Summary Basis of Decision for Vonvendi

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 Vonvendi is located below.

Recent Activity for Vonvendi

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 Vonvendi, a product which contains the medicinal ingredient von Willebrand factor (recombinant). For more information on the type of information found in PAATs, please refer 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: 2025-09-26

Drug Identification Number (DIN):

  • DIN 02484420 - von Willebrand factor 650 IU/vial, lyophilized powder for solution, intravenous administration
  • DIN 02484439 – von Willebrand factor 1,300 IU/vial, lyophilized powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 274580 2023-04-20 Issued NOC 2023-11-28 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions 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.
NC # 264814 2022-06-02 Issued NOL 2022-09-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance purification process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 262806 2022-03-30 Issued NOL 2022-06-21 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 262040 2022-03-07 Issued NOL 2022-05-25 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard used for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 261810 2022-02-24 Issued NOL 2022-05-09 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 242931 2020-08-27 Issued NOC 2021-02-04 Submission filed to change the name of the drug sponsor from Shire Pharma Canada ULC to Takeda Canada Inc., and to update the inner and outer labels. An NOC was issued.
NDS # 240960 2020-06-23 Cancellation Letter Received 2020-07-30 Submission filed to change the name of the drug sponsor from Shire Pharma Canada ULC to Takeda Canada Inc. and to update the inner and outer labels. Changes were not in scope of an Administrative NDS. The sponsor cancelled the submission administratively.
NC # 237073 2020-03-13 Issued NOL 2020-04-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 232542 2019-10-15 Issued NOL 2020-01-16 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions 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 # 231692 2019-09-18 Issued NOL 2019-12-12 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 213188 2018-01-26 Issued NOC 2019-01-10 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Vonvendi

Date SBD issued: 2019-06-18

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

von Willebrand factor (Recombinant)

Drug Identification Number (DIN):

  • DIN 02484420 - 650 IU/vial, lyophilized powder for solution, intravenous administration
  • DIN 02484439 - 1,300 IU/vial, lyophilized powder for solution, intravenous administration

Shire Pharma Canada ULC

New Drug Submission Control Number: 213188

 

On January 10, 2019, Health Canada issued a Notice of Compliance to Shire Pharma Canada ULC for the drug product Vonvendi.

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 Vonvendi is favourable for:

  • Treatment and control of bleeding episodes in adults (ages ≥18 years) diagnosed with von Willebrand Disease (VWD).
  • Perioperative management of bleeding in adults (ages ≥18 years) diagnosed with VWD.

 

1 What was approved?

 

Vonvendi, a recombinant von Willebrand factor (rVWF), was authorized for:

  • Treatment and control of bleeding episodes in adults (ages ≥18 years) diagnosed with von Willebrand Disease (VWD).
  • Perioperative management of bleeding in adults (ages ≥18 years) diagnosed with VWD.

Vonvendi is contraindicated in patients who have had a serious hypersensitivity reaction to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, mouse or hamster proteins, or component of the container.

Vonvendi 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.

Vonvendi (650 IU VWF:RCo/vial and 1300 IU VWF:RCo/vial von Willebrand factor [Recombinant]) is presented as a powder for solution. The dosage forms are expressed in international units (IU) of rVWF activity based on the Ristocetin Cofactor assay (VWF:RCo); an optical density measurement of agglutinated platelets induced by rVWF in the presence of ristocetin, and calibrated against a reference blood standard. In addition to the medicinal ingredient, the powder contains glycine, mannitol, polysorbate 80 (Tween-80), trehalose dihydrate, and tri-sodium citrate dihydrate.

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

 

2 Why was Vonvendi approved?

 

Health Canada considers that the benefit-risk profile of Vonvendi is favourable for:

  • Treatment and control of bleeding episodes in adults (ages ≥18 years) diagnosed with von Willebrand disease (VWD).
  • Perioperative management of bleeding in adults (ages ≥18 years) diagnosed with VWD.

Vonvendi is not authorized for use in pediatric patients (<18 years of age), as no data are available to Health Canada regarding its safety and efficacy in this patient population. Additionally, there is insufficient data to recommend the use of Vonvendi in geriatric patients (≥65 years of age).

