Summary Basis of Decision for Esperoct

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 Esperoct is located below.

Recent Activity for Esperoct

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.

AnchorThe following table describes post-authorization activity for Esperoct, a product which contains the medicinal ingredient antihemophilic factor VIII (recombinant, B-domain truncated), PEGylated. 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 AnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-09-15

Drug Identification Number (DIN):

  • DIN 02490064 – 500 IU/vial, powder for solution, intravenous administration
  • DIN 02490072 – 1,000 IU/vial, powder for solution, intravenous administration
  • DIN 02490080 – 1,500 IU/vial, powder for solution, intravenous administration
  • DIN 02490099 – 2,000 IU/vial, powder for solution, intravenous administration
  • DIN 02490102 – 3,000 IU/vial, powder for solution, intravenous administration
  •  

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 268221

2022-09-27

Issued NOC 2023-09-11

Submission filed as a Level I – Supplement to update the PM with safety and efficacy data based on the completed trial NN7088-3908 in previously untreated patients with hemophilia A. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications, Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued and a Regulatory Decision Summary was published.

NC # 275109

2023-05-08

Issued NOL 2023-08-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a new container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 267191

2022-08-23

Cancellation Letter Received 2022-10-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for new material / reagent (detergent) used in production of raw material. A number of issues were identified with the submission during review, and the sponsor was therefore recommended to withdraw and refile. The submission was cancelled by the sponsor.

Drug product (DIN 02490102) market notification

Not applicable

Date of first sale: 2022-09-15

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

SNDS # 263861

2022-04-29

Issued NOC 2022-08-05

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

Drug product (DINs 02490064, 02490072, 02490099) market notification

Not applicable

Date of first sale: 2022-03-10

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

NC # 240606

2020-06-15

Issued NOL 2020-08-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a modification to a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 235688

2020-01-31

Issued NOL 2020-05-06

Submission filed as a Level II (90 day) Notifiable Change to update the PM based on an interim analysis of trial NN7088-3908. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections 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.

NC # 231579

2019-09-13

Issued NOL 2019-11-25

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

NC # 230977

2019-08-22

Issued NOL 2019-09-16

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

NDS # 218531

2018-07-23

Issued NOC 2019-07-04

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

Date SBD issued: 2019-12-11

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

Antihemophilic factor VIII (recombinant, B-domain truncated), PEGylated

Drug Identification Number (DIN):

  • DIN 02490064 - 500 IU/vial, powder for solution, intravenous administration
  • DIN 02490072 - 1,000 IU/vial, powder for solution, intravenous administration
  • DIN 02490080 - 1,500 IU/vial, powder for solution, intravenous administration
  • DIN 02490099 - 2,000 IU/vial, powder for solution, intravenous administration
  • DIN 02490102 - 3,000 IU/vial, powder for solution, intravenous administration

Novo Nordisk Canada Inc.

New Drug Submission Control Number: 218531

 

On July 4, 2019, Health Canada issued a Notice of Compliance to Novo Nordisk Canada Inc. for the drug product Esperoct.

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 Esperoct is favourable for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:

  • routine prophylaxis to prevent or reduce the frequency of bleeding episodes;
  • on-demand treatment and control of bleeding episodes;
  • perioperative management of bleeding.

Esperoct is not indicated for the treatment of von Willebrand disease.

 

1 What was approved?

 

Esperoct is a recombinant antihemophilic factor VIII. It was authorized for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:

  • routine prophylaxis to prevent or reduce the frequency of bleeding episodes;
  • on-demand treatment and control of bleeding episodes;
  • perioperative management of bleeding.

Esperoct is not indicated for the treatment of von Willebrand disease.

Clinical studies of Esperoct did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects.

Esperoct is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient (including hamster protein), or component of the container.

Esperoct 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.

Esperoct (500 IU/vial, 1,000 IU/vial, 1,500 IU/vial, 2,000 IU/vial and 3,000 IU/vial antihemophilic factor VIII [recombinant, B-domain truncated] PEGylated, also known as turoctocog alfa pegol) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains calcium chloride dihydrate, L-histidine, L-methionine, polysorbate 80, sodium chloride, and sucrose.

