Summary Basis of Decision for Hemlibra

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 Hemlibra is located below.

Recent Activity for Hemlibra

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.

The following table describes post-authorization activity for Hemlibra, a product which contains the medicinal ingredient emicizumab. 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.

Updated: 2023-03-01

Drug Identification Number (DIN):

  • DIN 02479621 – 30 mg/1 mL emicizumab, solution, subcutaneous administration
  • DIN 02479648 – 60 mg/0.4 mL emicizumab, solution, subcutaneous administration
  • DIN 02479656 – 105 mg/0.7 mL emicizumab, solution, subcutaneous administration
  • DIN 02479664 – 150 mg/mL emicizumab, solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 261138 2022-02-02 Issued NOC 2022-12-23 Submission filed as a Level I – Supplement to update the PM with data from study HAVEN 6. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications, Warnings and Precautions, Adverse Reactions, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 267758 2022-09-09 Issued NOL 2022-11-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 256842 2021-09-21 Issued NOC 2022-05-04 Submission filed as a Level I – Supplement for a new drug substance manufacturing site and a scale-up of the drug substance manufacturing process. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 253853 2021-06-16 Issued NOC 2021-11-10 Submission filed as a Level II – Supplement (Safety) to update the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Clinical Trials sections of the PM. An NOC was issued.
NC # 250133 2021-03-03 Issued NOL 2021-04-01 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add an alternate site for testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 247456 2020-12-11 Issued NOL 2021-01-21 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to reduce the shelf-life of the drug product from 30 months to 24 months, and to add a transfer needle with filter for subcutaneous administration. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 222209 2018-11-22 Issued NOC 2019-06-14 Submission filed as a Level I – Supplement for a new indication and two new alternative maintenance doses. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the treatment of hemophilia A patients without inhibitors to Factor VIII. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Drug product (DIN 02479656) market notification Not applicable Date of first sale: 2019-02-21 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 220277 2018-09-19 Issued NOC 2019-02-12 Submission filed as a Level I – Supplement to add an alternate site for manufacturing and testing of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02479664) market notification Not applicable Date of first sale: 2018-11-27 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 (DINs 02479621, 02479648) market notification Not applicable Date of first sale: 2018-10-19 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 212635 2018-01-09 Issued NOC 2018-08-02 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Hemlibra

Date SBD issued: 2018-12-18

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

Emicizumab
30 mg/mL, 150 mg/mL (available as 60 mg/0.4 mL, 105 mg/0.7 mL, and 150 mg/1 mL), solution, subcutaneous injection

Drug Identification Number (DIN):

  • DIN 02479621 - 30 mg/1 mL solution
  • DIN 02479648 - 60 mg/0.4 mL solution
  • DIN 02479656 - 105 mg/0.7 mL solution
  • DIN 02479664 - 150 mg/1 mL solution

Hoffmann-La Roche Ltd.

New Drug Submission Control Number: 212635

 

On August 2, 2018, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product, Hemlibra.

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 Hemlibra is favourable for hemophilia A (congenital factor VIII deficiency) patients with factor VIII inhibitors as routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes.

1 What was approved?

Hemlibra, an antihemorrhagic, was authorized for hemophilia A (congenital factor VIII deficiency) patients with factor VIII inhibitors as routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes.

Hemlibra is contraindicated in patients who are hypersensitive to the medicinal ingredient, emicizumab, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Hemlibra 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.

Hemlibra (30 mg/1 mL, 60 mg/0.4 mL, and 105 mg/0.7 mL, 150 mg/1 mL) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient, emicizumab, the solution contains L-arginine, L-histidine, L-aspartic acid, Poloxamer 188 and water for injection.

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

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

2 Why was Hemlibra approved?

Health Canada considers that the benefit-risk profile of Hemlibra is favourable for hemophilia A (congenital factor VIII deficiency) patients with factor VIII inhibitors as routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes.