Von Willebrand disease is an inherited bleeding disorder (autosomal dominant or recessive) which affects approximately one in 1,000 people. It is caused by quantitative, structural, or functional abnormalities in the coagulation factor, von Willebrand factor (VWF), which is involved in platelet adhesion at sites of vascular injury. Von Willebrand factor also serves as a carrier and stabilizer of the coagulation factor VIII (FVIII), which contributes to blood coagulation. Symptoms of VWD are typically bleeding anomalies such as mucocutaneous hemorrhage (e.g., heavy nosebleed or menstrual bleeding), hematomas, or bleeding into joint spaces. Life-threatening hemorrhage can occur after childbirth, surgery, or trauma.

Von Willebrand disease is classified into three main types. Type 1 VWD is characterized by partial deficiency of VWF due to reduced secretion or increased clearance. Type 2 VWD is caused by qualitative defects of VWF, and is further classified into subtypes 2A, 2B, 2M and 2N. Type 3 VWD is the most severe form, caused by the complete absence of VWF.

The measurement of VWF activity is based on the Ristocetin Cofactor assay (VWF:RCo), in which VWF binds to platelets in the presence of ristocetin. The extent to which agglutination occurs is an indicator of the presence of functional VWF, and is expressed as a percentage of normal VWF activity. The activity of FVIII is measured as FVIII coagulant activity (FVIII:C), and is expressed as a percentage of normal FVIII activity.

The treatments currently approved for the management of VWD are desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and plasma-derived clotting factor concentrates containing both VWF and FVIII. The latter treatment is the preferred option for most patients undergoing surgical procedures.

The market authorization of Vonvendi was based primarily on the outcomes of two pivotal, open-label Phase III studies. Study 071001 evaluated Vonvendi as a treatment for bleeding episodes, and Study 071101 evaluated Vonvendi for use in the perioperative management of bleeding during elective surgery. Both studies are also described in greater detail in the Clinical Efficacy section. Additional information on adverse events is provided in the Clinical Safety section.

In Study 071001, 37 patients were treated for minor, moderate, and major or severe bleeding episodes. The majority of patients had Type 3 VWD (29 patients, or 78.4%). The study consisted of two parts, which lasted for six months each. In Part A, patients were divided between four treatment arms for pharmacokinetic assessments and/or treatment of bleeding episodes. In Part B, all patients received hemostatic treatment for bleeding episodes.

Treatment success for the control of bleeding episodes was based on a hemostatic efficacy score on a four-point scale (1-Excellent; 2-Good; 3-Moderate; 4-None). The main criterion in determining treatment success was the actual number of infusions of rVWF needed, with or without rFVIII, compared to the expected number of infusions needed to treat the bleeding episode. All bleeding episodes were successfully treated and controlled, and assigned hemostatic efficacy scores of excellent (96.9%) or good (3.1%). The rate of treatment success was 100%.

Study 071101 evaluated the efficacy and safety of Vonvendi for the perioperative management of bleeding during elective surgical procedures in 15 patients with various types of VWD. Priming doses were administered 12-24 hours before surgery, and subsequent doses of Vonvendi were administered with or without rFVIII. The activated partial thromboplastin time (aPTT) was normalized before surgery began. During surgery, the dose and frequency were customized according to the severity and duration of the bleeding episode and the activity levels of coagulant factors.

Hemostatic efficacy was assessed either 24 hours after the final perioperative infusion of Vonvendi, or at post-operative Day 14. Treatment success was based on a four-point scale (1-Excellent; 2-Good; 3-Moderate; 4-None), determined mainly by comparing the intra- and post-operative hemostasis observed in patients to the expected hemostasis that would be achieved for the same type of surgical procedure in a normal subject. All 15 patients experienced treatment success of excellent or good. The overall hemostatic efficacy scores were excellent for 11 patients, and good for four patients.

Collectively, the outcomes of the pivotal studies support the efficacy of Vonvendi for the approved indications.