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

 

2 Why was Esperoct approved?

 

Health Canada considers that the benefit-risk profile of Esperoct is favourable for use in adults and children with hemophilia A (congenital factor VIII [FVIII] deficiency) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative management of bleeding. Esperoct is not indicated for the treatment of von Willebrand disease.

Hemophilia A or congenital FVIII deficiency is a serious and potentially life-threatening bleeding disorder. Standard treatment for patients with hemophilia A is the replacement of the missing protein by either plasma-derived FVIII or recombinant FVIII.

Esperoct is a novel recombinant FVIII product conjugated with a 40 kDa polyethylene glycol (PEG) moiety.

Esperoct has been shown to be efficacious in routine prophylactic treatment, control of bleeding episodes, and perioperative management of patients with hemophilia A. The market authorization was primarily based on efficacy and safety data derived from a pivotal trial conducted in adults and adolescents (12 years of age and older), a pediatric clinical trial, and a clinical trial in adult and adolescent patients who underwent major surgeries. All patients had been previously treated with other FVIII products for at least 150 exposure days (adolescents and adults) and at least 50 exposure days (pediatric patients younger than 6 years of age). The prophylactic effect of Esperoct was demonstrated for both the pediatric and the adult/adolescent patients. In children younger than 12 years of age, who received 60 IU/kg (50-75 IU/kg) Esperoct twice weekly, the estimated median annualized bleeding rate was 1.95 (interquartile range [IQR]: 0.00; 2.79). Adult and adolescent patients (over 12 years of age) treated with 50 IU/kg Esperoct every three to four days, had an estimated median annualized bleeding rate of 1.18 (IQR: 0.00; 4.25). In 1,314 of the 1,506 bleeds (87.3%) reported in the clinical trials, the response to treatment with Esperoct was rated as "excellent" or "good". The hemostatic effect of Esperoct was rated as "excellent" or "good" in 43 of 45 major surgical procedures (95.6%).

The most frequently reported adverse reactions were rash (5.2%), injection-site reactions (2.6%), erythema (1.9%), and pruritus (1.5%). One previously treated patient developed confirmed neutralizing antibodies to FVIII. The formation of neutralizing antibodies (inhibitors) to FVIII is a known complication in the management of individuals with hemophilia A and has been addressed in the Warnings and Precautions section of the Esperoct Product Monograph.

No PEG-related adverse effects were identified in the non-clinical and clinical studies of Esperoct (see Non-Clinical Basis for Decision and Clinical Safety).

The safety and efficacy of Esperoct in previously untreated patients with FVIII products have not yet been established.

A Risk Management Plan (RMP) for Esperoct was submitted by Novo Nordisk 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 Esperoct Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Esperoct was accepted.

Overall, the therapeutic benefits of Esperoct seen in the clinical studies are considered to outweigh the potential risks for the target patient population. Esperoct 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 Esperoct 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 Esperoct?

 

Submission Milestones: Esperoct

Submission Milestone Date
Pre-submission meeting: 2018-05-03
Submission filed: 2018-07-23
Screening  
Screening Acceptance Letter issued: 2018-09-07
Review  
On-Site Evaluation: 2019-03-18 - 2019-03-22
Review of Risk Management Plan complete: 2019-04-24
Quality Evaluation complete: 2019-06-28
Clinical/Medical Evaluation complete: 2019-06-25
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2019-07-03
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2019-07-04

 

The Canadian regulatory decision on the review of Esperoct was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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?

 

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

 

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

 

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 Esperoct 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

The administration of Esperoct, a glycoPEGylated form of recombinant antihemophilic factor VIII (FVIII), increases plasma levels of FVIII and temporarily corrects the coagulation defect in hemophilia A patients, as reflected by a decrease in activated partial thromboplastin time (aPTT). The FVIII in Esperoct is conjugated to a 40 kDa polyethylene glycol (PEG) molecule, which slows down its removal from the blood circulation, thereby prolonging its half-life in comparison to the non-PEGylated FVIII molecule.

Pharmacokinetic studies with Esperoct were conducted in previously treated patients with severe hemophilia (FVIII activity level below 1%). Sixty-nine patients (including 24 pediatric patients younger than 12 years) received a single dose of 50 IU/kg, and blood samples were collected prior to dosing and at multiple time points up to 96 hours after dosing. In total, 108 single-dose pharmacokinetic profiles of Esperoct were evaluated in these patients.

