release and stability testing. All analytical methods have been appropriately validated and are suitable for the intended purpose.

Zolgensma is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory.

The stability data support the proposed shelf life of 12 months for the drug product, when stored at or below -60 °C.

Facilities and Equipment

An on-site evaluation of the drug substance and drug product manufacturing facility could not be conducted by Health Canada due to the coronavirus disease 2019 (COVID-19) pandemic and travel restrictions at the time of the review. An evaluation of the suitability of the facility was performed by a thorough review of additional documentation provided upon Health Canada's request. This evaluation was considered adequate to support the final quality review recommendation.

The design, operations, and controls of the facility and equipment involved in production are considered suitable for the activities and products manufactured.

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing process of the drug substance to prevent contamination and maintain microbial control.

The risk of introducing replication-competent adeno-associated virus is minimized by the vector design, manufacturing process, and testing strategy. Thorough testing of the master cell bank, working cell bank, and unprocessed bulk provides confirmation that the cell substrate and starting materials for the drug substance manufacturing process are free of detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). Viral clearance studies using model viruses demonstrate that the purification process is able to provide sufficient capacity to remove or inactivate viruses with broad ranges of biochemical and biophysical properties. Testing of the cells beyond the limit of in vitro cell age allows assessment as to whether expression of endogenous retroviruses is induced due to the production process and provides assurance that the production process is not prone to contamination by adventitious viruses.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens.

No excipients of human or animal origin are used in the manufacture of the drug product.

 

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