Summary Basis of Decision for Strensiq

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 Strensiq is located below.

Recent Activity for Strensiq

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.

Post-Authorization Activity Table (PAAT) for Strensiq

Updated: 2023-09-01

The following table describes post-authorization activity for Strensiq, a product which contains the medicinal ingredient asfotase alfa. 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 that are found in PAATs..

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

Drug Identification Number (DIN):

  • DIN 02444607 – 40 mg/mL asfotase alfa (12 mg/0.3 mL vial), solution, subcutaneous administration
  • DIN 02444615 – 40 mg/mL asfotase alfa (18 mg/0.45 mL vial), solution, subcutaneous administration
  • DIN 02444623 – 40 mg/mL asfotase alfa (28 mg/0.7 mL vial), solution, subcutaneous administration
  • DIN 02444631 - 40 mg/mL asfotase alfa (40 mg/1 mL vial), solution, subcutaneous administration
  • DIN 02444658 – 40 mg/mL asfotase alfa (80 mg/0.8 mL vial), solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 272284 2023-02-13 Issued NOC 2023-08-21 Submission filed as a Level I – Supplement to add a drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 254422 2021-07-08 Issued NOL 2021-09-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the cell bank qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 251587 2021-04-09 Issued NOC 2021-08-25 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, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 246727 2020-11-19 Issued NOL 2020-12-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the working reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 245930 2020-10-30 Issued NOC 2020-12-22 Submission filed as a Level I – Supplement for an additional drug substance manufacturing suite and changes to the drug substance manufacturing process. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 240608 2020-06-11 Issued NOL 2020-09-23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the storage conditions for the drug product and the working reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 231406 2019-09-06 Cleared 2020-05-27 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #7 for the period 2018-07-04 to 2019-01-03 and PBRER-C #8 for the period 2019-01-04 to 2019-07-03. The information was reviewed and found acceptable. No further action was required.
SNDS-C # 229061 2019-06-21 Issued NOC 2020-05-26 Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission included final study reports for studies ENG-006-09/ENB-008-10, ENG-010-10, ENB-009-10, ENB-002-08/ENB-003-08, and AA-HPP-208. The information was reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2015-08-14.
NC # 228778 2019-06-18 Issued NOL 2019-10-08 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the controls applied during the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 224481 2019-02-07 Issued NOL 2019-05-22 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 220076 2018-09-12 Cleared 2019-02-14 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #5 for the period 2017-07-04 to 2018-01-03 and PBRER-C #6 for the period 2018-01-04 to 2018-07-03. The information was reviewed and found acceptable. No further action was required.
SNDS # 217007 2018-06-19 Issued NOC 2019-01-29 Submission filed as a Level I – Supplement to add a manufacturing site for the production of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 222614 2018-11-30 Issued NOL 2019-01-16 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and to change the controls applied during the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 217857 2018-07-03 Issued NOL
2018-10-17		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new testing site and for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 214682 2018-03-20 Issued NOL
2018-06-19		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 215608 2018-04-19 Issued NOL
2018-05-02		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 209212 2017-09-08 Cleared
2017-11-10		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #3 for the period 2016-07-04 to 2017-01-03 and PBRER-C #4 for the period 2017-01-04 to 2017-07-03. The information was reviewed and found acceptable.
NC # 204145 2017-03-28 Issued NOL
2017-07-06		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Contraindications, Warnings and Precautions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 198374 2016-09-09 Cleared
2016-11-29		 Submission filed in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. PBRER-C #1 for the period 2015-07-03 to 2016-01-03 and PBRER-C #2 for the period 2016-01-04 to 2016-07-03. The information was reviewed and considered acceptable, and the sponsor committed to filing a Notifiable Change with changes to the Product Monograph.
NC # 195491 2016-05-26 Issued No Objection Letter
2016-07-19		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add drug product testing sites and revise specifications and stability testing protocol. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02444623) market notification Not applicable Date of first sale:
2016-06-07		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02444631) market notification Not applicable Date of first sale:
2016-06-01		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 194540 2016-04-25 Issued No Objection Letter
2016-05-16		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information. As a result of the Notifiable Change, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 191831 2016-01-29 Issued No Objection Letter
2016-02-26		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the drug substance purification process. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02444658) market notification Not applicable Date of first sale:
2016-02-17		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02444615) market notification Not applicable Date of first sale:
2015-10-20		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 179340 2014-10-30 Issued NOC
2015-08-14		 Notice of Compliance issued under the Notice of Compliance with Conditions (NOC/c) Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Strensiq