The half-life was 19 hours for Esperoct and 12 hours for unmodified FVIII products in adults, using the chromogenic assay.

The single-dose pharmacokinetic parameters were comparable between young children (<6 years) and older children (6 to <12 years), and between adolescents (12 to <18 years) and adults (≥18 years). Incremental recovery appeared to be lower while body weight adjusted clearance appeared to be higher in children as compared to adults and adolescents. In general, there was a trend of increasing incremental recovery and decreasing clearance (mL/h/kg) with age. This corresponds to a higher volume of distribution per kg body weight in children compared to adults.

The clinical pharmacology data support the use of Esperoct for the recommended indication.

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

Clinical Efficacy

The efficacy of Esperoct has been evaluated in three multinational, open-label, non-controlled trials conducted in male patients with severe hemophilia A (FVIII activity level below 1%). Trial 3859 was considered a pivotal trial and included adult and adolescent patients, trial 3885 enrolled pediatric patients, and trial 3860 was conducted in adult and adolescent patients who underwent major surgeries. All patients had been previously treated with other FVIII products for at least 150 exposure days (adolescents and adults) and at least 50 exposure days (pediatric patients younger than 6 years of age). The key exclusion criteria across trials included known or suspected hypersensitivity to trial or related products and known history of FVIII inhibitors or FVIII inhibitor ≥0.6 Bethesda Units (BU) at screening.

Pivotal Trial (Trial 3859)

The pivotal trial (trial 3859) evaluated the efficacy of Esperoct for prophylaxis and treatment of bleeds (on-demand treatment) in 186 patients: 161 adults (18 to 65 years old) and 25 adolescents (12 to 17 years old). It consisted of a main phase and two extension phases, extension 1 and extension 2 (the latter was not reviewed as it was ongoing at the time of this drug submission).

During the main phase, 175 patients received the prophylaxis regimen of 50 IU/kg Esperoct administered every three to four days (Q3-4D), while 12 adults chose to be treated on-demand. All patients received at least one dose of Esperoct and 165 patients (91%) completed the main phase of the trial. The estimated median annualized bleeding rate in adults and adolescents treated with the prophylaxis regimen was 1.18 (interquartile range [IQR]: 0.00; 4.25). The main phase of the pivotal trial demonstrated the prophylactic effect of Esperoct in the adult/adolescent patient population.

Extension 1 compared two dose regimens, 75 IU/kg Esperoct every seven days (Q7D) and 50 IU/kg Esperoct Q4D. Of the 150 patients who continued into extension 1, 55 patients chose to be randomized (2:1) to 75 IU/kg Q7D (38 patients) or 50 IU/kg Q4D (17 patients). Of the remaining 95 patients, 7 were treated on-demand, 23 were not eligible to be randomized, and 65 eligible patients chose to continue on 50 IU/kg Q3-4D. Overall, 139 (93%) patients completed extension 1. The mean annualized bleeding rate was 3.59 (standard deviation [SD]: 6.62) in the Q7D treatment group and 1.77 (SD: 2.42) in the Q4D treatment group. Nine (24%) of the 38 patients who were randomized to the Q7D regimen switched to Q4D dosing. Eight of these patients switched the regimen due to bleeding events, and one patient due to investigator's recommendation. As the robustness of the findings for the Q7D treatment group was considered weak, and hence, the treatment success of the Q7D treatment group was not established, there was insufficient evidence to support the Q7D regimen for routine prophylaxis. Consequently, the Q7D regimen was not included in the Esperoct Product Monograph. The recommended starting dose of Esperoct for routine prophylaxis in adults and adolescents (12 years of age and over) is 50 IU per kg body weight every four days. The dose regimen may be individually adjusted to less or more frequent dosing based on bleeding episodes.

During the main phase and extension 1 of the pivotal trial, 1,436 bleeds occurred in 132 patients. The majority (65.9%) of the bleeds were spontaneous bleeding episodes, 33.5% were traumatic bleeds and 0.6% occurred after minor surgery. Of the total 1,436 bleeds in the trial, 82.2% were resolved with one injection and 12.8% were resolved with two injections of Esperoct. The success rate for treatment of all bleeds (including the missing responses as "failure") was 83.3% (95% confidence interval [CI]: 79.4; 86.6). The results confirmed the hemostatic effect of Esperoct in the treatment of bleeds.

