Summary Basis of Decision for HyQvia

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 HyQvia is located below.

Recent Activity for HyQvia

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

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

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

Updated: 2024-02-09

Drug Identification Number (DIN):

DIN 02524368 - immunoglobulin (human) 2.5 g/25 mL (10%), solution, with hyaluronidase (human recombinant) 200 U/1.25 mL, solution, subcutaneous administration

DIN 02524376 - immunoglobulin (human) 5 g/50 mL (10%), solution, with hyaluronidase (human recombinant) 400 U/2.5 mL, solution, subcutaneous administration

DIN 02524384 - immunoglobulin (human) 10 g/100 mL (10%), solution, with hyaluronidase (human recombinant) 800 U/5 mL, solution, subcutaneous administration

DIN 02524392 - immunoglobulin (human) 20 g/200 mL (10%), solution, with hyaluronidase (human recombinant) 1,600 U/10 mL, solution, subcutaneous administration

DIN 02524406 - immunoglobulin (human) 30 g/300 mL (10%), solution, with hyaluronidase (human recombinant) 2,400 U/15 mL, solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 278013

2023-08-01

Issued NOL 2023-11-09

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in product-contact equipment/material used in the drug substance manufacturing process, a change in the drug product manufacturing process, and the generation of a new Working Cell Bank for a recombinant product. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DINs 02524368, 02524376, 02524384, 02524392, 02524406) market notification

Not applicable

Date of first sale: 2023-11-07

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

NC # 272271

2023-02-08

Issued NOL 2023-05-11

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

NC # 271579

2023-01-25

Issued NOL 2023-04-28

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

NC # 271308

2023-01-11

Issued NOL 2023-04-17

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.

SNDS # 264950

2022-06-10

Issued NOC 2022-12-09

Submission filed as a Level II – Supplement (Safety) to update the PM with long-term safety data from Study 161301, related to pregnancy exposure and breastfeeding in women treated with HyQvia. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM. An NOC was issued.

NC # 264231

2022-05-12

Issued NOL 2022-08-30

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

NC # 264480

2022-05-20

Issued NOL 2022-08-09

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the qualification of a new lot of reference standard against the approved reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 263590

2022-04-21

Issued NOL 2022-07-20

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

NDS # 247727

2020-12-18

Issued NOC 2022-01-14

NOC issued for New Drug Submission.

 

Summary Basis of Decision (SBD) for HyQvia

Date SBD issued: 2022-06-28

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

Normal immunoglobulin (human) and recombinant human hyaluronidase

Drug Identification Number (DIN):

  • DIN 02524368 - immunoglobulin (human) 2.5 g/25 mL (10%), solution, with hyaluronidase (human recombinant) 200 U/1.25 mL, solution, subcutaneous administration
  • DIN 02524376 - immunoglobulin (human) 5 g/50 mL (10%), solution, with hyaluronidase (human recombinant) 400 U/2.5 mL, solution, subcutaneous administration
  • DIN 02524384 - immunoglobulin (human) 10 g/100 mL (10%), solution, with hyaluronidase (human recombinant) 800 U/5 mL, solution, subcutaneous administration
  • DIN 02524392 - immunoglobulin (human) 20 g/200 mL (10%), solution, with hyaluronidase (human recombinant) 1,600 U/10 mL, solution, subcutaneous administration
  • DIN 02524406 - immunoglobulin (human) 30 g/300 mL (10%), solution, with hyaluronidase (human recombinant) 2,400 U/15 mL, solution, subcutaneous administration

Takeda Canada Inc.

New Drug Submission Control Number: 247727

 

On January 14, 2022, Health Canada issued a Notice of Compliance to Takeda Canada Inc. for the drug product HyQvia.

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 HyQvia is favourable for the intended use of HyQvia as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients.

 

1 What was approved?

 

HyQvia (normal immunoglobulin [human] 10% and recombinant human hyaluronidase) is a product for facilitated subcutaneous administration of the human normal immunoglobulin. It was authorized as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients.

The safety and efficacy of HyQvia in pediatric patients have not been established. Therefore, HyQvia is not authorized for use in this population.