Congenital hemophilia A is an X-linked recessive bleeding disorder that occurs in about one in every 5,000 live-born male births, and accounts for approximately 80% of all cases of hemophilia. This condition is characterized by underproduction or dysfunction of factor VIII (FVIII); an essential protein that promotes clot formation. Many hemophilia A patients have severe disease, which is defined by less than one percent of normal FVIII activity. In Canada, the standard treatment of patients with hemophilia A is intravenous (IV) FVIII replacement therapy with recombinant FVIII or plasma-derived FVIII concentrates. This is administered either episodically ("on demand") in response to the occurrence of bleeding symptoms, or prophylactically on a scheduled basis to prevent the onset of bleeding symptoms.

In patients with severe hemophilia A, FVIII prophylaxis is usually started after their first joint bleed or by 2 years of age, with the aim of avoiding the development of any joint abnormality in the future. Unfortunately, 20% to 30% of patients with hemophilia A develop neutralizing alloantibodies (inhibitors) against FVIII after exposure to therapeutic FVIII concentrates. Inhibitors can develop very early during the course of FVIII therapy (within 50-150 days of treatment initiation), and half of all cases occur before the age of 5 years. Pediatric patients therefore represent the population at highest risk of inhibitor development. For hemophilia A patients who have high levels of inhibitors (high-titre or ≥5 Bethesda units [BU]/mL), FVIII replacement therapy is rendered ineffective, precluding the use of a safe and effective standard of care and markedly increasing the risk of morbidity and mortality due to bleeding complications. These patients require alternative treatments with "bypassing agents" that alter the concentrations of other hemostatic proteins to promote clotting. However, the effectiveness of bypassing agents is not ideal for most hemophilia A patients with FVIII inhibitors, as they often experience frequent bleeding episodes while on these therapies.

The market authorization of Hemlibra was based on one pivotal study, Haven 1, that enrolled adolescent (12-17 years of age) and adult (≥18 years of age) hemophilia A patients with factor VIII inhibitors. Interim reports from a supportive study, Haven 2, were also assessed. Haven 2 was ongoing at the time of review, and included pediatric (1-12 years of age) hemophilia A patients with factor VIII inhibitors. The vast majority of patients in both studies had severe hemophilia A.

In Haven 1, patients who received weekly Hemlibra prophylaxis experienced significantly fewer bleeds requiring treatment with bypassing agents compared to patients who received no prophylaxis. Nearly two-thirds (63%) of patients treated with Hemlibra had zero treated bleeds during the study, while only 5.6% of patients in the control arm (no prophylaxis) had zero treated bleeds. Patients' responses to a validated and disease-specific quality of life assessment, Haem-A-QoL, also indicated a clinically meaningful improvement in quality of life among Hemlibra-treated patients. An additional arm of Haven 1 included hemophilia A patients with factor VIII inhibitors who had previously received prophylactic bypass therapy in a non-interventional study. Upon switching to weekly Hemlibra therapy in this study, these patients had a 79% reduction in bleeding events requiring treatment when compared with prior prophylactic bypass therapy.

Reports from the Haven 2 study showed that weekly administration of Hemlibra for 12 weeks resulted in a low treated annualized bleed rate (ABR) of 0.2 in 23 pediatric (1-12 years of age) hemophilia A patients with FVIII inhibitors. Another group of Haven 2 patients who had previously received prophylactic bypass therapy in a non-interventional study had a decline in ABR from 17.2 on bypass therapies to 0.2 following treatment with Hemlibra. This translates to a 99% reduction in the treated bleed rate following 12 weeks of Hemlibra prophylaxis. Consistent with the outcomes of the pivotal Haven 1 study, these results collectively demonstrate a clinically meaningful impact of Hemlibra therapy, which reduces or eliminates bleeding events requiring treatment.

In a pooled dataset of 189 hemophilia A patients (seven patients did not have FVIII inhibitors), the most common adverse reactions observed were injection site reactions (19%), pyrexia (7%), headaches (15%), diarrhea (6%), arthralgia (10%), myalgia (5%), and thrombotic microangiopathy (2%).

The primary safety concern with use of Hemlibra is the risk of thromboembolism or thrombotic microangiopathy, which occurred in some Haven 1 patients who received activated prothrombin complex concentrate (aPCC) at daily doses exceeding 100 U/kg concurrently with Hemlibra. Patients are instructed to discontinue use of aPCC at least 24 hours prior to initiating therapy with Hemlibra, and to avoid using aPCC and Hemlibra simultaneously unless no other treatment options are available. A Serious Warnings and Precautions box is included for these events in the Hemlibra Product Monograph, along with additional details in the Warnings and Precautions section.