Date SBD issued: 2015-10-21

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

Asfotase alfa, 40 mg/mL and 100 mg/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • 02444607 - 12 mg/0.3 mL, solution
  • 02444658 - 80 mg/0.8 mL, solution
  • 02444615 - 18 mg/0.45 mL, solution
  • 02444623 - 28 mg/0.7 mL, solution
  • 02444631 - 40 mg/mL, solution

Alexion Pharma International SARL

New Drug Submission Control Number: 179340

 

On August 14, 2015, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Alexion Pharma International SARL for the drug product Strensiq. 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 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 Strensiq is favourable as an enzyme replacement therapy for patients with confirmed diagnosis of paediatric-onset hypophosphatasia.

 

1 What was approved?

 

Strensiq, an enzyme replacement therapy, was authorized as an enzyme replacement therapy for patients with confirmed diagnosis of pediatric-onset hypophosphatasia.

Treatment with Strensiq should be initiated by a physician with experience in the management of patients with metabolic bone disorders.

The safety and efficacy of Strensiq have not been established in the elderly populations (˃65 years of age).

Strensiq is contraindicated in patients who are hypersensitive to the active substance (asfotase alfa), or to any of the excipients in the formulation. Strensiq was approved for use under the conditions stated in the Strensiq Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Strensiq (40 mg/mL and 100 mg/mL, asfotase alfa) is presented as solution for subcutaneous injection. In addition to the medicinal ingredient, the solution contains sodium chloride, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (monohydrate), and water for injections.

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

 

2 Why was Strensiq approved?

 

Health Canada considers that the benefit/risk profile of Strensiq is favourable as an enzyme replacement therapy for patients with confirmed diagnosis of pediatric-onset hypophosphatasia (HPP). Strensiq was authorized under the Notice of Compliance with Conditions (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.

Hypophosphatasia is a rare genetic metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation. Hypophosphatasia is caused by loss-of-function mutation(s) in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP) causing elevated concentrations of the TNSALP substrates including inorganic pyrophosphate (PPi) and pyridoxal-5’-phosphate (PLP). Hypophosphatasia can lead to progressive skeletal deformity, fractures, impaired bone healing, muscle weakness, reduced physical function, seizures, impaired renal function, and respiratory failure. In those most severely affected, HPP can be fatal. Currently, there are no approved disease-modifying treatments for patients with HPP.

There are five major clinical forms of HPP that range from an extremely severe form that can cause stillbirth to a form associated with only premature loss of baby (deciduous) teeth, but no bone abnormalities. Hypophosphatasia affects males and females in equal numbers. In Canada, the severe forms of hypophosphatasia are estimated to affect approximately 1 in 100,000 live births. The overall incidence and prevalence of all forms of hypophosphatasia is unknown.

Based on the preliminary results obtained from the ongoing clinical studies, the benefit of Strensiq for the treatment of patients with hypophosphatasia fulfil the level of scientific requirements for a rare disease as assessed under the Notice of Compliance with Conditions (NOC/c) guidance.

The safety profile of Strensiq is considered to be acceptable for a product intended to be used for enzyme replacement therapy.

A Risk Management Plan (RMP) for Strensiq was submitted by Alexion Pharma International SARL 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.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Strensiq has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Strensiq therapy are considered to outweigh the risks. Strensiq has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling. Appropriate warnings and precautions are in place in the Strensiq Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Strensiq 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 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 Strensiq?

 

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission (NDS) for Strensiq. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness that the drug has the potential to provide:

  1. Effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada, or
  2. 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.

