Summary Basis of Decision for Hemgenix

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.


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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Hemgenix is located below.

Recent Activity for Hemgenix

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. At this time, no PAAT is available for Hemgenix. When the PAAT for Hemgenix becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Hemgenix

Date SBD issued: 2024-05-05

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

Etranacogene dezaparvovec

Drug Identification Number (DIN): DIN 02542560 – 1 × 1013 genome copies/mL, suspension, intravenous administration

CSL Behring Canada Inc.

New Drug Submission Control Number: 273721

Submission Type: New Drug Submission (New Active Substance) - Priority Review

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): B02 Antihemorrhagics

Date Filed: 2023-03-27

Authorization Date: 2023-10-23

On October 23, 2023, Health Canada issued a Notice of Compliance to CSL Behring Canada Inc. for the drug product Hemgenix.

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 Hemgenix is favourable for treatment of adults (18 years of age or older) with hemophilia B (congenital factor IX [FIX] deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

There is no clinical experience of Hemgenix use in patients with mild or moderate hemophilia B (FIX activity over 2% of normal values).

1 What was approved?

Hemgenix, an antihemorrhagic, was authorized for the treatment of adults (18 years of age or older) with hemophilia B (congenital factor IX [FIX] deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

There is no clinical experience of Hemgenix use in patients with mild or moderate hemophilia B (FIX activity over 2% of normal values).

The safety and efficacy of Hemgenix in children under 18 years of age have not been studied.

Out of 54 patients in the Phase III clinical study with Hemgenix, 6 patients were over 65 years of age at the time of enrollment. There were no differences in the safety and efficacy of Hemgenix in these patients compared to younger patients. However, such comparisons are limited by the small numbers of patients.

Hemgenix (etranacogene dezaparvovec 1 × 1013 genome copies/mL) is an adeno-associated virus vector-based gene therapy. It is presented as a suspension. In addition to the medicinal ingredient, the suspension contains disodium phosphate, hydrochloric acid (for pH adjustment), polysorbate-20, potassium chloride, potassium dihydrogen phosphate, sodium chloride, sucrose, and water for injection.

The use of Hemgenix is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Hemgenix 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 Hemgenix approved?

Health Canada considers that the benefit-risk profile of Hemgenix is favourable for the treatment of adults (18 years of age or older) with hemophilia B (congenital factor IX [FIX] deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

There is no clinical experience of Hemgenix use in patients with mild or moderate hemophilia B (FIX activity over 2% of normal values).

Hemophilia B is a bleeding disorder caused by mutations in the gene for FIX located on the long arm of the X chromosome, primarily inherited via the germline and therefore occurs almost exclusively in males. The mutations result in a lack of production of or a dysfunctional FIX coagulation protein, leading to abnormally decreased blood clot formation and prolonged bleeding. Bleeding episodes may occur spontaneously or after a traumatic event. The World Federation of Hemophilia (WFH) annual global survey of 2021 identified 33,076 individuals with hemophilia B globally, 727 of whom (across all disease severities) are in Canada. The estimated incidence of hemophilia B is 5.0 cases per 100,000 males for all severities, and 1.5 cases per 100,000 males for severe hemophilia B (where FIX activity is less than 1% of normal values).

In Canada, children and adults with hemophilia B currently rely primarily on intravenously administered FIX replacement therapies to treat and prevent bleeding episodes. Patients with severe disease (less than 1% of normal FIX activity) or moderately severe disease (1% to less than 2% of normal FIX activity) are the most likely to require routine prophylaxis with FIX. Individuals with moderate disease (2% to 5% of normal FIX activity) or mild disease (6% to less than 50% of normal FIX activity) may only need periodic treatment with FIX replacement therapy to treat random bleeds, or to use before surgery (episodic use).

For routine prophylaxis in individuals who require regular therapy, FIX replacement therapy is administered intravenously every 2 to 3 days (for products with standard half‑life) or every 5 to 7 days (for products with extended half‑life). Although replacement therapy can be effective, it is also burdensome, particularly in very young patients where adequate venous access may be challenging and a central line is required (or preferred) for the administration of the FIX product. For other patients, FIX replacement therapy is still not adequate to prevent or control bleeding episodes leading to chronic joint pain, which can eventually result in crippling disabilities. In rare instances, internal bleeding such as intracranial hemorrhages can occur, which could be fatal.