The available clinical data are too limited to draw conclusions on the safety of HyQvia when used in the geriatric population (patients over 65 years of age). It is recommended to monitor geriatric patients who have an increased risk for developing renal failure or thrombotic events.

HyQvia is a dual vial unit consisting of one vial of human normal immunoglobulin 10% and one vial of recombinant human hyaluronidase. Each single-use vial of human normal immunoglobulin 10% solution (2.5 g/25 mL, 5 g/50 mL, 10 g/100 mL, 20 g/200 mL, and 30 g/300 mL) is supplied with a corresponding single-use vial of recombinant human hyaluronidase (160 U/mL) solution (200 U/1.25 mL, 400 U/2.5 mL, 800 U/5 mL, 1,600 U/10 mL and 2,400 U/15 mL). Non-medicinal ingredients present in the human normal immunoglobulin 10% solution are glycine and water for injection. Sodium chloride, sodium phosphate dibasic dihydrate, human albumin, edetate disodium dihydrate, calcium chloride dihydrate, and water for injection are the non-medicinal ingredients in the recombinant human hyaluronidase solution. The two components of HyQvia must be infused sequentially through the same subcutaneous needle set, beginning with the recombinant human hyaluronidase.

The use of HyQvia is contraindicated in:

  • patients with a history of anaphylactic or severe systemic reactions to immunoglobulin G (IgG), or immunoglobulin A (IgA)-deficient patients with antibodies to IgA;
  • patients with known hypersensitivity to hyaluronidase, including recombinant human hyaluronidase (rHuPH20) of HyQvia; and
  • patients who are hypersensitive to this drug or to any of the ingredients in the formulation, including any non-medicinal ingredients, or component of the containers.

HyQvia was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The HyQvia Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

2 Why was HyQvia approved?

 

Health Canada considers that the benefit-risk profile of HyQvia is favourable for the intended use of HyQvia as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients.

Primary immunodeficiencies (also known as inborn errors of immunity) represent a heterogeneous group of genetic disorders that result in the specific impairment of normal immune development and function. Patients with immunodeficiencies that affect humoral (i.e., antibody-mediated) immunity have absent or deficient antibody production and typically present with recurrent, often severe, bacterial infections. Secondary immunodeficiencies are more frequent than primary immunodeficiencies and are caused by external factors, such as infectious agents (e.g., human immunodeficiency virus), diseases (e.g., diabetes, leukemia), drugs (e.g., chemotherapy), malnutrition, and aging. Patients with humoral immunodeficiencies often require lifelong immunoglobulin replacement therapy to prevent severe infections. The immunoglobulin preparations are given monthly or weekly depending on the route of administration (intravenously or subcutaneously).

HyQvia (normal immunoglobulin [human] 10% and recombinant human hyaluronidase) is a product for facilitated subcutaneous administration of the human normal immunoglobulin. The two components of HyQvia are infused sequentially through the same subcutaneous needle set, beginning with the recombinant human hyaluronidase PH20 (rHuPH20) followed by the immunoglobulin component (herein denoted as IG 10%). While the IG 10% provides the therapeutic effect of HyQvia, the rHuPH20 component temporarily modifies the permeability of the connective tissue through the local degradation of hyaluronan, thereby facilitating the subcutaneous infusion of large volumes of IG 10% and their absorption into the bloodstream.

The market authorization of HyQvia was primarily based on data from one pivotal, non-controlled, open-label, Phase III study (Study 160603, described in the Clinical Efficacy section) and its extension, a non-controlled, open-label Study 160902 (described in the Clinical Safety section). The efficacy, pharmacokinetics, and tolerability of HyQvia were demonstrated in 83 patients with primary immunodeficiency disease, 66 of whom entered the extension study.

The subcutaneous dose of the IG 10% component of HyQvia was based on the patient’s weekly equivalent to 108% of the intravenous dose of IG 10%. Seventy-eight of 83 patients (94%) treated with HyQvia attained the same 3- or 4-week dosing interval as with their previous intravenous IG 10% treatment.