 

Submission Milestones: Strensiq

Submission Milestone Date
Pre-submission meeting: 2014-06-25
Request for priority status  
Filed: 2014-08-08
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: 2014-09-08
Submission filed: 2014-10-30
Screening  
Screening Acceptance Letter issued: 2014-12-12
Review  
On-Site Evaluation  
Quality Evaluation complete 2015-06-29
Clinical Evaluation complete 2015-08-14
Labelling Review complete: 2015-06-24
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: 2015-06-30
Response filed (Letter of Undertaking) 2015-07-10
Notice of Compliance (NOC) issued by Director General under the Notice of Compliance with Conditions (NOC/c) Guidance 2015-08-14

 

The Canadian regulatory decision on the quality review of Strensiq was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

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

 

4 What follow-up measures will the company take?

 

In addition to the requirements outlined in the the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the following reports:

  1. The final clinical study reports (CSRs) for studies ENB-006-09/ENB-008-10 entitled : ENB-006-09 "A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Children with Hypophosphatasia (HPP)" and ENB-006-10 "Extension Study of Protocol ENB-006-09 Evaluating the Long-Term Safety and Efficacy of ENB-0040 (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Children with Hypophosphatasia (HPP)".

    In addition, these studies will provide efficacy and safety data in patients who will be reaching 13 to 18 years of age by the time the study is completed.
  2. The final CSR of completed Study ENB-010-10 entitled: “An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy, and Pharmacokinetics of Asfotase Alfa (human recombinant tissue-nonspecific alkaline phosphatase fusion protein) in Infants and Children ≤5 Years of Age with Hypophosphatasia (HPP)”.
  3. The final CSR of completed Study ENB-009-10 entitled “A Randomized, Open‑Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, and Pharmacokinetics of ENB-0040 (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults with Hypophosphatasia (HPP)”.
  4. The final CSR of completed Studies ENB-002-008/ ENB-003-08 entitled: ENB‑002-008 “A multicenter, open-label study of the safety, tolerability, and pharmacology of Study ENB-0040 (Enobia’s human recombinant tissue-nonspecific alkaline phosphatase fusion protein) in up to 10 severely affected patients with infantile hypophosphatasia (HPP)” and ENB-003-08 entitled: “Extension study of ENB-0040 (human recombinant tissue-nonspecific alkaline phosphatase fusion protein) in severely affected infants and young children with hypophosphatasia (HPP)”.
  5. In order to evaluate pharmacokinetic profile of asfotase alfa in adults at the authorized dose, to demonstrate the dose response on plasma inorganic pyrophosphate (PPi) and pyridoxal-5’-phospate (PLP) (tissue-nonspecific alkaline phosphatase biochemical substrates) and to explore evidence of clinical benefit, a pharmacokinetic/pharmacodynamic study of asfotase alfa in adult patients with HPP should be conducted and CSR should be submitted to Health Canada as a Supplemental New Drug Submission – Confirmatory.

 

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

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Strensiq 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

Strensiq replaces the defective tissue-nonspecific alkaline phosphatase (TNSALP) enzyme.

In clinical trials in patients with hypophosphatasia (HPP), increase in alkaline phosphatase (ALP) was noted almost immediately after initiation of treatment with asfotase alfa. Levels of TNSALP biochemical substrates, inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP), also improved rapidly with stable reductions in the normal range by approximately 3 and 20 weeks, respectively.

Pharmacokinetic (PK) data with asfotase alfa were evaluated in a wide range of HPP patients (age 1 day to 66 years). Based on population PK analysis, asfotase alfa PK exposure increased proportionally over the studied doses of up to 28 mg/kg/wk.

Following weekly subcutaneous administrations of Strensiq, the observed median time to maximum serum concentration (Tmax) ranged from 24 to 48 hours and the absolute bioavailability ranged from 45.8% to 98.4%. The mean [± standard deviation (SD)] observed maximum serum concentration (Cmax) and area under the serum concentration curve from time zero to the time of the last quantifiable concentration (AUClast) were 1,020 ± 326 U/L and 284,926 ± 79,652 U*h/L, respectively for the 2 mg/kg dose group.