Hemgenix (etranacogene dezaparvovec) is a somatic gene therapy product. It consists of a human FIX-Padua expression cassette, which is packaged within a recombinant adeno‑associated virus (AAV) serotype 5 vector (rAAV5), under the control of a liver‑specific promoter. The gene encoding the Padua variant of human FIX has been reported to give rise to a 5‑ to 10‑fold increase in FIX activity relative to the wild‑type FIX gene sequence. In patients amenable to this therapy, one‑time treatment with Hemgenix via intravenous infusion is expected to deliver sufficient copies of functional FIX-Padua coding deoxyribonucleic acid (cDNA) to cells of the body, primarily to the liver, where it remains mainly in episomal form within the nuclei of cells. The FIX-Padua variant is under control of a liver specific promoter to ensure the functional FIX protein is produced within hepatocytes and secreted into the circulation to aid in hemostasis. This results in a relatively stable expression of FIX in adult patients with hemophilia B to help reduce or eliminate dependence on FIX therapy, although long-term follow-up is ongoing at the patient-level to determine if effective bleeding control can be maintained over many years without requiring FIX replacement therapy.

The market authorization of Hemgenix was based on efficacy and safety data derived from one pivotal and two supportive clinical studies. Data from the supportive studies informed decisions made in the pivotal study. The 2.0 × 1013 genome copies (gc)/kg dose used in the pivotal study was chosen based on an acceptable safety profile observed in the supportive study CT‑AMT‑060‑01, a Phase I first‑in‑human trial of the AAV5 vector containing the wild‑type human FIX gene (the predecessor to Hemgenix). Subsequently, to achieve higher FIX activity and superior bleeding control, the hyperactive FIX-Padua variant was used in the clinical development of Hemgenix. Study CT‑AMT‑061‑01 was then conducted to confirm the FIX activity level following a single infusion of the AAV5 vector containing the FIX-Padua variant (AAV5-hFIXco-Padua, i.e., etranacogene dezaparvovec) (2 × 1013 gc/kg) in 3 adult patients with severe or moderately severe hemophilia B.

The pivotal study, CT‑AMT‑061‑02 (HOPE B), was a Phase III, open‑label, single‑arm, single‑dose study that enrolled adult male patients with severe or moderately severe hemophilia B. Patients were treated with 2 × 1013 gc/kg of Hemgenix (etranacogene dezaparvovec). The primary objective was to establish the non‑inferiority of Hemgenix compared to lead-in treatment with prophylactic FIX. Patient annualized bleeding rates (ABRs) during months 7 to 18 following Hemgenix treatment (i.e., after the establishment of stable FIX expression by Month 6 following Hemgenix infusion) were compared to the ABRs reported during the observational lead‑in period, during which patients were treated with prophylactic FIX. Fifty‑four patients were included in the efficacy analysis.

The non‑inferiority of Hemgenix compared to the lead‑in treatment with prophylactic FIX was demonstrated, as the upper bound for the 95% confidence interval (CI) of the ABR ratio between ABRs reported after Hemgenix treatment and those reported in the lead‑in period was lower than the pre‑specified and acceptable non‑inferiority margin of 1.8.

An overall reduction in the rates of all bleeding events was demonstrated following Hemgenix treatment compared to the lead‑in period. The mean‑adjusted ABR was 1.73 (95% CI: 0.64, 4.02) in patients treated with Hemgenix and 4.13 (95% CI: 2.95, 5.22) in patients receiving prophylactic FIX replacement therapy. The overall efficacy outcome measures for all bleeds (ABRs reported above), treated bleeds, joint bleeds, traumatic bleeds, and spontaneous bleeds were considered positive for Hemgenix. Effective bleeding control following Hemgenix administration is supported by relatively stable FIX activity reported from 3 to 24 months after treatment, as determined by a central laboratory one‑stage assay.