Pediatric Trial (Trial 3885)

The pediatric trial (trial 3885) included 68 patients who were evenly divided in two age groups (34 patients younger than 6 years of age, and 34 patients older than 6 years but younger than 12 years of age). All patients received the same prophylaxis regimen of approximately 60 IU/kg (50-75 IU/kg) Esperoct twice weekly. Sixty-three patients (93%) completed the main phase and were continuing treatment with Esperoct in the ongoing extension at the time of this drug submission.

The trial demonstrated the prophylactic effect of Esperoct in the pediatric patient population. The estimated median annualized bleeding rate was 1.95 (IQR: 0.00; 2.79) and was comparable between the two age groups.

Of the 68 children receiving routine prophylaxis, 39 patients (57%) had 70 bleeding episodes treated with Esperoct. The estimated success rate for the hemostatic effect of Esperoct was 78.6% (including three missing observations counted as "failure"). Eighty percent of all bleeding episodes were resolved with one or two injections of Esperoct.

Surgery Trial (Trial 3860)

In the surgery trial, the hemostatic effect of Esperoct was evaluated in 33 previously treated adolescents/adults who underwent 45 major surgeries. The procedures included 15 joint replacements, 9 arthroscopic orthopedic interventions, 17 other orthopedic interventions, and 4 non-orthopedic surgeries. The dose level of Esperoct was chosen based on target FVIII activity levels as per the World Federation of Hemophilia guidelines. All subjects returned to the adult/adolescent trial after the surgery trial assessments were completed. The clinical evaluation of the hemostatic response during major surgery used a four-point scale of "excellent", "good", "moderate", or "none". The hemostatic effect of Esperoct was rated as "excellent" or "good" in 43 of 45 surgeries (95.6%). In two surgeries (4.4%), the effect was rated as "moderate".

Indication

The New Drug Submission for Esperoct was filed by the sponsor with the following indication, which Health Canada subsequently approved:

  • Esperoct (antihemophilic factor VIII [recombinant, B-domain truncated], PEGylated) is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:
    • routine prophylaxis to prevent or reduce the frequency of bleeding episodes;
    • on-demand treatment and control of bleeding episodes;
    • perioperative management of bleeding.

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

Conclusion

Based on the clinical data provided in this submission, the efficacy of Esperoct in adults and children with hemophilia A is considered acceptable for routine prophylaxis, on-demand treatment and control of bleeding episodes, as well as for perioperative management of bleeding. The clinical and pharmacological data support the use of Esperoct for the specified indication.

Clinical Safety

The safety of Esperoct has been evaluated in 270 unique subjects (202 adults/adolescents and 68 children) across five prospective multicentre clinical studies conducted in previously treated patients with severe hemophilia A (three of the studies are described in the Clinical Efficacy section). All patients received at least one dose of Esperoct. Total exposure to Esperoct was 80,425 exposure days corresponding to 889 patient-years of treatment.

During the clinical trials, adverse reactions occurred at a rate of 0.10 events per patient-year of exposure. The most frequently reported adverse reactions were rash (5.2%), injection-site reactions (2.6%), erythema (1.9%), and pruritus (1.5%). There were no drug-related serious adverse reactions other than hypersensitivity reactions and FVIII inhibitor development, both of which were highlighted in the Warnings and Precautions section of the Esperoct Product Monograph. No anaphylactic allergic reactions were observed. One previously treated patient developed confirmed neutralizing antibodies to FVIII (13.5 Bethesda Units [BU]). The formation of neutralizing antibodies (inhibitors) to FVIII is a known complication in the management of individuals with hemophilia A. The neutralizing antibodies are usually IgG immunoglobulins that inhibit the FVIII procoagulant activity. They are quantified in BU using the modified Bethesda assay. Appropriate monitoring and laboratory tests are addressed in the Warnings and Precautions section of the Esperoct Product Monograph.

Pre-existing anti-PEG antibodies were detected in 32 patients, 20 of whom had no anti-PEG antibodies at the end of the trials. Eleven patients developed anti-PEG antibodies. Nine of these patients had transient anti-PEG antibodies, while two patients remained positive for anti-PEG antibodies at the end of the trials. The anti-PEG antibodies had no clinical significance. Nine subjects developed anti-Chinese hamster ovary (CHO)-host cell protein (HCP) antibodies with no clinical consequences.