The estimated mean [95% confidence interval (CI)] central and peripheral volumes of distribution, were 5.66 L (2.76, 11.6 L) and 44.8 L (33.2, 60.5 L), respectively. The estimated mean clearance (95% CI) was 15.8 (13.2, 18.9) L/day. The average (± SD) elimination half-life of Strensiq was 2.28 (± 0.58) days with a range of 0.740 to 9.94 days.

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

Clinical Efficacy

Data from 52 patients with pediatric HPP onset, including perinatal/infantile (<6 months at onset of symptoms) and juvenile (6 months to 18 years at onset of symptoms), enrolled in two pivotal prospective studies and their extensions (ENB-010-10 and ENB-006-09/ENB-008-10) as well as supportive clinical studies (ENB-002-08/ENB-003-08) were used to evaluate the efficacy of Strensiq in the treatment of HPP patients with pediatric onset. A retrospective natural history study (ENB-011-10) was conducted to gain additional information on the etiology, range of manifestations, and clinical progression of HPP in patients with perinatal/infantile-onset HPP. In addition, a supportive study (ENB-009-10) enrolled 19 patients aged 13 to 66 years.

Baseline characteristics of patients with pediatric-onset HPP evaluated in the clinical trials included low ALP and one or more of the elevated TNSALP biochemical substrates (PPi and PLP). Baseline characteristics also included abnormal bone structure (elevated osteoid indices, reduced bone mineral content, skeletal deformities of rickets such as bowed legs, abnormally shaped chest, below normal Z score for height) and impaired physical function (gross motor weakness, developmental delay, impaired walking, inability to perform activities of daily living).

At baseline patients less than 5 years of age presented with additional morbidities including nephrocalcinosis, seizures, and respiratory compromise (including respiratory failure requiring support) and gross motor delays. In Study ENB-002-08 most patients (9/11, 81.8%) presented with significant gross motor delays on the Bayley Scales of Infant Development (BSID-III) [for example (e.g.), Gross Motor scaled scores of 1, which is 3 SDs below the mean for healthy age-matched peers].

Study ENB-006-09/ENB-008-10

Study ENB-006-09/ENB-008-10 is an ongoing Phase II, open-label, non-randomised study. Thirteen patients were enrolled. Five patients presented with HPP before 6 months of age and 8 patients presented after 6 months of age. Age at inclusion in the study ranged from 6 to 12 years old. Among the patients enrolled, 12 patients continue to be a part of this study. The study employed historical controls from the same centre as patients who received Strensiq and who had been subject to a similar protocol of clinical management.

Improvement in skeletal system (mineralization, structure, and growth)

Radiographic evidence of healing of HPP-induced rickets

X-ray changes from baseline were rated using the Radiographic Global Impression of Change (RGI-C) rating scale as follows:

  • -3 = severe worsening,
  • -2 = moderate worsening,
  • -1 = minimal worsening,
  •  0 = no change,
  • +1 = minimal healing,
  • +2 = substantial healing,
  • +3 = near-complete or complete healing.

Patients who received Strensiq moved to scores of +2 and +3 over the first 6 months of exposure and this was sustained with on-going treatment. Historical controls did not show change over time.

Improvement in bone histomorphology

For 10 patients in the per-protocol set (excludes those patients who received oral vitamin D between baseline and week 24) who underwent biopsy of the transiliac bone crest before and after receiving Strensiq, the mean osteoid thickness (± SD) was 12.8 µm (3.5 µm) at baseline and 9.5 µm (5.1 µm) at week 24. The mean osteoid volume/bone volume was 11.8% (5.9%) at baseline and 8.6% (7.2%) at week 24.

Improvement in growth

In the Strensiq treatment group, 9/13 patients displayed persistent apparent catch-up height-gain compared to 1/16 in the historical control group as shown by movement over time to a higher percentile on Centres for Disease Control and Prevention (CDC) growth charts. Progress through Tanner stages (a scale of physical development in children) appeared appropriate. Some patients required oral vitamin D supplements during the study.