One patient with Type 3 VWD developed binding antibodies against rVWF during Study 071101, which were determined not to have a neutralizing effect. There were no other reports in either of the pivotal studies of binding antibodies or neutralizing antibodies against rVWF, rFVIII, or trace amounts of animal proteins present in the final drug product.

Two treatment-emergent events of deep vein thrombosis were observed post-operatively in one patient in Study 071101. This patient had undergone a major surgery (i.e., total hip replacement) and had a disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) level at 37% of the normal plasma level. ADAMTS13 is responsible for the proteolysis of high molecular weight VWF multimers, and a deficiency of this enzyme can contribute to thrombotic events. One event was considered serious, and the other was considered non-serious. Both were considered possibly related to the treatment upon reassessment by the sponsor based on the mechanism of action of the drug.

A Risk Management Plan (RMP) for Vonvendi was submitted by Shire Pharma Canada ULC to Health Canada. The RMP is considered acceptable, with updates expected within 90 days of receiving marketing authorization for Vonvendi. 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 Vonvendi 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 Vonvendi was accepted.

Overall, the therapeutic benefits of Vonvendi therapy seen in the pivotal studies are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Vonvendi 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 Vonvendi?

 

Submission Milestones: Vonvendi

Submission Milestone Date
Pre-submission meeting: 2017-07-18
Submission filed: 2018-01-26
Screening  
Screening Acceptance Letter issued: 2018-03-16
Review  
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-06-29
Review of Risk Management Plan complete: 2018-11-07
Quality Evaluation complete: 2018-12-20
Clinical/Medical Evaluation complete: 2018-12-21
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2019-01-10

 

The Canadian regulatory decision on the non-clinical, clinical, and quality review of Vonvendi 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) were consulted during the review of Vonvendi 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.

The sponsor has made commitments to provide Health Canada results of additional assessments regarding the reconstitution behaviour of Vonvendi. The result of this assessment is to be submitted to Health Canada at least one month in advance of any commercial lot release to the Canadian market.

Additionally, the sponsor is expected to make certain revisions to the Risk Management Plan (RMP) within 90 days of receiving market authorization. Requested updates include reclassification of thromboembolic events as an important identified risk, and the addition of pediatric patients and patients with hepatic and/or severe renal impairment to the listed safety concerns. The sponsor is also expected to make these updates to the Pharmacovigilance Plan for Vonvendi.

 

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

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's life cycle.

The PAAT for Vonvendi 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

Administration of Vonvendi introduces functional, recombinant von Willebrand factor (rVWF) in patients where the endogenous protein is defective or absent. Von Willebrand factor (VWF) plays a central role in hemostasis by mediating platelet aggregation as well as platelet adhesion at sites of vascular injury. It additionally acts as a carrier for the blood clotting protein, factor VIII (FVIII), protecting it from rapid proteolysis.

The drug product contains human rVWF multimers ranging from dimers (500 kDa) up to intact ultra-large multimers (approximately 20 000 kDa or 80 monomers ). The activity of rVWF is in part dependent on the presence of these ultra-large multimers, which are regulated by the endogenous plasma proteinase ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 13), which cleave the ultra-large multimers into smaller units.

The pharmacokinetics of rVWF and rFVIII were characterized in patients with VWD in three clinical studies: Studies 071001 and 071101 (pivotal Phase III studies described in the Clinical Efficacy section), and a Phase I study, Study 070701.

All three studies examined the pharmacokinetics of rVWF at 50 IU rVWF:RCo/kg. Study 071001 additionally examined the pharmacokinetics of rVWF at 80 IU rVWF:RCo/kg, and Study 070701 examined the pharmacokinetics of 50 IU rVWF:RCo/kg co-infused with 38.5 IU rFVIII:C/kg. The pharmacokinetic profile of rVWF at 50 IU rVWF:RCo/kg was comparable with and without rFVIII, as well as with the pharmacokinetic profile observed at 80 IU rVWF:RCo/kg.

Recombinant von Willebrand factor reached peak plasma concentration within 60 minutes of administration. It also binds endogenous FVIII and remains primarily in circulation. The mean half-life (t½) of rVWF ranged from 17.8 hours to 22.6 hours.