Of note, PEG accumulation in the choroid plexus was observed in non-clinical studies of a similar PEGylated product (Rebinyn, which contains a recombinant coagulation factor IX conjugated with a 40 kDa PEG). Therefore, both non-clinical and clinical studies of Esperoct were focused on investigating safety signals that could arise from exposure to the 40 kDa PEG moiety of Esperoct. No safety concerns were identified in the long-term repeat-dose toxicity studies, and no PEG was detected in any brain tissues (including the choroid plexus). In the clinical studies, 192 patients (including 63 children) had been dosed with Esperoct for more than 3 years, 139 patients for more than 4 years, and 18 patients for more than 5 years at the cut-off date for the data provided in this drug submission. No PEG-related adverse effects were identified in the clinical trials. Based on the available non-clinical and clinical data, the potential risk of safety issues related to the 40 kDa PEG moiety of Esperoct is considered low.

The safety profile of Esperoct was comparable between previously treated pediatric and previously treated adult patients.

Appropriate warnings and precautions are in place in the approved Esperoct Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

In vitro and in vivo studies characterized the pharmacological properties of the medicinal ingredient in Esperoct (antihemophilic factor VIII [FVIII], recombinant, B-domain truncated, PEGylated, also known as turoctocog alfa pegol) in comparison to non-PEGylated recombinant FVIII (rFVIII) products, Advate (antihemophilic factor [recombinant]) and/or Zonovate (turoctocog alfa).

The hemostatic effect of turoctocog alfa pegol was prolonged as compared to non-PEGylated rFVIII products.

The pharmacokinetics of turoctocog alfa pegol was evaluated after single intravenous administration in mice, rats, rabbits, dogs, and monkeys (at dose levels of 125 to 280 IU/kg). An approximately twofold increase in the terminal half-life of turoctocog alfa pegol was observed as compared to non-PEGylated rFVIII products (Zonovate, ReFacto and/or Advate). This was caused by an approximately twofold decrease in the clearance of turoctocog alfa pegol in comparison to the non-PEGylated rFVIII products.

Toxicology studies included one single-dose study and four repeat-dose studies. In general, turoctocog alfa pegol was well tolerated after a single dose of up to 25,000 IU/kg and doses of up to 2,500 IU/kg administered every second day for two weeks in Wistar rats, and after doses of up to 1,200 IU/kg administered every fourth day for 26 and 52 weeks in Rowett nude rats. In cynomolgus monkeys, turoctocog alfa pegol was administered at doses of up to 2,500 IU/kg every third day for two weeks. For repeat-dose toxicity studies, the highest dose levels tested were identified as a no-observed-adverse-effect level (NOAEL) for non-immunogenic effects.

Development of anti-drug antibodies was observed in both rats and monkeys, due to the species-foreign nature of the turoctocog alfa pegol protein.

Polyethylene glycol (PEG) was not detected in any brain tissues (including the choroid plexus) in Rowett nude rats after 52 weeks of repeated dosing of turoctocog alfa pegol (1,200 IU/kg every fourth day). In the 52-week chronic toxicity study, plasma PEG concentrations measured by nuclear magnetic resonance (NMR) were found to be around or below the lower limit of quantification. In the cerebrospinal fluid, PEG was not measurable by NMR. The dose level employed in this study was approximately 20-fold higher than the proposed prophylactic clinical dose levels.

The results of the non-clinical studies have been included in the Esperoct Product Monograph. In view of the intended use of Esperoct, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Esperoct 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 medicinal ingredient in Esperoct is a recombinant B-domain truncated human coagulation factor VIII (FVIII), site-specifically conjugated with a 40 kDa polyethylene glycol (PEG) moiety. It is also known as turoctocog alfa pegol. The PEG moiety prolongs the circulatory half-life of the recombinant FVIII. When turoctocog alfa pegol is activated by thrombin, the B-domain containing the PEG moiety and the a3-region are cleaved off, thus generating activated recombinant FVIII, which is similar in structure to native FVIIIa.

Detailed characterization studies were performed to provide assurance that the drug substance consistently exhibits the desired characteristic structure and biological activity.