The clinical safety of Hemgenix was evaluated in 57 adult male patients with moderately severe or severe hemophilia B, which included 3 patients from the supportive CT-AMT-061-01 study. All 57 patients received a single intravenous dose of 2 × 1013 gc/kg body weight of Hemgenix.

The most frequently reported adverse drug reactions in the clinical studies were alanine aminotransferase (ALT) elevations (10 of 57 patients; 17.5%), headache (9 of 57 patients; 15.8%), influenza‑like illness (8 of 57 patients; 14%), and aspartate aminotransferase (AST) elevations (5 of 57 patients; 8.8%). The most common adverse reactions were infusion‑related reactions (19 of 57 patients; 33%), including serious events.

Immune-mediated events that gave rise to significant elevations in liver enzymes required corticosteroid use in 9 patients. These patients had a numerically lower mean transgene FIX activity level. Infusion‑related reactions were reported in nearly one third of patients (19 of 57 patients; 33%), including some serious reactions.

Vector integration into the human genome is expected to occur at low frequency, but presents the potential for insertional mutagenesis which could lead to the development of malignancies. Clonal expansion or carcinogenicity associated with Hemgenix have not been observed in non‑clinical or clinical studies. One patient with pre‑existing risk factors for liver cancer developed a hepatocellular carcinoma following treatment with Hemgenix. This was unlikely to be related to the gene therapy, based on vector integration site analyses and whole-genome sequencing. Nonetheless, it is recommended that patients with pre‑existing risk factors for hepatocellular carcinoma (such as hepatic cirrhosis, advanced hepatic fibrosis, hepatitis B or C disease, or non‑alcoholic fatty liver disease) receive regular abdominal ultrasound screenings and are monitored annually for alpha‑fetoprotein elevations in the 5 years following the administration of Hemgenix.

Shedding of Hemgenix viral/transgene DNA into semen has been reported. Since viral/transgene DNA was detected in the semen of patients up to 2 years following a dose of 2 × 1013 gc/kg body weight of Hemgenix, the Product Monograph has been updated to recommend barrier contraception for male patients and their female partners of child-bearing potential for 2 years after receiving Hemgenix.

A Risk Management Plan (RMP) for Hemgenix was submitted by CSL Behring Canada Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Hemgenix Product Monograph met the necessary regulatory labelling, plain language, and design element requirements.

Hemgenix has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Hemgenix 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 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 Hemgenix?

The New Drug Submission (NDS) for Hemgenix was subject to an expedited review process under the Priority Review of Drug Submissions Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Hemgenix provides effective treatment of a serious, life-threatening or severely debilitating disease, and that the overall benefit-risk profile of Hemgenix is improved over existing therapies.

The review of the quality, non-clinical, and clinical components of the NDS for Hemgenix 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. The Canadian regulatory decision on the Hemgenix NDS was made independently based on the Canadian review.

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

Submission Milestones: Hemgenix

Submission Milestone

Date

Pre-submission meeting

2022-12-02

Request for priority status filed

2023-02-08

Request for priority status approved

2023-03-01

New Drug Submission filed

2023-03-27

Screening

Screening Acceptance Letter issued

2023-04-26

Review

Review of Risk Management Plan completed

2023-09-24

Non-clinical evaluation completed

2023-10-20

Clinical/medical evaluation completed

2023-10-20

Biostatistics evaluation completed

2023-10-20

Labelling review completed

2023-10-20

Quality evaluation completed

2023-10-23

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2023-10-23
4 What follow-up measures will the company take?

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

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

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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.

At this time, no PAAT is available for Hemgenix. When available, the PAAT will be incorporated into this SBD.