The potential for developing anti-drug antibodies (ADAs) to emicizumab was also identified as a concern in the clinical studies. One patient in the Haven 2 study withdrew due to loss of efficacy of Hemlibra. This was caused by low plasma concentrations of emicizumab; likely the result of neutralizing antibodies. Two patients in Haven 1 also had decreased plasma concentrations of emicizumab while on treatment with Hemlibra, which is potentially indicative of the development of ADAs. The sponsor is developing assays to more accurately evaluate the immunogenicity of Hemlibra, and is expected to file related safety updates with the Biologics and Genetic Therapies Directorate (BGTD).

A Risk Management Plan (RMP) for Hemlibra was submitted by Hoffmann-La Roche Limited to Health Canada, and was considered acceptable upon review. Immunogenicity and the development of neutralizing antibodies are recognized as important potential risks in the RMP. 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 implemented to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Hemlibra 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 Hemlibra was accepted.

Hemlibra was found to have a favourable benefit-risk profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Hemlibra Product Monograph to address these 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 Hemlibra?

The drug submission for Hemlibra was reviewed under the Priority Review Policy. Hemlibra demonstrated a significant increase in efficacy with an improved benefit/risk profile compared to existing therapies for hemophilia A, a condition that is not adequately managed by a drug marketed in Canada.

Submission Milestones: Hemlibra

Submission Milestone Date
Pre-submission meeting: 2017-11-15
Request for priority status  
Filed: 2017-11-22
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biologics: 2017-12-22
Submission filed: 2018-01-09
Screening  
Screening Acceptance Letter issued: 2018-02-05
Review  
On-Site Evaluation: 2018-07-23 - 2018-07-27
Quality Evaluation complete: 2018-07-31
Clinical Evaluation complete: 2018-08-01
Review of Risk Management Plan complete: 2018-06-11
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-08-02
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-08-02

The Canadian regulatory decision on the non-clinical and clinical review of Hemlibra was based on a critical assessment of the data package submitted to Health Canada. Review reports from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were consulted during the review of Hemlibra for relevant supplementary information.

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. As the potential to develop neutralizing anti-drug antibodies (ADAs) has been identified in clinical studies, the sponsor (Hoffmann-La Roche) is currently developing additional assays to more accurately assess the immunogenicity of Hemlibra. The sponsor is expected to file the results as important safety updates to the Biologics and Genetic Therapies Directorate (BGTD).

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

Emicizumab, the medicinal ingredient in Hemlibra, bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII, which is needed for effective hemostasis. Emicizumab has no structural relationship or sequence homology to FVIII and, as such, does not induce or enhance the development of direct inhibitors to FVIII.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Hemlibra for the recommended indication.

Hypercoagulability was observed when emicizumab was combined with activated prothrombin complex concentrate (aPCC) and other bypassing agents in cynomolgus monkey plasma. Clinical outcomes were consistent with this observation, as thrombotic events (thromboembolism and thrombotic microangiopathy) occurred in certain patients who received aPCC concurrently with Hemlibra. Instructions on safe use and risk minimization for patients who have used aPCC are included in a Serious Warnings and Precautions box as well as in the Warnings and Precautions section of the Product Monograph.

Anti-drug antibodies (ADAs) were detected in 24-30% of monkeys during non-clinical studies; the majority of which were neutralizing and affected the pharmacokinetics of emicizumab. However, high concentrations of neutralizing ADAs in monkeys are not necessarily indicative of a high incidence of ADAs in humans. Although no ADAs were directly detected in patients in the pivotal Haven 1 study, two patients had reductions in emicizumab plasma concentrations; indicating that neutralizing antibodies may have been present. Additionally, one pediatric patient developed a suspected ADA response in the Haven 2 study. This resulted in the loss of Hemlibra efficacy, and was attributed to very low detectable emicizumab plasma concentrations.