No dedicated pharmacodynamics studies were conducted. The pharmacodynamic properties of rVWF were nonetheless characterized in vitro at physiological concentrations, using whole blood from VWD patients. The observed platelet adhesion was comparable to plasma-derived VWF/FVIII concentrates, and within the range observed using whole blood from healthy donors.

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

Clinical Efficacy

The efficacy of Vonvendi was based primarily on the outcomes of two pivotal, open-label Phase III studies, each in support of one of the approved indications. Study 071001 evaluated Vonvendi for the treatment of bleeding episodes, and Study 071101 evaluated Vonvendi in the perioperative management of bleeding during elective surgery. Exclusion criteria for the clinical studies included a history of hypersensitivity to VWF, neutralizing antibodies against VWF or FVIII, and a history of thromboembolic events.

The dosage forms are expressed as international units (IU) of rVWF activity based on the Ristocetin Cofactor assay (VWF:RCo); an optical density measurement of agglutinated platelets induced by rVWF in the presence of ristocetin, and calibrated against a reference blood standard. The extent to which agglutination occurs is an indicator of the presence of functional VWF, and is expressed as a percentage of normal VWF activity. The activity of FVIII is measured as FVIII coagulant activity (FVIII:C), and is expressed as a percentage of normal FVIII activity.

Patients initially received Vonvendi with recombinant FVIII (rFVIII) based on body weight, and dosages were personalized according to activity levels of rVWF and rFVIII, and the severity and duration of the bleeding episode. Laboratory monitoring was performed at suitable intervals in order to maintain normal activity levels of rVWF at 60% and rFVIII at 40%.

Study 071001 (For the treatment of bleeding episodes)

Study 071001 enrolled 37 patients; the majority of whom had Type 3 VWD (29 patients, or 78.4%). Five patients (13.5%) had Type 2A VWD, one patient (2.7%) had Type 2N VWD, and two patients (5.4%) had Type 1 VWD. The study was divided into two consecutive six-month periods, Parts A and B, for a total study duration of 12 months.

In Part A, patients were divided into four treatment groups for pharmacokinetic assessments and/or treatment of bleeding episodes. Patients in Groups 1 and 3 were subject to pharmacokinetic assessments following administration of Vonvendi at 50 ± 5 IU rVWF:RCo/kg and 80 ± 5 IU rVWF:RCo/kg, respectively, and also received hemostatic treatment for bleeding episodes. Patients in Group 2 were subject to pharmacokinetic assessments following administration of 50 IU rVWF:RCo/kg, without treatment for bleeding episodes. Patients in Group 4 received hemostatic treatment for bleeding episodes only, and were not subject to pharmacokinetic assessments. In Part B, all patients received hemostatic treatment for bleeding episodes.

Bleeding episodes were initially treated with an infusion of rVWF and rFVIII at a ratio of 1.3 to 1.0, with the objective of achieving plasma levels greater than 60 IU rVWF:RCo/dL and greater than 40 IU rFVIII:C/dL (i.e., 60% of normal VWF:RCo and 40% of normal FVIII:C). The initial dose was followed by Vonvendi alone or with rFVIII, depending on the patient's needs. For minor bleeding episodes, patients received a second dose of Vonvendi at 40-50 IU rVWF:RCo/kg if needed. For major bleeding episodes, Type 1 VWD patients received an initial dose of 50 to 75 IU rVWF:RCo/kg. Type 2 and Type 3 VWD patients received an initial dose of 60 to 80 IU rVWF:RCo/kg. For all major bleeding episodes, the initial dose was followed by doses of 40 to 60 IU rVWF:RCo/kg every eight to 12 hours as needed for the next three days, to maintain a rVWF:RCo level above 50%. Afterwards, patients were given 40 to 60 IU rVWF:RCo/kg daily, for a total of up to seven days of treatment for the bleeding episode.