The primary efficacy endpoint of the pivotal study was defined as less than one validated acute serious bacterial infection per subject per year. Acute serious bacterial infections included bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess, caused by a recognized bacterial pathogen. The pivotal study demonstrated a rate of 0.025 validated acute serious bacterial infections per year (upper limit of the 99% confidence interval [CI] of 0.046), which was significantly (p<0.0001) lower than the rate of one infection per year.

The extension Study 160902 assessed the long-term tolerability and safety of HyQvia. It included 63 HyQvia-treated patients who had completed the pivotal trial. The cumulative exposure of HyQvia across the two studies was 188 subject-years and 2,959 infusions, with a maximum exposure up to approximately 3.5 years.

There were no serious adverse events related to HyQvia during the two studies. Causally related local adverse events, i.e., those determined by the investigator to be related to HyQvia, occurred at a rate of 0.103 per infusion in Study 160902. This was lower than the rate of 0.203 observed in the pivotal Study 160603, suggesting that long-term treatment with HyQvia did not negatively impact the rate of local reactions.

Across four clinical studies, the most frequently reported causally related adverse events with the use of HyQvia were infusion site pain, infusion site erythema, infusion site swelling, headache, asthenic conditions (fatigue), nausea, and infusion site pruritus.

With respect to the long-term use of rHuPH20, there is the potential for development of anti-rHuPH20 antibodies which could theoretically interfere with the physiological functions of endogenous hyaluronidase PH20 present in adult human testes. However, none of the patients developed neutralizing anti-rHuPH20 antibodies during exposure to HyQvia. Thirteen of 66 patients treated with HyQvia had high titers (≥1:160) of antibodies capable of binding to rHuPH20. In the majority of these patients, anti-rHuPH20 antibody titers progressively declined during HyQvia treatment. There was no indication that the development of binding antibodies to rHuPH20 influences the occurrence of adverse events. Both non-clinical data and clinical experience support an acceptable safety profile for the use of rHuPH20.

As known for other immunoglobulin products, the use of HyQvia may be associated with thrombotic and thromboembolic events, renal failure, transfusion-related acute lung injury, aseptic meningitis syndrome, hemolysis, and spreading a localized infection. Additionally, given that the IG 10% and human serum albumin (stabilizer of the rHuPH20) are produced from human plasma, the possibility of transmitting infective agents (including unknown or emerging viruses and other pathogens) cannot be totally excluded, despite the standard measures to prevent infections resulting from the use of products prepared from human blood or plasma (selection of donors, screening of individual donations and plasma pools for specific markers of infection, and inclusion of effective manufacturing steps for the inactivation/removal of viruses).

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

The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name HyQvia was accepted.

Overall, based on the non-clinical data and clinical studies, HyQvia has an acceptable efficacy and safety profile for the intended patient population. The identified safety issues can be managed through adequate labelling and post-market monitoring. Appropriate warnings and precautions are in place in the HyQvia Product Monograph to address the 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 issued 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 HyQvia?

 

The review of the New Drug Submission (NDS) for HyQvia was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Method 4 (foreign documents not referenced or relevant) was used for the review of the quality component of the submission. The Canadian regulatory decision on the HyQvia NDS was made independently based on the Canadian review.

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

 

Submission Milestones: HyQvia

Submission Milestone Date
Pre-submission meeting 2020-10-13
New Drug Submission filed 2020-12-18
Screening  
Screening Acceptance Letter issued 2021-02-05
Review  
Request granted to pause review clock for 28 days (extension to respond to clarification request) 2021-11-04
Non-clinical evaluation completed 2021-12-14
Clinical/medical evaluation completed 2021-12-14
Review of Risk Management Plan completed 2021-12-14
Request granted to pause review clock for 18 days (extension to respond to clarification request) 2021-12-23
Labelling review completed 2022-01-10
Quality evaluation completed 2022-01-12
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-01-14

 

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 HyQvia?

 

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 HyQvia 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

In the pivotal clinical study (Study 160603, described in the Clinical Efficacy section), the pharmacokinetics of the immunoglobulin component (human normal immunoglobulin 10%, herein denoted as IG 10%) of HyQvia was determined following intravenous IG 10% administration and compared with the pharmacokinetics of IG 10% after subcutaneous administration with recombinant human hyaluronidase [rHuPH20] in patients aged 12 years and older. The subcutaneous dose of the IG 10% was calculated at 108% of the patient’s weekly equivalent dose utilized during intravenous administration of IG 10%, and adjusted in order to maintain immunoglobulin G (IgG) trough levels above 4.5 g/L.