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

Drug Substance

Recombinant human FVIII is produced in Chinese hamster ovary (CHO) cells and contains 21 amino acids of the endogenous B-domain. The recombinant FVIII protein is purified by a series of chromatographic steps, including an affinity chromatography step using a monoclonal antibody, expressed in CHO cells, to selectively isolate recombinant FVIII from the cell culture medium. The conjugation of the PEG group is performed by an enzymatic reaction during the purification of Esperoct. The production process includes two dedicated, validated viral clearance steps (a detergent treatment step for inactivation and a 20 nm filtration step for removal of viruses).

The control strategy for the turoctocog alfa pegol drug substance manufacture has been developed in accordance with the International Council for Harmonisation (ICH) Q11 guideline on development and manufacture of drug substances (chemical entities and biotechnological/biological entities).

The sponsor demonstrated adequately that the commercial manufacturing process of the drug substance is reproducible, can be maintained within established parameters, and consistently produces product that meets the defined quality parameters.

Drug Product

The manufacturing process of the drug product included thawing of the frozen drug substance, formulation, sterile filtration and fill, freeze-drying, and vial capping. Esperoct is manufactured to nominal turoctocog alfa pegol strengths of 500 IU/vial, 1,000 IU/vial, 1,500 IU/vial, 2,000 IU/vial, and 3,000 IU/vial, with identical excipient levels. All drug product excipients are included in the drug substance formulation.

The vial of Esperoct lyophilized powder for solution is accompanied by a prefilled syringe with 4 mL of solvent and a sterile vial adapter (with 25 µm filter) for reconstitution. The solvent for reconstitution of Esperoct is 0.9% sodium chloride solution.

The sponsor adequately demonstrated reproducible commercial drug product manufacturing that meets established quality parameters.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the drug substance with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

A comprehensive list of raw materials identifying the compendial and non-compendial items was provided in the drug submission package. No raw materials of direct animal origin were used in the cell banking or drug substance production. Compendial methods in accordance with the European Pharmacopoeia are employed as per the predefined acceptance criteria for in-house testing for most of the raw materials used in the drug substance manufacture.

Test parameters for the drug substance specifications were selected based on critical quality attributes necessary for the assessment of identity, protein content, specific activity, purity, PEG profile, quality, and safety of the drug substance within the shelf life period. The specification limits were established based on one or more of the following considerations: process capability, analytical variation, stability data, product characteristics, relation to drug product specification, and clinical relevance.

The specification test parameters for the drug product (Esperoct) were selected based on critical quality attributes that should be controlled to confirm the quality, efficacy, and safety of the drug product. The specification limits were established based on the knowledge obtained during pharmaceutical development as well as the knowledge from production of clinical batches, process justification batches, and the related stability studies.

Upon request by Health Canada, a number of specification limits were tightened to reflect additional batch data and to allow for harmonization with the limits recommended by the European Medicines Agency. The specification limits are adequately justified.

The analytical methods are validated according to ICH guidelines.

Three lots of consecutively manufactured, commercial scale product were provided to Health Canada with diluent, supporting documentation, and vials of the current secondary reference standard. Sample testing demonstrated consistent product quality.

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 satisfactory. The proposed drug product shelf life of 30 months at 2ºC to 8ºC is considered acceptable. During the shelf life, Esperoct may also be stored at room temperature (up to 30°C) for a single period not exceeding 12 months.

The compatibility of the drug product with the container closure system was demonstrated by stability studies. The container closure system demonstrated adequate container closure integrity.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An on-site evaluation of the facility involved in the manufacture and testing of the drug substance was conducted by Health Canada, with a satisfactory rating.

An on-site evaluation of the facility involved in the manufacture and testing of the drug product was not considered necessary, since the facility had received a satisfactory rating during a recent on-site evaluation.

Adventitious Agents Safety Evaluation

The manufacturing process of Esperoct incorporates adequate control measures to prevent contamination and maintain microbial control.

Control of viral agents is achieved through designated viral clearance steps. Testing demonstrated adequate clearance of potential viruses.

The CHO-derived anti-FVIII monoclonal antibody and the enzymes used in the manufacturing process are considered safe with regard to adventitious agents.

The excipients used in the drug product formulation are not of animal or human origin.

 

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