The primary efficacy endpoint was the number of patients for whom the treatment successfully controlled bleeding episodes. Treatment success for the control of bleeding episode was based on a hemostatic efficacy score on a four-point scale (1-Excellent; 2-Good; 3-Moderate; 4-None). Scores were determined by comparing the expected and actual numbers of infusions required to treat the bleeding episode. Scores were also affected by the need, if any, for additional coagulation factors to treat the bleeding episode. Treatment success was defined as an average efficacy score less than 2.5 for all bleeding episodes during the study period in a patient treated with Vonvendi, with or without rFVIII. All 18 patients included in a primary analysis experienced treatment success. A total of 192 bleeding episodes were treated in 22 out of 37 patients. All bleeding episodes were treated and controlled, and assigned hemostatic efficacy scores of excellent (96.9%) or good (3.1%) across all degrees of bleeding severity and in various locations. The rate of treatment success was 100%.

Study 071101 (For the perioperative management of bleeding during surgery)

Study 071101 evaluated the efficacy and safety of Vonvendi for the perioperative management of bleeding during major, minor, or oral elective surgical procedures in 15 patients. Eight patients (53.3%) had Type 3 VWD, two patients (13.3%) had Type 2A VWD, one patient (6.7%) had Type 2B VWD, one patient (6.7%) had Type 2M VWD, and three patients (20%) had Type 1 VWD. Major surgery was defined as any surgery accompanied by significant risks of a high volume of blood loss. Minor surgery was defined as a minimally invasive procedure or endoscopy. Oral surgeries involved extractions of less than three "non-molar" teeth, with no bone involvement.

Baseline pharmacokinetic assessments were conducted for all patients within 42 days preceding surgery, following an infusion of 50 ± 5 IU/kg rVWF. These data were used to determine appropriate preoperative priming doses for each patient, which were administered 12-24 hours before surgery to allow endogenous FVIII activity levels to rise to at least 30 IU/dL for minor or oral surgeries, or at least 60 IU/dL for major surgeries. The patients' FVIII levels were measured within three hours before the surgery. If endogenous FVIII activity levels did not reach the target levels, subsequent doses of rVWF were administered concurrently with rFVIII. Surgery began after normalization of the activated partial thromboplastin time (aPTT).

Within one hour before surgery, patients received a dose of Vonvendi along with rFVIII if needed. In patients undergoing minor or oral surgery, the target peak activity levels were 50 to 60 IU VWF:RCo/dL and 40 to 50 IU FVIII:C/dL. In patients undergoing major surgery, the target peak activity levels were 100 IU VWF:RCo/dL and 80-100 IU FVIII:C/dL.

During surgery, patients continued to receive Vonvendi, with or without rFVIII. The dose and frequency were customized for each patient according to the severity and duration of the bleeding episode, the activity levels of coagulant factors, and aPTT normalization.

The primary efficacy endpoint was the proportion of patients who had treatment success, defined as hemostatic efficacy (an "excellent" or "good" score) assessed either 24 hours after the final perioperative infusion of Vonvendi, or on post-operative Day 14. Treatment success was evaluated on a four-point scale (1-Excellent; 2-Good; 3-Moderate; 4-None). Scores were determined mainly by comparing the intra- and post-operative hemostasis observed in patients to the expected rates in a hemostatically normal individual undergoing the same type of surgical procedure. Other considerations in evaluating treatment success include blood loss during surgery, post-operative bleeding, and the need for additional hemostatic medications.

All 15 patients treated with Vonvendi, with or without rFVIII, had overall hemostatic efficacy scores of "excellent" or "good". Eleven patients (73.3%) had an "excellent" score. Seven of these patients had major surgery, and four patients had minor surgery. Four patients (26.7%) had a "good" score. Three of these patients had major surgery, and one patient had oral surgery.

Collectively, the outcomes of the pivotal studies support the efficacy of Vonvendi for the approved indications.

Indication

Health Canada approved the following indications for Vonvendi:

Vonvendi (von Willebrand factor [Recombinant]) is indicated for:

  • Treatment and control of bleeding episodes in adults (ages ≥18 years) diagnosed with von Willebrand disease (VWD).
  • Perioperative management of bleeding in adults (ages ≥18 years) diagnosed with VWD.

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

Clinical Safety

The safety of Vonvendi was evaluated primarily in the pivotal studies, Study 071001 and Study 071101. The design and results of both studies are detailed in the Clinical Efficacy section. No deaths occurred during either study.