The bioavailability of serum IgG as determined by the ratio of the area under concentration versus dosing time curve (AUC) for HyQvia to intravenous administration of IG 10% was 93.3% (90% confidence interval [CI]: 91.4%; 95.2%). In terms of IgG trough levels, the median ratio of IgG trough levels for HyQvia to intravenous administration of IG 10% was 103.8% (95% CI: 97.5%; 115.4%) in patients aged 4 to under 12 years and 98.5% (95% CI: 94.4%; 102.5%) in patients aged 12 years and older. These ratios were within bioequivalence margins of 80% to 125%. Median IgG trough levels were comparable between HyQvia and intravenously administered IG 10%.

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

Clinical Efficacy

The efficacy of HyQvia was primarily supported by one pivotal, non-controlled, open-label, Phase III study (Study 160603) conducted in 87 patients with primary immunodeficiency disease. The most frequently diagnosed primary immunodeficiency disease was common variable immune deficiency (49 of 87 patients), followed by hypogammaglobulinemia (17 of 87 patients) and X-linked agammaglobulinemia (6 of 87 patients). Patients had a median age of 35 years (range: 4 to 78 years) and 49.4% were females. The majority of patients were Caucasian (90.8%), followed by Asian (3.4%), and Black (2.3%).

The study consisted of two parts (Epoch 1 and Epoch 2). Epoch 1 was a pharmacokinetic assessment of the IG 10% component following intravenous administration (see Clinical Pharmacology). Patients received IG 10% at their pre-study dose and interval (minimum 300 mg/kg body weight every 4 weeks) for 3 months. Patients who previously participated in a similar pharmacokinetic study proceeded directly to Epoch 2.

In Epoch 2, patients began subcutaneous treatment with HyQvia (the rHuPH20 component of HyQvia was given at a dose of 75 U per gram IgG). The initial doses and treatment intervals were gradually increased (ramped up) from 1-week intervals to 3- or 4-week intervals during an up to 7-week ramp-up period. The ramp-up period allowed patients to become familiar with the large volumes required for a 3- or 4-week treatment interval. Sixty-eight patients completed the study including 8 patients younger than 12 years of age.

Patients received a mean equivalent dose of IG 10% of 0.143 g/kg/week during intravenous treatment and 0.155 g/kg/week during HyQvia treatment; with a median time of infusions of 2.33 and 2.08 hours, respectively. Following patient/caregiver training, self-administration and documenting adverse events at home were allowed during Epoch 2.

The primary efficacy endpoint was defined as less than one validated acute serious bacterial infection per subject per year. Acute serious bacterial infections included bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess, caused by a recognized bacterial pathogen. After the ramp-up period, two acute serious bacterial infections were reported during the observation period, both of which were episodes of pneumonia. This number corresponded to a rate of 0.025 validated acute serious bacterial infections per year (upper limit of the 99% confidence interval [CI] of 0.046), which was significantly lower than the rate of one infection per year (p<0.0001), in line with the relevant regulatory guidelines for demonstrating the efficacy of immunoglobulin products.

The annual rate of all infections was lower during HyQvia treatment (2.97 [95% CI: 2.51; 3.47]) than that during intravenous IG 10% treatment (4.51 [95% CI: 3.50; 5.69]). Among 30 of the 44 patients who were naïve to subcutaneous administration, the annual rate of all infections was 3.50 (95% CI: 2.79; 4.32) during HyQvia treatment and 4.42 (95% CI: 3.31; 6.06) during intravenous IG 10% treatment.

Indication

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

HyQvia is indicated as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult and pediatric patients two years of age and older.

Health Canada revised the proposed indication to limit the target patient population to adult patients only, due to the risks and uncertainties related to the chronic use of rHuPH20 in pediatric patients. Accordingly, Health Canada approved the following indication:

HyQvia is indicated as replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients.