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

As outlined in the What steps led to the approval of Hemgenix? section, during the clinical review of the New Drug Submission for Hemgenix, foreign reviews were used as added references in accordance with Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Hemgenix is a gene therapy designed to introduce many copies of the human coagulation factor IX (FIX) transgene into cells of the body, with specific expression in hepatocytes to prevent or reduce bleeding events in patients with hemophilia B. Hemgenix consists of a codon‑optimized coding deoxyribonucleic acid (DNA) sequence of the gain-of-function Padua variant of the human FIX (hFIXco‑Padua), under control of the liver‑specific LP1 promoter, encapsulated in a non‑replicating recombinant adeno‑associated viral vector of serotype 5 (AAV5).

Following single intravenous infusion, Hemgenix enters cells of the body, where the vector DNA mostly resides in episomal form. After transduction, Hemgenix directs liver‑specific expression of FIX‑Padua protein using a liver‑specific promoter (LP1). As a result, Hemgenix helps to restore circulating FIX procoagulant activity in hemophilia B patients, which limits bleeding episodes and the need for exogenous FIX treatment.

Traditional pharmacology studies were not conducted with Hemgenix, as it is a gene therapy product administered only once. Pharmacology assessments were reviewed in the context of the pivotal study. A trend was observed for a higher mean level of transgene FIX activity in patients 60 years of age and older, compared to patients younger than 40 years of age. Although the analysis is limited by small numbers of patients in the older age group, the results suggest that patients in this group may have better and more sustained bleed control than younger patients, although this will require long-term follow-up and additional patients to establish any trends based on age. There were 13 patients who had alanine transaminase (ALT) elevations greater than the upper limit of normal (ULN) when baseline ALT < ULN or 2 times baseline ALT, within 90 days postdose. In these patients, the mean FIX activity ranged from 23‑28% from months 3 to 24 after the administration of Hemgenix, compared to 40‑47% for the remaining 40 patients who did not satisfy the ALT elevation criterion defined above. Patients with advanced hepatic impairment were not included in the clinical studies, therefore the impact of significant liver dysfunction on transgene FIX activity following treatment with Hemgenix is unclear. Due to this uncertainty, the Product Monograph recommends consultation with a liver disease specialist when considering treating hemophilia B patients with Hemgenix who have advanced hepatic impairment. Patients with pre‑existing neutralizing antibodies against AAV5 (number of patients [n] = 21) had slightly reduced FIX activity levels compared to patients who did not have pre‑existing anti-AAV5 antibodies (n = 33). An exception was observed, in one patient who had a very high titer of pre‑existing anti-AAV5 antibodies and who did not respond to therapy. Based on results obtained from the Phase III study, a threshold for an acceptable anti-AAV5 antibody titer was established using a sponsor‑developed assay. To determine the eligibility for treatment of hemophilia B patients with Hemgenix, a blood sample will be screened to ensure the AAV5 titer is acceptable.

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

Clinical Efficacy

Supportive Studies

Study CT‑AMT‑060‑01 was a Phase I, open‑label, dose‑ascending, first‑in‑human trial of the AAV5 vector containing the wild‑type human FIX gene (the predecessor to Hemgenix) in adult patients with severe or moderately severe hemophilia B. Patients received a single infusion of 5.0 × 1012 genome copies (gc)/kg (number of patients [n] = 5) or 2.0 × 1013 gc/kg (n = 5). After 5 years of follow‑up, the mean FIX activity levels determined by a one stage assay ranged from 2.8% to 8.2% and 4.0% to 10.7% for the lower- and higher-dose cohorts, respectively. Given the acceptable safety profile, the higher dose of 2.0 × 1013 gc/kg was chosen for subsequent clinical trials.

Study CT‑AMT‑061‑01 was a Phase IIb, open‑label, single‑arm, single‑dose trial to confirm the FIX activity level following a single infusion of the AAV5 vector containing the FIX-Padua variant (AAV5-hFIXco-Padua) (2 × 1013 gc/kg) in 3 adult patients with severe or moderately severe hemophilia B. After 30 months of follow‑up, the mean FIX activity level for all 3 patients was 50.0% (range: 37.1% to 58.6%). After 36 months of follow‑up, the FIX activity level was available for 2 patients (41.5% and 32.3%). The small patient number (n = 3) and preliminary design (including the lack of a run‑in period) preclude a meaningful evaluation of bleeding events before and after the infusion. The 3 patients enrolled in the study were included in the overall safety analysis (Pivotal Study, below).