Improvement in physical function and mobility

The Strensiq-treatment group showed improvement in mobility in patients with pediatric onset aged 5 to 12 years resulting in improvements from baseline for the six-minute walk test (6MWT) distance and 6MWT % predicted values. Results were generally observed from week 12 and continued through week 192. The observed improvement with Strensiq-treatment was 125 metres at week 24 and 189 metres at week 120.

Study ENB-010-10

Study ENB-010-10 is an ongoing Phase II, open-label, multicentre, multinational, safety/efficacy, pharmacokinetic (PK) study. Twenty-eight patients were enrolled and are receiving treatment in the study. Onset of hypophosphatasia was under 6 months in all patients. Age at inclusion was 0 to 71 months.

The primary efficacy endpoint for this study was the change in rickets severity on skeletal radiographs as measured by the RGI-C scale from baseline to week 24. Improvements in rickets severity were reported for patients treated in this study.

At week 24, 21/28 patients (75%) achieved RGI-C scores of 1 or greater, indicative of at least "minimal healing of rickets", 13/28 patients (46.4%) had RGI-C scores of 2 or greater, indicative of "substantial healing of rickets", and 4/28 patients (14.3% of the full analysis set - included all randomized patients that received any treatment with Strensiq and historical controls, where appropriate, even if they discontinued or were lost to follow-up during the conduct of the clinical trials) achieved scores of 3, indicating "complete or near complete healing of rickets".

Supportive Studies

Study ENB-002-08/ENB-003-08

Study ENB-002-08/ENB-003-08 is an ongoing Phase II, open-label, non-randomised, non-controlled study. Eleven patients were enrolled and 9 patients are on-going in the study. Onset of HPP was under 6 months in all patients. Age at inclusion in the study was between 0.5 to 35 months.

This study met its primary efficacy endpoint of improvement in rickets severity on skeletal radiographs as measured by the RGI-C at week 24.

Study ENB-009-10

Study ENB-009-10 is an ongoing Phase II, open-label, non-randomised study. Nineteen patients were enrolled and 18 patients continue to take part in this study. Onset of HPP was under 6 months in 4 patients, between 6 months and 18 years in 12 patients and over 18 years in 2 patients. The median duration of Strensiq therapy was approximately 174 weeks (min, max: 96.0, 192.0). Age of onset was not known for one patient. Age at inclusion was from 13 to 66 years. The number of patients 13-18 years of age was limited; therefore results in this age group should be interpreted with caution.

Study ENB-011-10

Study ENB-011-10 was a non-interventional, multicentre, multinational, retrospective chart review study of the natural history of patients with perinatal/infantile onset HPP (that is, where signs of the disease are present before 6 months of age). The objective of this study was to characterize the natural history of patients with severe perinatal and infantile HPP. Data were abstracted for 48 patients, 13 of whom were alive and 35 of whom were deceased at the time of data abstraction.

This study showed how significant the burden of disease and mortality in patients with perinatal/infantile-onset HPP associated with clinical characteristics of respiratory compromise, rachitic chest deformity, and/or vitamin B6-responsive seizures.

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

Clinical Safety

The safety of Strensiq was established in the clinical studies described under the Clinical Efficacy section. In clinical trials, 68 pediatric-onset patients (age 1 day to 66 years) were treated with Strensiq. The most common adverse reactions observed were injection site reactions and injection-associated reactions (IARs). The majority of these reactions were non-serious and mild to moderate in intensity. Serious adverse reactions of IARs were reported in two patients with no discontinuation of Strensiq treatment: in one patient with infantile-onset reported as fever and chills, and in one patient with juvenile-onset HPP reported as hypoaesthesia oral, pain in extremity, chills, and headache.

In the Pooled Safety Set [number of patients (n) = 71], there were six treatment-emergent adverse events (TEAEs) in three patients that led to discontinuation of treatment and study withdrawal. Almost half (1,314/2,706) of the TEAEs reported occurred within the first 24 weeks of treatment, with all (100%) patients experiencing at least one TEAE during that time period. In the Pooled Safety Set, a total of 183 non-fatal serious adverse events (SAEs) were reported by 32 patients (45.1%); eleven of these events (in four patients) were considered by the Investigator to be related to Strensiq.