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

Clinical Efficacy

The clinical efficacy, safety, and pharmacokinetics of Hemlibra were evaluated in the Haven 1 study (BH29884); a multicentre, open-label, Phase III clinical study in adult and adolescent (≥12 years of age) male hemophilia A patients with FVIII inhibitors. These patients had previously received episodic ("on demand") bypassing therapy. The primary endpoint of this pivotal study was to assess the effect of weekly Hemlibra prophylaxis versus no prophylaxis on the number of bleeds requiring treatment with coagulation factors over time. The secondary endpoints assessed in this study were the efficacy of weekly Hemlibra prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, target joint bleeds, and in improving patients' health-related quality of life and health status. All patients receiving Hemlibra in this study received 3 mg/kg/week subcutaneously for 4 weeks, and 1.5 mg/kg/week thereafter.

The study design included two randomized arms, in which patients either received Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B). Patients who received Hemlibra experienced significantly fewer bleeds requiring treatment with bypassing agents, compared to patients who received no prophylaxis. This is indicated by the median annualized bleed rates (ABR) of 2.9 and 23.3 in Arm A and Arm B, respectively. Additionally, 63% of patients treated with Hemlibra experienced zero treated bleeds during the course of the study, compared to only 5.6% of patients who received no prophylaxis.

A clinically significant improvement in health-related quality of life was also observed among adult (≥18 years of age) Hemlibra-treated patients, compared to patients who received no prophylaxis. This was calculated based on patients' responses to the Haem-A-QoL assessment; a validated, disease-specific method for evaluating the quality of life of individuals with hemophilia.

An additional non-randomized arm of this study was comprised of patients who had previously received prophylactic bypass therapy in a non-interventional study, and switched to weekly Hemlibra prophylaxis. This group of patients experienced a 79% reduction in bleed rate for treated bleeds, with their median ABR decreasing from 15.7 at the beginning of the study to 3.3 after 24 weeks of Hemlibra prophylaxis.

The sponsor also submitted interim data from a Phase III study, Haven 2 (BH29992), which was ongoing at the time of review. The main objective was to investigate the safety and efficacy of Hemlibra in pediatric and adolescent hemophilia A patients with FVIII inhibitors. All 60 patients in the study are male; comprising pediatric patients from 1 to ≤2 years of age, or adolescent patients from12 to 17 years of age and weighing less than 40 kg. All patients received 3 mg/kg/week subcutaneously for 4 weeks, and 1.5 mg/kg/week thereafter; in line with the dosage regimen for Hemlibra-treated patients in Haven 1.

Interim results of Haven 2 are consistent with the outcomes of Haven 1, and showed that Hemlibra prophylaxis led to a statistically and clinically significant improvement in reducing bleeding events requiring treatment. The ABR for treated bleeds was 0.2 in a group of 23 patients who received at least 12 weeks of Hemlibra therapy. A significant decline in ABR was also observed in a sub-group of 13 patients who were previously treated with prophylactic bypassing agents in a non-interventional study (BH29768). These patients experienced a 99% reduction in the bleed rate for treated bleeds, with the ABR dropping from 17.2 at the start of the study to 0.2 after 12 weeks of Hemlibra prophylaxis. One patient, who enrolled after the data cut for the interim analysis, developed anti-emicizumab antibodies with neutralizing potential. The patients discontinued emicizumab treatment due to loss of efficacy.

Although both trials were open to male and female patients, the all-male patient populations of Haven 1 and Haven 2 may be attributed to the X-linked recessive nature of hemophilia A. X-linked recessive conditions disproportionately affect males; therefore, male hemophilia A patients significantly outnumber female patients. Additionally, male patients are far more likely to have a severe form of hemophilia A, while female patients are more likely to have a mild form of this condition.

Indication

Sponsor's proposed indication Health Canada-approved indication
Hemlibra (emicizumab) is indicated for routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors.

Hemlibra can be used in all age groups.
Hemlibra (emicizumab injection) is indicated for hemophilia A (congenital factor VIII deficiency) patients with factor VIII inhibitors as routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes.