Pivotal Study

Study CT‑AMT‑061‑02 (HOPE B) was a Phase III, open‑label, single‑arm, single‑dose trial that enrolled adult male patients with severe or moderately severe hemophilia B. Patients were treated with 2 × 1013 gc/kg of Hemgenix. Sixty‑seven patients were screened and followed for a minimum of six months in a lead‑in phase, where bleeds were recorded while patients received prophylactic FIX replacement therapy. After the lead‑in phase, 54 patients were considered eligible to receive Hemgenix. Notably, patients were not excluded from treatment for having pre‑existing neutralizing antibodies against the AAV5 serotype.

The primary objective was to establish the non‑inferiority of Hemgenix to prophylactic FIX replacement therapy by comparing patient annualized bleeding rates (ABRs) during months 7 to 18 following Hemgenix treatment (after the establishment of stable FIX expression by Month 6 following Hemgenix infusion) to the ABR reported during the observational lead‑in period, during which patients were treated with prophylactic FIX. For this purpose, all bleeding episodes, regardless of investigator assessment, were considered. Multiple secondary analyses were pre‑specified, including ABR comparisons for FIX‑treated bleeds including traumatic, joint and spontaneous bleeding events.

While Hemgenix is considered a candidate therapy for most hemophilia B patients, certain criteria had to be met to be enrolled in clinical studies with this gene therapy. Thirteen patients were excluded from the study due to one or more of the following:

  • were younger than 18 years of age,

  • had FIX inhibitors,

  • presented with hepatic or renal dysfunction (more than two times the upper limit of normal [ULN] in either alanine transaminase [ALT], aspartate aminotransferase [AST], total bilirubin, alkaline phosphatase [ALP], or creatinine),

  • had human immunodeficiency virus (HIV) infection not controlled with anti‑viral therapy,

  • had a hepatitis B or C infection,

  • had thrombocytopenia (platelet count below 50 × 109/L),

  • had an active infection, or

  • had a medical condition expected to interfere with liver transduction of the vector (i.e., disseminated intravascular coagulation, accelerated fibrinolysis, or advanced liver fibrosis).

The non‑inferiority of Hemgenix compared to the lead‑in treatment with prophylactic FIX was demonstrated in the study. The upper bound for the 95% confidence interval (CI) of the ABR ratio between ABRs reported after Hemgenix treatment and the ABRs reported in the lead‑in phase was lower than the pre‑specified and acceptable non‑inferiority margin of 1.8. For the bleeding episodes that required FIX treatment during the period from 7 to 18 months after the treatment with Hemgenix, lower bleeding rates were demonstrated as compared to the lead-in period of prophylactic FIX treatment, including the rates of treated joint and spontaneous bleeds.

An overall reduction was demonstrated in the rates of all bleeding events following Hemgenix treatment compared to the lead‑in period. The mean‑adjusted ABR was 1.73 (95% CI: 0.64, 4.02) in patients treated with Hemgenix and 4.13 (95% CI: 2.95, 5.22) in patients receiving prophylaxis with FIX replacement therapy. The overall efficacy outcome measures for all bleeds (ABRs reported above), treated bleeds, joint bleeds, traumatic bleeds, and spontaneous bleeds were considered positive for Hemgenix, including the observed independence of exogenous FIX for many patients following Hemgenix infusion.

Effective bleeding control following Hemgenix administration is supported by relatively stable FIX activity reported from 3 to 24 months after infusion, determined by a central laboratory one‑stage assay. The mean uncontaminated FIX activity (i.e., blood sampling did not occur within 5 half‑lives of exogenous FIX use) was 36.8% at Month 3 (n = 51), 39.0% at Month 6 (n = 51), 41.5% at Month 12 (n = 50), 36.9% at Month 18 (n = 50) and 36.7% at Month 24 (n = 50). At enrollment, all patients had FIX activity less than or equal to 2% of normal values. Preliminary results from Study CT-AMT-061-01 suggest that this level of FIX activity is expected to be maintained for up to 36 months with longer-term follow-up ongoing post-marketing authorization.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Hemgenix (etranacogene dezaparvovec) is an adeno-associated virus (AAV) vector-based gene therapy indicated for treatment of adults with hemophilia B (congenital factor IX deficiency) and with a preexisting neutralizing AAV5 antibody titer below 1:900 to reduce the frequency of bleeding episodes and the need for factor IX replacement therapy who:

  • currently use factor IX prophylaxis therapy, or

  • have current or historical life-threatening hemorrhage, or

  • have repeated, serious spontaneous bleeding episodes.