One non-fatal SAE led to treatment discontinuation and study withdrawal. Five deaths were reported in the clinical database, 4 deaths were considered to be treatment-emergent. One death was reported prior to the first dose of Strensiq.

The most frequently reported (≥3 patients in the Pooled Safety Set) TEAEs, regardless of relationship to Strensiq treatment were from the following System Organ Class: general disorders and administration site conditions (88.7%), infections and infestations (76.1%), gastrointestinal disorders (73.2%), injury, poisoning and procedural complications (70.4%), respiratory, thoracic and mediastinal disorders (57.7%), musculoskeletal and connective tissue disorders and skin and subcutaneous tissue disorders (56.3%, each), nervous system disorders (45.1%), eye disorders and investigations (42.3% each), metabolism and nutrition disorders and renal and urinary disorders (25.4%, each), psychiatric disorders (23.9%), congenital, familial and genetic disorders (21.1%), immune system disorders (16.9%), vascular disorders (14.1%), blood and lymphatic system disorders (11.3%), and cardiac disorders (9.9%).

Adverse events of craniosynostosis (associated with increase of intracranial pressure) related to underlying disease were observed in patients <5 years of age. Periodic monitoring (including funduscopy for signs of papilloedema) and prompt intervention for increased intracranial pressure is recommended in the labelling for patients with infantile-onset HPP below 5 years of age.

Other adverse events reported include ophthalmic (conjunctival and corneal) calcification and nephrocalcinosis. Periodic ophthalmology examinations are recommended in HPP patients.

The above reported adverse events as well as the monitoring measures have been properly captured in the Product Monograph.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical program included safety pharmacology, repeat dose toxicity, and reproduction and development studies.

The studies revealed transient injection reactions in rats. These injections reaction were accompanied with ectopic calcifications in monkeys. No other observations were reported including the effects of Strensiq on fertility, embryofetal and prenatal/perinatal development.

No genotoxicity or carcinogenicity studies were performed. Asfotase alfa is a large protein and as such, interaction with the cellular deoxyribonucleic acid (DNA) or other chromosomal material is not likely because the molecule would not pass through the cellular and nuclear membranes to reach those targets. There are no impurities in the drug product or substance that would require these tests. Therefore genotoxicity studies have not been conducted. Asfotase alfa is not expected to be carcinogenic or induce cellular proliferation because it has no known anabolic effects. Binding to hydroxyapatite does not cause signal transduction. Moreover, there are no impurities in the drug product or substance that would require these tests. Therefore carcinogenicity studies were not conducted.

The general toxicology program for asfotase alfa included maximum tolerated dose (MTD) studies, definitive toxicity studies of varying durations, and a study to compare the local irritation potential of asfotase alfa. One of the MTD studies was a single‑dose toxicity study in monkeys, and the other was a repeat‑dose toxicity study in rats. A cardiovascular pharmacology safety study was conducted as part of the six-month repeated dose primate toxicity.

Four-week definitive toxicity studies were then conducted in rats and monkeys using the intravenous route of administration. Subsequently, chronic six-month monkey (subcutaneous administration) and rat (intravenous administration) studies were performed.

Reproductive and developmental studies were done in rats and rabbits to determine potential effects on fertility, as well as embryofetal and prenatal/perinatal observations. Stand-alone pharmacology safety studies were conducted to assess the potential effects of asfotase alfa on central nervous system and respiratory function in rats.

In general, asfotase alfa was well-tolerated. The only consistent observation was a transient injection reaction observed in rats in most studies following intravenous injection. Acute reactions were not completely alleviated by antihistamines or a steroid. There was no evidence of complement involvement in the development of the injection reaction. None of the clinical signs that were typical of the post-dose reaction in rat intravenous toxicity studies were observed in monkeys or rabbits regardless of the route of administration, or in rats given subcutaneous injections. Thus, it is unlikely that these findings are clinically relevant.