The proposed indication was revised, as it was not considered necessary to define use in all age groups in the indication. This information was included in the Pediatric and Geriatrics sections of the Product Monograph. The Pediatric section of the Product Monograph was also amended to include the statement, "There are no clinical efficacy or safety data of Hemlibra in patients less than 1 years of age." Additionally, a separate line was included below the approved indication to acknowledge that clinical experience of Hemlibra in patients with mild or moderate hemophilia A is limited (nearly all patients treated with Hemlibra had severe hemophilia A).

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

Clinical Safety

The results from the Haven 1 and Haven 2 studies have established both the clinical efficacy and safety of Hemlibra in adult, adolescent and pediatric populations, and are described in the Clinical Efficacy section. It should be noted that there is currently no data regarding the safety and efficacy of Hemlibra in patients under 1 year old, or on the long-term use of Hemlibra.

Injection site reactions were the most common adverse reaction in both studies, and were reported at similar rates. Other commonly observed adverse reactions include pyrexia, headaches, diarrhea, arthralgia, myalgia, and thrombotic microangiopathy.

Thromboembolism and thrombotic microangiopathy were observed in four Haven 1 patients taking aPCC along with Hemlibra; all of whom received a daily dose greater than 100 U/kg. Based on the severity of these events and examination of the adverse reaction data, it was determined that treatment with aPCC should be discontinued at least 24 hours prior to initiating treatment with Hemlibra. Additionally, concurrent use of aPCC and Hemlibra must be avoided unless no other alternatives are available. If they must be taken together, the initial dose of aPCC should not exceed 50 U/kg, and the patient must be monitored closely due to the risk of thrombotic events. Warnings and instructions regarding the safe use of Hemlibra in connection with aPCC are included in the Serious Warnings and Precautions box and the Warnings and Precautions section of the Hemlibra Product Monograph.

As with any therapeutic antibody, immunogenicity (the development of anti-drug antibodies [ADAs]) may occur. One case of a suspected ADA response was reported in the Haven 2 study. The affected patient discontinued Hemlibra treatment after experiencing loss of efficacy, which was attributed to the development of ADAs with neutralizing potential against emicizumab. Two patients in Haven 1 were also reported to have decreased emicizumab plasma concentrations while on Hemlibra therapy. The sponsor is developing assays to more accurately detect total and neutralizing ADAs against emicizumab, and is expected to provide future safety updates to the Biologics and Genetic Therapies Directorate (BGTD).

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Hemlibra, and to promote its safe and effective use. Overall, the risk-benefit profile of Hemlibra is favourable. For more information, refer to the Hemlibra Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The utility of emicizumab as an antihemorrhagic is largely attributable to its binding specificity for human Factor IX and Factor X. In order to be effective, it must bind selectively to these two proteins, and not to other proteins involved in regulating blood coagulation. As determined by surface plasmon resonance, emicizumab binds to non-active and active forms of human Factor IX and Factor X. Emicizumab does not bind to FVII, FXII, or Protein C.

Non-clinical safety studies were carried out in cynomolgus monkeys, as emicizumab displayed similar activity in cynomolgus monkey plasma and human plasma. The combination of emicizumab with bypassing agents (aPCC or rFVIIa) caused hypercoagulability in cynomolgus monkey plasma, presenting a potential safety concern. This observation was reinforced by clinical reports of thrombotic events in patients receiving high doses of aPCC along with Hemlibra. Appropriate warnings and precautionary instructions were included in the Hemlibra Product Monograph to address this safety concern.

Anti-drug antibodies (ADAs) were detected in 24-30% of monkeys in the non-clinical studies; almost all of which neutralized emicizumab. Clinical studies later showed a much lower incidence of neutralizing ADAs in humans. It is possible to develop an immune response against any therapeutic antibody, which can lead to its loss of efficacy. Additionally, all the analytical techniques used to assess ADAs to emicizumab had limitations, and it is possible that not all incidences of total or neutralizing ADAs were detected in the clinical trials. To address this issue, the Sponsor is developing assays to improve detection of total and neutralizing ADAs against emicizumab, and is expected to provide future safety updates to the Biologics and Genetic Therapies Directorate (BGTD).