Hemgenix (etranacogene dezaparvovec) is indicated for treatment of adults (18 years of age or older) with hemophilia B (congenital factor IX deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The indication was revised to better align with the population in which the pivotal study was conducted. A statement was also added to the Product Monograph specifying that there is no clinical experience of Hemgenix use in patients with mild or moderate hemophilia B (FIX activity greater than 2% of normal values).

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

Clinical Safety

The clinical safety of Hemgenix was evaluated in 57 patients from two clinical studies: 3 patients from the supportive Phase IIb study (CT AMT-061-01) and 54 patients from the Phase III pivotal study (CT‑AMT-061-02). Both studies enrolled adult male patients with moderately severe or severe hemophilia B. All 57 patients received a single intravenous dose of 2 × 1013 gc/kg body weight of Hemgenix.

The most frequently reported adverse drug reactions observed were infusion related reactions (19 of 57 patients; 33%), including serious events, alanine aminotransferase (ALT) elevations (10 of 57 patients; 17.5%), headache (9 of 57 patients; 15.8%), influenza‑like illness (8 of 57 patients; 14%), and aspartate aminotransferase (AST) elevations (5 of 57 patients; 8.8%). Immune-mediated events that gave rise to significant elevations in liver enzymes required corticosteroid use in 9 patients. These patients had a numerically lower mean transgene FIX activity level.

One patient experienced a serious hypersensitivity reaction. The infusion was stopped after 12 minutes, and only 10% of the required dose could be administered. The patient’s heart rate decreased from 64 beats per minute to 34 beats per minute, and his blood pressure increased from 133/85 mmHg to 162/94 mmHg. The patient experienced severe left leg cramps and was sent to an emergency room. Three other patients required a temporary pause in treatment due to infusion reactions, although in all three cases, the full dose of Hemgenix (2 × 1013 gc/kg body weight) was administered. Other adverse reactions reported with Hemgenix include nausea, headaches, fatigue, malaise, influenza‑like illness, and increased blood creatinine phosphokinase levels.

Important potential safety concerns of AAV vector‑based gene therapies, such as Hemgenix, include integration of viral/transgene deoxyribonucleic acid (DNA) into the genome of the host. Although Hemgenix is composed of a non‑replicating AAV5 vector and its DNA remains largely in episomal form in cells, DNA integration events have been reported in non‑clinical and clinical studies. This has the potential to lead to tumourigenesis but clonal expansion or carcinogenicity associated with Hemgenix have not been observed in non‑clinical or clinical studies. One patient with pre‑existing risk factors for liver cancer developed a hepatocellular carcinoma following treatment with Hemgenix. This was assessed as not likely related to the gene therapy, based on vector integration site analyses and whole-genome sequencing. Nonetheless, it is recommended that patients with pre‑existing risk factors for hepatocellular carcinoma (such as hepatic cirrhosis, advanced hepatic fibrosis, hepatitis B or C disease, or non‑alcoholic fatty liver disease) receive regular abdominal ultrasound screenings and are monitored annually for alpha‑fetoprotein elevations in the 5 years following the administration of Hemgenix.

Shedding of Hemgenix viral/transgene DNA fragments into semen has been observed. Since the fragments of viral/transgene DNA were detected in the semen of patients up to 2 years following a dose of 2 × 1013 gc/kg body weight of Hemgenix, the Product Monograph has been updated to recommend barrier contraception for male patients and their female partners of child-bearing potential for 2 years after receiving Hemgenix.