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

Clinical Safety

The safety and tolerability of HyQvia was primarily supported by data from the pivotal Phase III Study 160603 (described in the Clinical Efficacy section) and its extension, Study 160902, as well as data from two Phase I/II and Phase II/III studies in 124 unique patients receiving 3,202 infusions. Patients ranged in age from 4 to 80 years. The studies included similar numbers of male and female patients.

Study 160902 assessed the long-term safety of HyQvia. The study also intended to evaluate whether a more frequent administration of HyQvia improved IgG trough levels. Patients were requested to decrease the HyQvia administration interval from 3 or 4 weeks to 2 weeks during a 4-month period. After that, dosing intervals of 2, 3 or 4 weeks were allowed according to the patient’s preference. The majority of patients preferred the 4-week dosing interval (41/66; 62.1%). Of the 66 patients rolled over from Study 160603, 63 patients received HyQvia. The mean (minimum to maximum) duration of HyQvia treatment was 680 days (645 to 729) in 11 patients under 16 years of age; 524 days (60 to 728) in 44 patients aged 16 to under 65 years, and 637 days (414 to 715) in 8 patients aged 65 years and older.

In total, 1,359 infusions of HyQvia were administered during Study 160603, 1,129 of which were received by 81 patients during the observation period (which started with the day of the first subcutaneous administration at the final infusion interval after the ramp-up). Among the 1,129 HyQvia infusions, 456 adverse reactions occurred, with a corresponding rate per infusion of 0.40. Six subjects, two children and four adults, withdrew from Study 160603 during the efficacy treatment period with HyQvia due to mild or moderate adverse reactions. One child withdrew due to local pain and one due to fever, vomiting, and headaches. Of the four adults, two withdrew due to local pain and swelling, one had moderate swelling that transiently extended from the abdominal infusion site to the genitalia, and one had back injury.

The most frequently reported local adverse events during Study 160603 were infusion site reactions, including pain, erythema, swelling/edema, and pruritus. Mild swelling around the infusion site was present in most infusions due to the large volumes infused, but in general, it was not considered to be an adverse reaction. Among the 234 local adverse reactions, three were severe (infusion site pain, infusion site swelling, and infusion site edema that extended from the abdominal infusion site to the genitalia); all were transient and resolved without sequelae. More than 98% of local reactions were either mild (70.5%) or moderate (28.2%) in severity. No serious adverse events related to HyQvia were reported during the clinical studies.

During Study 160902, causally related local adverse events, i.e., those determined by the investigator to be related to HyQvia, occurred at a rate of 0.103 per infusion. This was lower than the rate of 0.203 observed in Study 160603, suggesting that long-term treatment with HyQvia did not negatively impact the rate of local reactions. The most frequently reported causally related adverse events per infusion (and their corresponding rates per infusion) were infusion site pain (0.053), infusion site pruritus (0.019), nausea (0.018), myalgia (0.016), infusion site erythema (0.014), headache (0.013), and fatigue (0.010).

Thirteen of the 66 patients treated with HyQvia (11 patients in Study 160603 and 2 patients in Study 160902) had high titers (≥1:160) of anti-rHuPH20 antibodies. However, none of the patients developed neutralizing anti-rHuPH20 antibodies. No temporal association between adverse reactions and the presence of anti-rHuPH20 antibodies could be demonstrated. In all patients, anti-rHuPH20 antibody titers decreased despite continued treatment. The effect of exposure to anti-rHuPH20 antibodies for periods longer than the duration of the clinical trials has not been evaluated.

As reported for other immunoglobulin products, the use of HyQvia may be associated with thrombotic and thromboembolic events, renal failure, transfusion-related acute lung injury, aseptic meningitis syndrome, hemolysis, and spreading a localized infection. Additionally, given that the IG 10% and human serum albumin (stabilizer of the rHuPH20) are produced from human plasma, the possibility of transmitting infective agents (including unknown or emerging viruses and other pathogens) cannot be totally excluded, despite the standard measures to prevent infections resulting from the use of products prepared from human blood or plasma (selection of donors, screening of individual donations and plasma pools for specific markers of infection, and inclusion of effective manufacturing steps for the inactivation/removal of viruses). The aforementioned risks have been addressed through appropriate warnings and precautions in the HyQvia Product Monograph.