The use of any therapeutic protein presents the risk of immunogenicity. In addition to immunogenicity against rVWF, immunogenicity against rFVIII, Chinese Hamster Ovary (CHO) cells, recombinant Furin (rFurin), and murine immunoglobulin G (IgG) were also recognized as potential risks, due to the involvement of these proteins in clinical studies or in the drug manufacturing process.

One patient with Type 3 VWD developed binding antibodies against rVWF during Study 071101, which were examined further and determined not to have a neutralizing effect. There were no other reports in either of the pivotal studies of binding antibodies or neutralizing antibodies against rVWF, rFVIII, or of animal proteins present in the final drug product (CHO cells, rFurin, or murine IgG).

In Study 071001, 125 adverse events were reported in 25 out of 37 patients. Nine adverse events were considered serious, and of these nine, two were determined to be related to the study drug, rVWF. The two serious adverse events, chest discomfort and increased heart rate, were reported in the same patient and resolved without sequelae. No signs or symptoms of thrombotic events were observed in Study 071001. Additionally, no clinically significant abnormal d-dimer values were observed post-treatment. Six non-serious adverse events were also reported in four patients and considered related to the study drug (tachycardia, infusion site paraesthesia, electrocardiogram T wave inversion, dysgeusia, generalized pruritus, and hot flush). These adverse events were transient, and ranged from mild to moderate in severity.

In Study 071101, 12 treatment-emergent adverse events (TEAEs) were reported during or after infusion with rVWF and considered unrelated to the study drug by the investigators. Six TEAEs were determined to be temporarily associated with the study drug. These included two TEAEs of deep vein thrombosis, which were observed post-operatively in one patient. The first was observed four days after surgery and considered non-serious, and the second was observed eight days after surgery and considered serious. This patient had undergone a major surgery (i.e., total hip replacement), and had ADAMTS13 level at 37% of the normal plasma level. ADAMTS13 is responsible for the proteolysis of high molecular weight VWF multimers, and a deficiency of this enzyme can contribute to thrombotic events. The other four TEAEs temporarily associated to the study drug were acne, headache, dizziness, and nasopharyngitis; all of which were considered non-serious.

The safety outcomes of Studies 071001 and 071101 provide evidence of a favourable benefit-risk balance for the use of Vonvendi alone or concurrently with rFVIII in patients with VWD, for each of the approved indications.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The pharmacological and toxicological properties of rVWF were initially examined in vitro and in animal models. Vonvendi was studied alone as well as in combination with rFVIII, and the findings were compared with the known pharmacology and toxicology of human plasma-derived von Willebrand factor (VWF)/factor VIII (FVIII) concentrate.

The pharmacokinetics of rVWF were similar whether administered alone, or concurrently with rFVIII. Additionally, rVWF did not cross human placentae in an ex vivo study (occurring outside the body), did not accumulate in any specific organs in animal studies, and was shown to be non-mutagenic and non-clastogenic.

Signs of acute toxicity were observed in mice which were deficient in ADAMTS13; a protein which proteolyzes high molecular weight multimers of VWF. Consistent with a deficiency in ADAMTS13, microthombosis was detected in the heart and several other organs at doses of 500 IU rVWF:RCo/kg or higher, and thrombocytopenia was detected at doses of 1000 IU rVWF:RCo/kg or higher. No signs of acute toxicity were observed in rats, rabbits and cynomolgus monkeys after single doses of 1,400 IU rVWF:RCo/kg (rats) or 1,200 IU rVWF:RCo/kg (rabbits, cynomolgus monkeys).

A repeat-dose toxicity study was conducted in which 1,400 IU/kg rVWF were administered daily to rats for 14 days. Adverse events detected in this study include mild regenerative hemolytic anemia, thrombocytopenia, and microthrombosis in the heart and liver. In monkeys, no adverse events were detected with daily administration of a dose of 100 IU VWF:RCo/kg, similar to the maximum recommended dose of 80 IU VWF:RCo/kg for humans. However, neutralizing antibodies were detected against human rVWF and rFVIII in most animal models.