An immune response to asfotase alfa was evident in several toxicology studies in rats and monkeys. No anti-drug antibody (ADA)-related adverse events were noted either in the general or reproductive toxicology studies. Moreover, the presence of ADA in the toxicology studies was considered irrelevant because asfotase alfa is derived from human proteins. No other observations were made in any of the toxicology studies that would preclude the clinical use of asfotase alfa.

Given that Strensiq is derived from human proteins, and based on its therapeutic indication in a small patient population with significant mortality, studies to assess the effects of asfotase alfa on the mutagenic and carcinogenic potential were not performed.

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

 

 

7.3 Quality Basis for Decision

 

Asfotase alfa is a recombinant immunoglobulin G1 (IgG1) Fc fusion glycoprotein. It is comprised of two identical polypeptide chains, each one made up of a soluble catalytic domain of human TNSALP, a human IgG1 Fc domain (which facilitates purification), and a peptide (D10) that targets bone. Each domain is joined via an amino acid linker which is two amino acids long.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that asfotase alfa consistently exhibits the desired characteristic structure. 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.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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

The drug substance, asfotase alfa, is expressed in a Chinese Hamster Ovary (CHO) cell line which has been engineered for asfotase alfa expression designated as ENB‑ALP‑01.

A vial of the Working Cell Bank (WCB) containing ENB‑ALP‑01 cells is thawed and cultures are progressively expanded using growth medium through a series of cell culture steps prior to inoculation into the 20,000 L production bioreactor. Upon completion of the cell culture, cells and cell debris are removed. The clarified harvest is concentrated and diafiltered prior to a viral inactivation step.

The downstream asfotase alfa drug substance manufacturing process includes three concentration and diafiltration steps along with three chromatography steps, and a virus filtration step. Following the final concentration and diafiltration step, asfotase alfa drug substance is 0.2 μm filtered into containers and stored at 2 to 8°C pending batch disposition and shipment to the drug product manufacturing facility.

All product contact equipment used in the filling process is single use disposables. Filling is performed utilizing a peristaltic pump system. The capped vials are subjected to a 100% visual inspection process by trained and qualified manufacturing personnel.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Conference on Harmonisation (ICH) guidelines.

Each lot of Strensiq drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada’s lot release testing and evaluation program, consecutively manufactured final product lots were tested for purity and potency. Test results met the drug product specifications and demonstrate consistency in manufacturing.

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 to 8°C for Strensiq is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

Facilities and Equipment

An On-Site Evaluation (OSE) of the drug substance manufacturing facility was not conducted since Health Canada had previously conducted a satisfactory OSE at this facility for another product. Also, the facility was deemed Good Manufacturing Practices (GMP)-compliant by the Health Canada Inspectorate and there were no critical issues flagged during review.

An OSE of the Strensiq drug product manufacturing facility was not conducted since the facility was deemed GMP-compliant by the Health Canada Inspectorate and there were no outstanding issues based on a more extensive paper review of the facility information.

Adventitious Agents Safety Evaluation

A comprehensive strategy, including raw material sourcing and testing, manufacturing process controls and process validation, is used to ensure asfotase alfa drug substance is free of endogenous and adventitious agents:

  • The ENB‑ALP‑01 cell line has been extensively tested for non‑viral and viral adventitious agents.
  • All raw materials used in the manufacture of asfotase alfa drug substance have been selected to ensure the quality and safety of the product.
  • Specifications for raw materials include testing for both non‑viral and viral adventitious agents where appropriate.
  • There is limited use of animal derived raw materials in the asfotase alfa drug substance manufacturing process and this is restricted to cell banking and cell culture steps.
  • Cleaning and sterilization procedures used during the routine manufacture of asfotase alfa drug substance have been validated for the removal of bioburden and endotoxin.
  • Closed manufacturing systems are used wherever possible.
  • Testing is undertaken during the routine manufacture of asfotase alfa drug substance to demonstrate that non‑viral and viral adventitious agents are controlled within acceptable levels.

 

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