Overall, based on the clinical data submitted, the safety profile of HyQvia is considered acceptable for the intended patient population.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

HyQvia is a dual vial unit consisting of one vial of human normal immunoglobulin 10% (IG 10%) and one vial of recombinant human hyaluronidase PH20 (rHuPH20). The IG 10% provides the therapeutic effect of HyQvia, whereas the rHuPH20 facilitates the subcutaneous administration and absorption of IG 10%.

The IG 10% solution contains a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral agents. It also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanism of action of IgG in the IG 10% of HyQvia have not been fully elucidated.

The rHuPH20 is a soluble recombinant form of human hyaluronidase PH20 that modifies the permeability of the connective tissue through degradation of hyaluronan (hyaluronic acid). Hyaluronan is a polysaccharide found in the intercellular matrix of the connective tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a very fast turnover with a half-life of approximately 0.5 days. The rHuPH20 increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. The effects of rHuPH20 are reversible and normal permeability of the subcutaneous tissue is restored within 24 to 48 hours.

The sponsor submitted a comprehensive non-clinical data package to support the use of HyQvia in humans by the subcutaneous route of administration.

The toxicity of subcutaneously administered rHuPH20 was evaluated in a repeat-dose toxicity study in male and female cynomolgus monkeys. Animals received rHuPH20 at doses up to a human equivalent dose of 74,193.5 U/kg once weekly for 39 weeks. Plasma levels of the rHuPH20 enzyme activity increased in a dose-dependent manner during the first 12 weeks of repeated administration, but declined thereafter as a result of the corresponding increase in neutralizing anti-rHuPH20 antibody titres. Antibody titres declined by 50% after a 4-week recovery period. Clinical and electrocardiogram analyses, as well as assessments of male and female reproductive parameters (semen analysis and menstrual cycle monitoring) revealed unremarkable results. At necropsy, only subcutaneous perivascular lymphoplasmacytic infiltration was observed at the injection site, a local response expected with the subcutaneous administration of human proteins in monkeys.

Reproductive and developmental toxicity studies with rHuPH20 were conducted in mice and rabbits. Female mice receiving rHuPH20 at doses up to a human equivalent dose of 175,609.8 U/kg/day during gestation had unremarkable clinical findings. Litter observations included reductions in fetal weights and increases in the number of late resorptions, without malformations or variations in embryo-fetal development. Therefore, rHuPH20 was considered fetotoxic, but not teratogenic. The developmental no-observed-adverse-effect level for rHuPH20 in mice was the human equivalent dose of 29,268.3 U/kg/day. In a subsequent perinatal/postnatal reproduction toxicity study, female mice received rHuPH20 at doses up to a human equivalent dose of 87,804.9 U/kg/day during gestation and lactation. Clinical observations of the male and female offspring (F1 generation) exposed to rHuPH20 only via the maternal milk during the lactation period revealed unremarkable findings.

A lifetime toxicity study in mice evaluated the toxicity of daily subcutaneous administration of rHuPH20 at a dose of 9,756 U/kg starting from postnatal Day 7 through 8 months of age. Anti-rHuPH20 antibody titers increased in juvenile mice, reached steady states by 90 days, and were sustained thereafter (a titre value of approximately 3 x 106). Clinical and developmental evaluations and neurobehavioural assessments showed unremarkable results, and no deaths were assessed as related to rHuPH20. There were no rHuPH20-related effects on sexual maturation or reproductive parameters (mating and fertility, sperm motility, concentration or morphology, ovarian, uterine, or litter observations), and rHuPH20 did not produce any fetal external, visceral, or skeletal abnormalities. Fertility indices in both males and females were similar between control (95%) and rHuPH20 (100%) treatment groups.

In a fertility and reproduction study in male rabbits, animals were dosed weekly with 91,200 U/kg rHuPH20 (to generate anti-rHuPH20 antibodies) prior to mating with untreated females. Anti-rHuPH20 antibody titres increased during the first 29 days of treatment, with steady state levels until necropsy. The results of clinical observations and necropsy evaluations, including examinations of male reproductive organs and semen analyses were unremarkable. The fertility index in males was 85% in the buffer control-treated group and 100% in the rHuPH20-treated group, indicating that persistent exposure to anti-rHuPH20 antibodies had no effect on the male reproductive potential.

Similar observations were reported in a fertility and reproduction study in female rabbits dosed weekly with 91,200 U/kg rHuPH20 (to generate anti-rHuPH20 antibodies) prior to mating with untreated males. The exposure of female rabbits to elevated titers of anti-rHuPH20 antibodies prior to mating and throughout gestation had no effect on mating and fertility. The fertility index was 94% in the buffer control-treated group and 88% in the rHuPH20-treated group. Maternal anti-rHuPH20 antibodies that were transferred to the offspring (F1 generation) during gestation and lactation persisted through at least 3 months of age. There were no adverse effects on the F1 generation embryo-fetal or postnatal development, maturation, and fertility, including sperm parameters. In the F1 generation females, the fertility index was higher in the maternal buffer control-treated group (95%) than in the maternal rHuPH20-treated group (81%). Similarly, in the F1 generation males, the fertility index was higher in the maternal buffer control-treated group (100%) than in the maternal rHuPH20-treated group (79%). Based on a fertility index of 80% in historical controls, these differences were considered unlikely related to the anti-rHuPH20 antibodies.

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

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

 

 

7.3 Quality Basis for Decision

 

HyQvia is supplied as a dual vial unit consisting of one vial of human normal immunoglobulin 10% and one vial of recombinant human hyaluronidase (rHuPH20).

Given that the immunoglobulin component of HyQvia is identical to an approved product (Gammagard Liquid, intended for intravenous administration) the review of the quality (chemistry and manufacturing) portion of the New Drug Submission (NDS) for HyQvia focused mainly on the data related to the rHuPH20 drug substance and drug product.

Characterization of the Drug Substance

The recombinant human hyaluronidase of HyQvia is a recombinant human hyaluronidase PH20 analog corresponding to the amino acid sequence of human hyaluronidase PH20 at positions 36-482. The purified recombinant enzyme is a glycoprotein with 447 amino acid residues and a molecular weight of 60,000 to 65,000 Da.

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

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

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

Recombinant Human Hyaluronidase Drug Substance

The enzyme rHuPH20 is produced by genetically engineered Chinese hamster ovary (CHO) cells containing a deoxyribonucleic acid (DNA) plasmid encoding for a soluble fragment of human hyaluronidase PH20.

The cell culture is expanded from the adequately qualified and characterized working cell bank over multiple expansion steps, after which the cells are transferred to a production bioreactor. Following completion of the production bioreactor process, the secreted rHuPH20 is harvested from the cell culture fluid and clarified. Subsequently, the clarified harvest is stabilized with a Tris-ethylenediaminetetraacetic acid (Tris-EDTA) buffer , ultrafiltered/diafiltered, subjected to a solvent/detergent treatment, purified over four column chromatography steps, nanofiltered, concentrated, formulated, filled into drug substance containers, and frozen.

The manufacturing process described in the drug submission evolved from prior generations of the process. Of note, the rHuPH20 drug substance utilized in all clinical studies was manufactured using the first-generation process. The second-generation process uses a different cell line, derived from the original process CHO cell line. The first version of the second-generation process used a small bioreactor scale and was subsequently scaled up. A stepwise and direct comparability assessment at each manufacturing step was carried out between the rHuPH20 drug substance manufacturing processes. The generated comparability data were used to establish potential critical parameters and quality attributes for each of the unit operations of the rHuPH20 drug substance manufacturing process. In the nonclinical studies, which utilized rHuPH20 drug substance preparations manufactured by the first-generation process or by the second-generation process, no significant differences were observed in the pharmacological properties of the two rHuPH20 drug substance materials.

The starting materials are adequately described and controlled, including the cell banking and the biological materials used in the cell culture or purification phase of the manufacturing process.

Process validation was conducted at full commercial scale with three consecutive drug substance batches. All process parameters, in-process controls, release testing results, characterization results, and stability results met predefined criteria, action limits, and acceptance criteria for all three validation runs. The data demonstrated that the facility and the manufacturing process could consistently produce rHuPH20 drug substance that met the predetermined acceptance criteria for quality attributes.

Recombinant Human Hyaluronidase Drug Product

The rHuPH20 drug product manufacturing process includes formulation, sterile filtration, filling, visual inspection, bulk packaging, and release and stability testing. Adequate process description, process validation data, and equipment qualification data were provided to show that the manufacturing process is robust and can consistently produce rHuPH20 drug product that meets the predetermined quality characteristics.

The process parameters and in-process controls are adequately supported by process validation and risk evaluations. Analytical methods were validated or verified and/or complied with compendial requirements.

The formulation of the rHuPH20 drug product includes human albumin as an excipient. Adequate data were provided to support the manufacture and control of the human albumin excipient, including information regarding the origin of plasma and viral marker testing at donation, mini-pool, and plasma pool levels.

Control of the Drug Substance and Drug Product

The rHuPH20 drug substance release specifications are suitable for control of the identity, content, purity, enzyme activity, and relevant safety characteristics of the drug substance. The associated analytical methods were validated or verified, and the acceptance criteria were appropriately justified.

The rHuPH20 drug product specifications are defined and justified and are considered suitable for control of the drug product quality. Notably, the release specification criterion for drug product purity, assessed by reversed-phase high-performance liquid chromatography (RP-HPLC), was tightened at Health Canada’s request.

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

Stability of the Drug Substance and Drug Product

The stability data support the proposed shelf life of 36 months for the drug product, when stored at 2 °C to 8 °C.

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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The immunoglobulin component (human normal immunoglobulin 10%) of HyQvia is identical to an approved product (Gammagard Liquid). According to the information provided in the NDS for HyQvia, no changes to the drug substance and drug product manufacturing processes or facilities were introduced with respect to the manufacture of the immunoglobulin component of HyQvia. Consequently, an on-site evaluation of the immunoglobulin manufacturing sites was not deemed necessary.

An on-site evaluation of the facility involved in the manufacture and testing of the rHuPH20 drug substance was not recommended, as the facility had already been approved by Health Canada for the manufacture of rHuPH20 used as an excipient (that functions as a permeation enhancer) in several monoclonal antibodies. In addition, no on-site evaluation was deemed necessary for the rHuPH20 drug product manufacturing facilities, taking into consideration the nature of the process (simple formulation, sterile filtration, and filling), the site location and stringency of the national regulatory authority, and the availability of recent certificates of compliance with good manufacturing practice standards.

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

Adventitious Agents Safety Evaluation

The adventitious agents safety of the plasma-derived human normal immunoglobulin and human albumin (an excipient present in the recombinant human hyaluronidase solution) is ensured by appropriate donor selection followed by viral marker testing of the individual donations, mini-pools of plasma, and manufacturing plasma pools. In addition, adequate overall viral clearance capacity of the manufacturing process was demonstrated for several representative model viruses using small-scale viral clearance studies that have been determined to suitably represent the commercial scale process or represent a worst-case scenario. Of note, for both the immunoglobulin and the excipient albumin, the relevant data had been previously reviewed in the context of other submissions.

Adequate overall viral reduction was demonstrated for four representative model viruses over five steps of the manufacturing process of recombinant human hyaluronidase: the solvent detergent treatment step, column chromatography purification steps, and viral filtration step.

The risk of contamination with non-viral adventitious agents (bacteria, fungi, mycoplasma) is mitigated by adequate control measures incorporated in the manufacturing processes of the two HyQvia components.

The risk of contamination with transmissible spongiform encephalopathy agents, specifically agents of variant Creutzfeldt-Jakob disease (vCJD), is minimized by sourcing plasma from countries without significant vCJD incidence and by process-specific prion reduction steps. Furthermore, the sourcing and control of raw materials and intermediates of animal origin are compliant with requirements specified in the relevant guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal products.

Apart from the plasma-derived human albumin excipient, no other excipients in HyQvia are of human or animal origin.

 

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