No significant concerns were detected in a cardiac safety study in dogs who received 240 IU VWF:RCo/kg; the equivalent of three times the maximum recommended human dose. The risk of thrombogenicity in rabbits was low at doses up to 1,262 IU/kg, which corresponds to 16 times the recommended human dose.

Carcinogenicity, fertility impairment, and fetal development studies were not conducted.

The non-clinical studies revealed no safety concerns for Vonvendi in humans based on safety pharmacology, acute toxicity, repeated dose toxicity, local tolerance, immunogenicity and genotoxicity. Considering the intended use of Vonvendi, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Detailed characterization studies were performed to confirm that recombinant von Willebrand factor (rVWF) consistently exhibits the desired characteristic structure and biological activity. Test results provided evidence of consistency with respect to protein composition, primary structure, and post-translational glycosylation patterns. Additionally, consistent with the biological activity of endogenous von Willebrand factor (VWF), rVWF displayed a high binding affinity for recombinant factor VIII (rFVIII), as well as susceptibility to proteolysis by a disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13).

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

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

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

The drug substance, rVWF, is manufactured from a line of Chinese Hamster Ovary (CHO) cells using recombinant deoxyribonucleic acid (DNA) technology. This specific CHO cell line was engineered to co-express rVWF and rFVIII, and was approved by Health Canada in 2005 for the production of a drug product containing both rVWF and rFVIII.

The cell culture is initiated from a single working cell bank vial, and allowed to expand through a fed-batch process. As the culture expands, rVWF and rFVIII proteins are produced intracellularly, and both are secreted into the culture medium. Recombinant von Willebrand factor is initially expressed as a pro-protein; a precursor to the mature protein containing an additional peptide segment. This segment is later cleaved to yield the mature protein.

Portions of the cell culture are routinely harvested to isolate rVWF. The rVWF pro-protein is separated from rFVIII through two chromatography steps. The pro-protein is then cleaved by the recombinant Furin (rFurin) protein, to separate the pro-peptide chain from the mature rVWF protein.

The mature rVWF protein is eluted, and then purified further through a series of filtration, virus inactivation, and chromatography steps. The drug substance, purified rVWF, is then suspended in the appropriate buffer solution and frozen at ≤-60ºC.

Manufacturing of the drug product begins with thawing the drug substance and testing the proteins for alterations or loss of activity. The drug substance is pooled, diluted to the desired concentration, adjusted to the correct pH, and sterilized by filtration. Vials are filled with the solution aseptically, and the solution is lyophilized to increase its stability.

In-process controls and lot release tests for the drug substance and drug product were established and validated.

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 rVWF with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

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

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. These include, but are not limited to: biological activity, appearance of the lyophilized and reconstituted products, composition, identity, potency, purity, and impurities. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

As an outcome of observations made during consistency testing carried out by Health Canada, the sponsor made additional clarifications to the Product Monograph regarding product resuspension and handling.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 36 months for the lyophilized drug product at <30ºC, and three hours for reconstituted Vonvendi at 25ºC are considered acceptable.

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

Facilities and Equipment

On-site evaluations (OSEs) of the two facilities involved in the manufacture and testing of Vonvendi were waived. One of the facilities has been manufacturing a product using the same cell line and similar processes for over 10 years, with a history of compliance and no significant incidents during this time. An OSE was recently conducted for the other facility, and no major site deficiencies have been reported since this evaluation. Since both facilities are considered low risk at this time, OSEs were not recommended in connection with this drug submission.

Adventitious Agents Safety Evaluation

The biological materials used to manufacture Vonvendi are the CHO cell line, anti-FVIII antibodies (used during the chromatography steps), and rFurin; none of which are of direct human or animal origin. They are therefore not considered to pose a risk for bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE).

The CHO cell line and anti-FVIII antibodies were previously approved in connection with another drug product manufactured by the sponsor. The cell lines used in production of rVWF, the anti-FVIII antibodies, and rFurin grow without additives of human or animal origin. The cell line and expression construct used to produce rFurin were characterized according to ICH guidelines and are considered acceptable for their intended uses.

 

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