Repeat-dose toxicology studies were conducted in which cynomolgus monkeys were administered emicizumab intravenously for four weeks, and subcutaneously for up to 26 weeks. Safety pharmacology and fertility endpoints were evaluated. No toxicological effects were observed that could be attributed to emicizumab, through either route of administration.

In view of the intended use of Hemlibra, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Hemlibra Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Emicizumab is a modified monoclonal antibody based on the structure of immunoglobulin G4 (IgG4), and is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. It has been engineered to increase its similarity to natural human antibodies (humanized), as well as to enhance certain functional properties in relation to Factor VIII. Emicizumab binds activated Factor IX (FIXa) and Factor X (FX); effectively assuming the role of activated Factor VIII in its absence to promote the smooth function of the coagulation cascade.

Comprehensive characterization studies were performed on several batches of the drug substance to provide assurance that emicizumab consistently exhibits the desired characteristic structure and biological activity. Primary structure, post-translational modifications, higher order structure, and structural variants were all examined. The biological and immunochemical properties of emicizumab were also assessed, especially as they relate to its binding ability to FIX and FX.

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

The drug substance, emicizumab, is manufactured from Chinese hamster ovary (CHO) cells using recombinant DNA technology. The culture is initiated from a single working cell bank (WCB) vial and allowed to expand through a fed-batch process to reach commercial scale. Cells expressing emicizumab are initially cultured in shake flasks, and then transferred through a series of successively larger bioreactors as the cell cultures grow. Eventually, they are combined into one 2,000 L single-use bioreactor. Emicizumab is isolated from the cell culture through four chromatography steps, interspersed with additional procedures to inactivate and remove any viral contaminants present. The purified drug substance is stored at ≤-50ºC in 2L EVA bags.

The drug product, Hemlibra, is produced by thawing and pooling the drug substance, and dilution (for the 30 mg/mL dosage strength only), mixing, and filtration steps to reduce bioburden and sterilize the solution. Single-use vials are then aseptically filled with the appropriate volume. The filling process employed in the manufacture of this product has been validated to ensure that the vials are filled with the appropriate volume, containing the expected concentration.

Proper development and validation studies were conducted, and adequate controls are in place for the commercial process. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

The Chemistry and Manufacturing information submitted for Hemlibra has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Each manufacturing facility was found to be compliant with Good Manufacturing Practices, and able to reliably manufacture the drug substance and the drug product to an acceptable standard. Additionally, a suitable control strategy is in place to verify that the quality of the final product is acceptable for release.

Control of the Drug Substance and Drug Product

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

Samples from consecutively manufactured batches of final product lots were tested for purity by Cation Exchange High-Performance Liquid Chromatography (HPLC) and potency was assessed through a chromogenic assay. The results from these analyses are consistent with those reported by the Sponsor. This confirmed that the methods used in-house are acceptable for their intended use, and positively supported the quality review recommendation.

For post-approval monitoring, Hemlibra is considered a low risk product as emicizumab is well characterized and any significant issues from the submission have been resolved. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

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 30-month shelf life at 2-8ºC for Hemlibra is considered acceptable.

Facilities and Equipment

An on-site evaluation (OSE) of the drug substance manufacturing and testing facility was conducted as part of the review of the New Drug Submission for Hemlibra. The site complies with Good Manufacturing Practices, and conclusions from the OSE supported the issuance of a Notice of Compliance (NOC).

The drug product manufacturing site had previously undergone an OSE for the approval of another drug, and was determined to be compliant with Good Manufacturing Practices. The site is considered low risk at this time, and therefore an OSE was not recommended in connection with this New Drug Submission.

Adventitious Agents Safety Evaluation

The viral clearance process consists of six steps; each of which was validated according to International Council for Harmonisation (ICH) guidelines. Under worst-case settings, the proposed strategy was found to be capable of consistently reducing viral contamination to levels below the acceptable limits. The final product contains less than 1.54 × 10-8 retrovirus-like particles per dose, or less than one retrovirus-like particle per 6.48 × 107 doses.

Amicase and lactose, which are of animal origin, are used as processing agents in the making of the culture medium used in the fermentation process. Neither is present in the final drug product. Both are obtained from bovine milk fit for human consumption and are not considered to be a risk for bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE).