Summary Basis of Decision for Nexviazyme

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 Nexviazyme is located below.

Recent Activity for Nexviazyme

SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Nexviazyme

Date SBD issued: 2022-01-27

The following information relates to the new drug submission for Nexviazyme.

Avalglucosidase alfa

Drug Identification Number (DIN):

  • DIN 02522365 - 100 mg/vial avalglucosidase alfa, powder for solution, intravenous administration

Sanofi-aventis Canada Inc.

New Drug Submission Control Number: 245680

On November 12, 2021, Health Canada issued a Notice of Compliance to Sanofi‑aventis Canada Inc. for the drug product Nexviazyme.

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 Nexviazyme is favourable for the long‑term treatment of patients with late‑onset Pompe disease (acid α‑glucosidase deficiency).

1 What was approved?

Nexviazyme, an enzyme replacement therapy, was authorized for the long‑term treatment of patients with late‑onset Pompe disease (acid α‑glucosidase deficiency).

Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Nexviazyme in pediatric late‑onset Pompe disease patients (>6 months of age) has been established. Therefore, Health Canada has authorized an indication for pediatric use in these patients. Nexviazyme is not indicated in patients with infantile onset Pompe disease (IOPD); a study in 22 patients with IOPD is ongoing.

Limited evidence from clinical studies does not suggest that use in the geriatric population (≥65 years of age) is associated with differences in efficacy or safety.

The use of Nexviazyme is contraindicated for those who have experienced life‑threatening allergic (hypersensitive) reactions to avalglucosidase alfa, its ingredients, or components of the container, and re‑administration of the medicine was not successful.

Nexviazyme (100 mg/vial avalglucosidase alfa) is presented as a lyophilized powder. In addition to the medicinal ingredient, the powder contains glycine, L‑histidine, L‑histidine hydrochloride monohydrate, mannitol, and polysorbate 80.

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

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 Nexviazyme Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Nexviazyme approved?

Health Canada considers that the benefit‑risk profile of Nexviazyme is favourable for the long‑term treatment of patients with late‑onset Pompe disease (LOPD; acid α‑glucosidase deficiency).

Pompe disease is a glycogen storage disease caused by mutations in the gene which encodes the lysosomal hydrolase acid α‑glucosidase (the GAA gene). There are more than 500 mutations of the GAA gene, resulting in a heterogeneous range of onset of clinical symptoms and symptom severity. The disease manifests as a broad spectrum of signs and symptoms, ranging from a rapidly progressive infantile‑onset Pompe disease (IOPD) to a more progressive late‑onset Pompe disease. No data are available for Canadian prevalence of disease; however, the prevalence of Pompe disease in the United States is estimated to be 1 in 40,000 people.

Avalglucosidase alfa, the medicinal ingredient in Nexviazyme, is a recombinant human α‑glucosidase (rhGAA) conjugated with multiple copies of synthetic bis‑mannose‑6‑phosphate glycan (bisM6P). It is an enzyme replacement therapy produced in Chinese hamster ovary (CHO) cells by recombinant deoxyribonucleic acid (DNA) technology. Prior to the development and authorization of enzyme replacement therapy, there was no available treatment for Pompe disease. The development and availability of enzyme replacement therapy has improved the survival of patients with IOPD and has also increased quality of life and functioning in patients with LOPD. In Canada, the current standard of care for Pompe disease is alglucosidase alfa (AGA), marketed by the same sponsor under the brand name Myozyme.

The main evidence of the clinical efficacy of Nexviazyme was provided through the results of the Phase III pivotal study, COMET (EFC14028). This study was conducted in 100 treatment‑naïve patients with LOPD with a confirmed GAA enzyme deficiency. Patients were randomized to receive either AGA (the current standard of care) or Nexviazyme. The primary efficacy endpoint was the change from baseline to Week 49 in the forced vital capacity (FVC) (% predicted) in the upright position. In the modified intent‑to‑treat population, the least squares mean change (standard error) in the FVC from baseline to Week 49 was 2.89 (0.88) in the group treated with Nexviazyme and 0.46 (0.93) in the group treated with AGA. The difference in least squares mean change of 2.43 with a lower boundary of the 95% confidence interval of ‑0.13 between the two treatment groups exceeded ‑1.1 (the predefined non‑inferiority margin of ‑1.1). This signifies that Nexviazyme is statistically non‑inferior to AGA (p = 0.0074); superiority was not established.

The clinical safety of Nexviazyme was evaluated in a pooled analysis of 138 patients, including patients from the pivotal study. At least one treatment‑emergent adverse event (TEAE) was reported by 126 of 138 patients (91.3%), and serious adverse events were reported by 35 patients (25.4%). The most frequently reported TEAEs included nasopharyngitis, headache, diarrhea, back pain, fall, and nausea.

A Serious Warnings and Precautions box has been included in the Nexviazyme Product Monograph to highlight the risks of hypersensitivity reactions including anaphylaxis, and infusion‑associated reactions (IARs). Appropriate medical support measures should be readily available during the administration of Nexviazyme. If a severe hypersensitivity reaction (e.g., anaphylaxis) or an IAR occurs, Nexviazyme should be discontinued immediately and appropriate medical treatment should be initiated. Further instructions are included in the Nexviazyme Product Monograph.

The safety profile of Nexviazyme appears to be consistent with the established safety profile for the current standard of care, AGA, and is considered acceptable for the target population. The data reviewed by Health Canada were supportive of an indication for LOPD, but there was insufficient evidence to support an indication for IOPD.

A Risk Management Plan (RMP) for Nexviazyme was submitted by Sanofi‑aventis Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Nexviazyme Product Monograph meet 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 Nexviazyme was accepted.

Nexviazyme has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nexviazyme 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 Nexviazyme?

The New Drug Submission (NDS) for Nexviazyme was reviewed as part of the New Active Substance Work Sharing Initiative (NASWSI), a work-sharing initiative between Canada, Australia, Singapore, Switzerland, and the United Kingdom. This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high‑quality therapeutic products.

For this submission, Health Canada completed the quality review of Nexviazyme, while Australia's Therapeutic Goods Administration (TGA) completed the clinical review and Swissmedic completed the non‑clinical review. Although the review of the submission was collaborative, each jurisdiction made its regulatory decision independently of the others.

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

Submission Milestones: Nexviazyme

Submission MilestoneDate
Pre-submission meeting2020-07-29
New drug submission filed2020-10-23
Screening
Screening Acceptance Letter issued2020-11-30
Review
Biostatistics evaluation complete2021-11-12
Quality evaluation complete2021-08-30
Non-clinical evaluation complete2021-10-13
Review of Risk Management Plan complete2021-11-04
Clinical/medical evaluation complete2021-11-09
Labelling review complete2021-11-10
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate2021-11-12

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

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

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.

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

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

The clinical review of Nexviazyme was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Health Canada and Switzerland’s Swissmedic. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Clinical Pharmacology

Pompe disease (also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II) is a rare metabolic muscle disease inherited in an autosomal recessive manner. It is defined by a deficiency of acid α‑glucosidase (GAA), which is necessary for the degradation of lysosomal glycogen. Pompe disease results in the intra‑lysosomal accumulation of glycogen in various tissues, particularly in cardiac and skeletal muscles, which leads to the development of cardiomyopathy, progressive muscle weakness, and impairment of respiratory function.

Avalglucosidase alfa is a recombinant human acid α‑glucosidase (rhGAA) that provides an exogenous source of GAA. Avalglucosidase alfa is modified from alglucosidase alfa (AGA) through the conjugation of approximately seven hexamannose structures, each containing two terminal mannose‑6‑bisphosphate (M6P) moieties. Avalglucosidase alfa therefore has a 15‑fold increase in M6P moieties relative to AGA, which drive uptake into the diaphragm and other skeletal muscle via the cation‑independent M6P receptor.

The clinical pharmacology data reviewed in support of Nexviazyme were provided in all three clinical studies included in the submission: the Phase III pivotal study (COMET [EFC14028]), a Phase II multiple ascending dose study (TDR12857), and an ongoing extension study (LTS13769). All three studies were conducted in patients with late‑onset Pompe disease (LOPD). Seventy‑five patients aged 16 to 78 years were evaluated, and all received a 5 mg/kg to 20 mg/kg dose of avalglucosidase alfa every other week for up to five years. Clinical pharmacology data from all three studies were used to generate an initial population pharmacokinetic (popPK) model of avalglucosidase alfa in patients with LOPD. This popPK model was subsequently extended into the infantile‑onset Pompe disease (IOPD) patient population from an ongoing multiple ascending dose study (ACT14132).

In patients with LOPD, avalglucosidase alfa exposure increased dose‑proportionally across the dose range of 5 mg/kg to 20 mg/kg. No accumulation of avalglucosidase alfa was observed following dosing every other week. The half‑life (t½) of avalglucosidase alfa was approximately 1.55 hours. Clearance was 1.22 L/h to 1.37 L/h, and volume of distribution in the popPK‑derived central compartment was 3.4 L. The pharmacokinetic profile of avalglucosidase alfa was consistent between treatment‑naïve patients and patients previously treated with alglucosidase alfa.

A robust decrease was observed in the levels of urinary glucose tetrasaccharide (Hex4; the primary pharmacodynamic marker) in patients with LOPD who received a 20 mg/kg dose every other week. This decrease was maintained throughout the duration of treatment, and increased following cessation of treatment. However, due to the heterogeneity of baseline Hex4 levels and the small number of patients at each dose level, the dose‑response relationship between avalglucosidase alfa and Hex4 could not be definitively assessed.

The impact of immunogenicity on the pharmacokinetic profile of avalglucosidase alfa was also evaluated. In the pivotal study (EFC14028), 45 of the 47 patients dosed with 20 mg/kg avalglucosidase alfa every other week were positive for anti‑drug antibodies (ADAs). No correlation was observed between ADA or neutralizing antibody titer and avalglucosidase alfa exposure. However, as this observation is based on a small sample size, the effects of ADAs or neutralizing antibodies on avalglucosidase alfa exposure cannot be determined.

No significant covariates were observed for avalglucosidase alfa exposure in patients with LOPD. Based on the lack of age as a covariate for exposure, the weight‑based dosing regimen, and the pathogenesis of LOPD, the popPK model was considered appropriate for the purpose of extrapolating the data from adult patients into pediatric patients.

The clinical pharmacology data were considered adequate to support an indication for patients with LOPD, with a dosing regimen of 20 mg/kg avalglucosidase alfa every other week, regardless of age. The review of the clinical pharmacology data did not support the proposed indication and dose in patients with IOPD.

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

Clinical Efficacy

The clinical efficacy of Nexviazyme was established through the results of the Phase III pivotal study, COMET (EFC14028), which was conducted in 100 treatment‑naïve patients (99 adult patients and one pediatric patient [16 years of age]) with late‑onset Pompe disease (LOPD). Patients were randomized to receive either alglucosidase alfa (AGA; 49 patients) or Nexviazyme (51 patients), and received the assigned study treatment as an intravenous infusion at a dose of 20 mg/kg body weight every second week. All patients in the study had a confirmed GAA enzyme deficiency. Patients excluded from the study included those who required invasive ventilation, who were not able to ambulate 40 m without stopping and without an assistive device, or who were unable to successfully perform repeated forced vital capacity (FVC) measurements in the upright position of ≥30% predicted and ≤85% predicted. The study included an open‑label, long‑term, follow‑up phase of up to 5 years for all patients, in which patients in the AGA arm were switched to treatment with Nexviazyme.

The primary efficacy endpoint was the change from baseline to Week 49 in the FVC (% predicted) in the upright position. In the modified intent‑to‑treat population (mITT; 100 patients), the least squares mean change (standard error [SE]) from baseline to Week 49 in the FVC was 2.89 (0.88) in the group treated with Nexviazyme and 0.46 (0.93) in the group treated with AGA. The difference in least squares mean change of 2.43 with a lower boundary of the 95% confidence interval of ‑0.13 between the two treatment groups exceeded ‑1.1 (the predefined non‑inferiority margin of ‑1.1). This signifies that Nexviazyme is statistically non‑inferior to AGA (p = 0.0074); superiority was not established.

Key secondary efficacy endpoints, including the 6‑minute walk test, hand‑held dynamometry, and the quick motor function test, supported the primary efficacy results. However, these results were not assessed for statistical significance due to the hierarchical testing strategy.

Indication

Sponsor's proposed indication Health Canada-approved indication
Nexviazyme (avalglucosidase alfa for injection) is an enzyme replacement therapy indicated for the long‑term treatment of patients with Pompe disease (acid α‑glucosidase deficiency). Nexviazyme (avalglucosidase alfa for injection) is an enzyme replacement therapy indicated for the long‑term treatment of patients with late‑onset Pompe disease (acid α‑glucosidase deficiency).

The indication was revised to more accurately reflect the patient population in the pivotal study. The indication originally proposed was for the treatment of patients with Pompe disease. The safety and efficacy of Nexviazyme has been established specifically in patients with LOPD. Health Canada has therefore authorized an indication for pediatric use in patients >6 months of age with LOPD. However, Nexviazyme is not indicated in patients with IOPD.

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

Clinical Safety

The clinical safety of Nexviazyme was evaluated in a pooled analysis of 138 patients (118 adult and 20 pediatric patients), including patients from the pivotal COMET study (described in the Clinical Efficacy section). At least one treatment‑emergent adverse event (TEAE) was reported by 126 of 138 patients (91.3%). The most frequently reported TEAEs included nasopharyngitis, headache, diarrhea, back pain, fall, and nausea. Serious adverse events were reported by 35 patients (25.4%). The frequency of serious adverse events was consistent between treatment‑naïve and treatment‑experienced adult patients, and a higher incidence of serious adverse events was observed in pediatric patients. One death was reported in a patient receiving Nexviazyme, which was determined to be unlikely related to the study drug.

A Serious Warnings and Precautions box is included in the Nexviazyme Product Monograph to highlight the risks of hypersensitivity reactions including anaphylaxis, and infusion‑associated reactions (IARs). Appropriate medical support measures should be readily available during the administration of Nexviazyme. If a severe hypersensitivity reaction (e.g., anaphylaxis) or an IAR occurs, Nexviazyme should be discontinued immediately and appropriate medical treatment should be initiated. Further instructions are included in the Nexviazyme Product Monograph.

The safety profile of Nexviazyme appears to be consistent with the established safety profile for the current standard of care, alglucosidase alfa, and is considered acceptable for the target population. The data reviewed were supportive of an indication for LOPD, but there was insufficient evidence to support an indication for IOPD. Appropriate risk management measures are in place to address the safety concerns identified, and to promote the safe and effective use of Nexviazyme. Health Canada concurs with the Therapeutic Goods Administration’s assessment of the clinical data package. Overall, the benefit‑risk profile of Nexviazyme is favourable for the approved indication.

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

7.2 Non-Clinical Basis for Decision

The non‑clinical review of Nexviazyme was completed by Switzerland’s Swissmedic as part of a work-sharing initiative with Health Canada and Australia’s Therapeutic Goods Administration. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

The key non‑clinical studies included primary pharmacodynamics, repeat‑dose toxicity, and reproductive and developmental toxicity studies. Overall, no major issues were identified in the non‑clinical data package during Swissmedic’s review.

In vivo pharmacokinetic and pharmacodynamic studies conducted with avalglucosidase alfa (the medicinal ingredient in Nexviazyme) demonstrated skeletal muscle biodistribution and glycogen reduction in these tissues.

A 26‑week repeat‑dose toxicity study was conducted in which either a vehicle control or avalglucosidase alfa (at doses of 50 mg/kg or 200 mg/kg body weight) was administered intravenously to monkeys once every two weeks. No adverse effects were attributed to the test article. One monkey in the mid-dose group and one monkey in the high‑dose group died due to infection following contamination at the injection site due to technical error. The no‑observed‑adverse‑effect level (NOAEL) is considered to be the highest dose administered, 200 mg/kg body weight every two weeks. The NOAEL is 23‑fold higher than the human exposure level at the maximum recommended human dose (MRHD), based on exposure as measured by the area under the plasma concentration‑time curve (AUC).

A fertility study was conducted in male and female mice to evaluate the effects of avalglucosidase alfa on mating performance, fertility, and early embryonic development. Doses of 0 (vehicle control), 10, 20, or 50 mg/kg body weight (equal to 3.5‑fold, 7‑fold, and 17.5‑fold higher than the MRHD on a mg/kg basis, respectively) were administered once every two days. Male mice were dosed for a period of 10 weeks prior to and during cohabitation, and female mice were dosed for a period of 2 weeks through conception to gestational day 7. No adverse effects were observed on male or female fertility. Death related to an immunologic response, including an anaphylactoid response, occurred at all doses. A NOAEL could not be determined, as deaths occurred due to hypersensitivity reactions at the lowest dose.

An embryo‑fetal development study was conducted in pregnant mice, with avalglucosidase alfa administered intravenously at doses of 0 (vehicle control), 10, 20, or 50 mg/kg body weight once daily during the period of organogenesis (gestational days 6 through 15). Caesarean sections were performed on gestational day 18. The results of placental transfer studies indicated that avalglucosidase alfa is not transported from the maternal circulation to the fetal circulation. The deaths of two female mice in the high‑dose group (50 mg/kg body weight per day) were attributed to an immunologic response, including an anaphylactoid response. Female mice in the high‑dose group also had an increased incidence of post‑implantation loss (16%) compared to female mice in the control group (6%). The increased post‑implantation loss may be related to the immunologic response in the mothers. The NOAEL for both maternal and embryo‑fetal toxicity was determined to be 20 mg/kg body weight per day, which is 4.8‑fold higher than the human exposure at the MRHD, based on exposure as measured by the AUC.

An embryo‑fetal development study was also conducted in pregnant rabbits, with avalglucosidase alfa administered intravenously at doses of 0 (vehicle control), 30, 60, or 100 mg/kg body weight once daily during the period of organogenesis (gestational days 6 to 19). Caesarean sections were performed on gestational day 29. Effects on maternal body weight and food consumption were observed. No adverse effects were observed on embryo‑fetal development. The NOAEL for maternal toxicity was 30 mg/kg body weight per day, and the NOAEL for embryo‑fetal toxicity was 100 mg/kg body weight per day. Respectively, these values are 14.5‑fold and 91‑fold higher than the human exposure at the MRHD, based on exposure as measured by the AUC.

In a pre‑ and postnatal development study, avalglucosidase alfa was intravenously administered to pregnant mice at doses of 0 (vehicle control), 10, 20, or 50 mg/kg every two days from implantation to weaning (gestational day 6 through postnatal day 20). No effects were observed on the development of the first filial (F1) generation, sexual maturation, or neurobehavioural parameters. The maternal and developmental NOAELs were 50 mg/kg/dose every two days, which is 17.5‑fold higher than the MRHD on a mg/kg basis. Exposure to avalglucosidase alfa from maternal milk was not assessed.

In a juvenile toxicity study, avalglucosidase alfa was administered intravenously at doses of 0 (vehicle control), 20, 50, or 100 mg/kg once every two weeks to female mice and doses of 0 (vehicle control), 25, 50, or 100 mg/kg once every two weeks to male mice. Respectively, the doses correspond to exposures below 1‑fold, 1‑fold, 2‑fold, and 4‑fold to 7‑fold higher than the human exposure at MRHD, based on exposure as measured by the AUC. Doses were administered for approximately 9 weeks from postnatal day 21. Death related to an immunologic response, including an anaphylactoid response, was observed at all doses without dose‑response. Increases were observed in surviving male mice with respect to white blood cell parameters, consistent with an immunologic (anaphylactoid) response. No effects were reported on developmental neurobehavioural functional parameters, sexual maturation, or fertility. A NOAEL could not be determined, as deaths occurred due to hypersensitivity reactions at the lowest doses administered.

The results of the non‑clinical studies as well as the potential risks to humans have been included in the Nexviazyme Product Monograph. Health Canada concurs with Swissmedic’s assessment of the non‑clinical data package. Considering the intended use of Nexviazyme, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

The quality review of Nexviazyme was completed by Health Canada as part of a work-sharing initiative with Australia’s Therapeutic Goods Administration and Switzerland’s Swissmedic. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Characterization of the Drug Substance

Avalglucosidase alfa (the drug substance) is a recombinant human acid α‑glucosidase (rhGAA) conjugated with multiple copies of glycan E13, a synthetic bis‑mannose‑6-phosphate (bis‑M6P)‑containing glycan. Binding of avalglucosidase alfa to the cation‑independent mannose‑6-phosphate receptor (CIMPR) on the cell surface occurs via the carbohydrate groups. After binding to the CIMPR, the enzyme is internalized and transported into the low pH environment of the lysosomes where it catalyzes the hydrolysis of glycogen to glucose.

Comprehensive characterization studies were performed on several batches of the drug substance to provide assurance that avalglucosidase alfa consistently exhibits the desired characteristic structure and biological activity. Primary structure, higher order structure, post‑translational modifications, glycosylation profile, purity, and potency were all examined.

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

The manufacturing process of avalglucosidase alfa (the drug substance) involves the manufacturing of alglucosidase alfa (AGA), which is oxidized and then undergoes conjugation with synthetic glycan E13 to generate avalglucosidase alfa.

Alglucosidase alfa is expressed from cells which have been engineered to express it through recombinant deoxyribonucleic acid (DNA) technology. A cell culture is initiated from a single vial from a working cell bank. As the cell culture expands, the pre‑oxidation intermediate (alglucosidase alfa) is expressed and secreted into the culture medium. Once the cells have grown for the targeted duration, the culture medium is harvested, clarified by depth filtration, followed by concentration and filtration steps. Purification is achieved through a series of chromatography and filtration steps. A final filtration step concentrates the enzyme and exchanges it into a buffer, to form the pre‑oxidation intermediate.

The pre‑oxidation intermediate is diluted, and a reagent is added for the oxidation reaction, which is subsequently quenched. The process stream is concentrated and filtered, and the glycan E13 is added for the conjugation reaction. The mixture is purified by chromatography, filtered, and formulated to form the drug substance, avalglucosidase alfa. The drug substance undergoes bioburden reduction filtration, and is stored at 2 °C to 8 °C.

The manufacturing process of Nexviazyme, the drug product, involves pooling and mixing of drug substance lots, sterile filtration, filling into vials, lyophilization, capping, and inspection.

Changes made throughout pharmaceutical development to both the drug substance and drug product manufacturing processes did not impact their quality and are considered acceptable upon review. Comparability was demonstrated across each process based on release testing, extended characterization and stability studies.

The sponsor leveraged the validated process for AGA (marketed by the same sponsor under the brand name Myozyme) from the thawing of the working cell bank vial to the production of the AGA pre‑oxidation intermediate. Continuous process verification data were provided to demonstrate continued control of these steps of the process. Process validation was performed for the steps from the production of the pre‑oxidation intermediate to the final avalglucosidase alfa drug substance as well as for the drug product manufacturing process. The process performance qualification data reviewed reflect consistency in the manufacturing process.

None of the non‑medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of avalglucosidase alfa with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

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

The control strategy for both the drug substance and the drug product includes in‑process controls and parameters, control of materials, and release and stability testing. Overall, the proposed control strategy is considered suitable to ensure control of the identified critical quality attributes (CQAs). A nitrosamine risk assessment was requested during the review cycle. The results confirmed that there is no significant risk of nitrosamine contamination and/or formation from the raw materials during the manufacturing process, and/or during storage of the drug substance or drug product.

Specifications for the drug substance and drug product include assays for identity, quantity, biological activity, purity and impurities, and safety. The acceptance criteria were set based on the regulatory expectations for safety‑related attributes, clinical experience for Nexviazyme, process capability, and stability data. Stability data for stability‑indicating attributes were assessed to ensure appropriate acceptance criteria at release and throughout the shelf life. For quality attributes that did not indicate any significant trends under long-term or accelerated stability conditions, limits were calculated where possible using a statistical approach from historical data. The proposed specifications were deemed acceptable to support quality and safety.

All in‑house methods were appropriately validated in accordance with the relevant International Council for Harmonisation (ICH) guidelines. No significant issues were identified with the methods, and all methods supported the proposed specifications. The results of consistency lot testing performed by Health Canada indicated that the drug product lots tested were within specifications, were consistent from batch to batch, and were similar to results reported on the Certificate of Analysis.

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 proposed 24‑month shelf life at 2 °C to 8 °C for Nexviazyme is considered acceptable. The reconstituted product can be stored for up to 24 hours when refrigerated at 2 °C to 8 °C. The diluted product (in 5% dextrose) can be stored for up to 24 hours when refrigerated at 2 °C to 8 °C, and for up to 9 hours, including infusion time, when stored at room temperature up to 27 °C.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on‑site evaluations were not recommended for the drug substance and drug product manufacturing sites.

Adventitious Agents Safety Evaluation

Viral clearance studies previously performed for the manufacturing of AGA were leveraged for this submission. The initial steps of the manufacturing process of avalglucosidase alfa are the same, and both products are marketed by the same sponsor. Additional viral clearance studies were performed for steps that are different in the manufacturing process of avalglucosidase alfa. Scaled‑down studies demonstrated the consistent clearance of several types of model viruses to levels below the acceptable threshold.

The raw materials of biological origin used in the Nexviazyme cell banking and upstream drug substance manufacturing process have been reviewed previously in the context of Myozyme and were shown to be suitable for use. Endotoxin and bioburden are controlled throughout the process.

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