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

7.2 Non-Clinical Basis for Decision

As outlined in the What steps led to the approval of Hemgenix? section, during the non‑clinical review of the New Drug Submission for Hemgenix foreign reviews were used as added references in accordance with Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Non-clinical studies were initiated with a recombinant adeno‑associated virus serotype 5 (rAAV5) expressing the wild-type human coagulation factor IX (FIX) (rAAV5‑hFIX). Hemgenix (rAAV5co‑hFIX‑Padua) was subsequently developed from rAAV5‑hFIX by introducing two nucleotide changes in the transgene for human FIX, resulting in the naturally occurring Padua variant of FIX which exhibits significantly augmented activity.

Hemgenix and its predecessor (rAAV5‑hFIX) were intravenously administered to mice and to non‑human primates to evaluate biodistribution and potential toxicity. Dose‑dependent preferential distribution to the liver was confirmed for both the vector and the transgene expression. Both products were well tolerated and were not associated with adverse effects during a 3‑ and 6‑month follow‑up period, respectively. The no‑observed-adverse-effect level (NOAEL) was set as 9 × 1013 genome copies (gc)/kg body weight, the highest dose tested in non‑human primates, which is 4.5‑fold higher than the recommended human dose of 2 × 1013 gc/kg body weight.

One of 10 healthy mice administered 5 × 1013 gc/kg body weight of Hemgenix and its predecessor developed pulmonary thrombi at 13 weeks post infusion. This dose level is 2.5‑fold higher than the recommended human dose of Hemgenix. In a follow‑up study in non‑human primates, pulmonary thrombi events were not observed at a dose level of 9 × 1013 gc/kg body weight, which is 4.5‑fold higher than the recommended human dose of Hemgenix. However, compared to control animals, prolonged prothrombin time, decreased activated partial thromboplastin time, and decreased heart rates were observed in non‑human primates administered 9 × 1013 gc/kg body weight Hemgenix during the 26‑week study.

No dedicated carcinogenicity or mutagenicity studies were conducted with Hemgenix.

Genotoxic and reproductive risks were evaluated with rAAV5‑hFIX (the predecessor to Hemgenix). The integration site analysis in host genomic deoxyribonucleic acid (DNA) was performed on liver tissue from mice and non‑human primates injected with rAAV5‑hFIX up to a dose of 2.3 × 1014 gc/kg body weight, which is approximately 10‑fold higher than the recommended human dose of Hemgenix. A low level of integrated rAAV5‑hFIX DNA was distributed throughout the host genome, with no preferred integration in genes associated with mediation of malignant transformation in humans.

The potential risk of germline transmission was evaluated in mice following the administration of 2.3 × 1014 gc/kg body weight rAAV5‑hFIX. Vector DNA was detected in the reproductive organs and sperm of male animals. However, following mating of these mice with naïve female animals 6 days after administration, rAAV5‑hFIX vector DNA was not detected in female reproductive tissues or in the resulting foetuses, indicating a low risk of paternal germline transmission.

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

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

7.3 Quality Basis for Decision

As outlined in the What steps led to the approval of Hemgenix? section, during the quality review of the New Drug Submission for Hemgenix foreign reviews were used as added references in accordance with Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

The drug substance, etranacogene dezaparvovec, is a recombinant adeno-associated viral vector containing a codon-optimized coding deoxyribonucleic acid (DNA) sequence for human coagulation factor IX variant R338L (FIX-Padua).

Detailed characterization studies were performed to provide assurance that etranacogene dezaparvovec consistently exhibits the desired characteristic structure and biological activity. Characterization of etranacogene dezaparvovec structure and function focused on capsid identity and composition, vector genome identity and composition, biophysical heterogeneity, post-translational modifications, and biological activity using a wide variety of techniques.

The potency of etranacogene dezaparvovec was demonstrated by a factor IX (FIX) chromogenic activity assay. In non‑clinical studies, a consistent dose‑dependent relationship was demonstrated between the amount of human FIX (hFIX)‑Padua expressed (measured by enzyme‑linked immunosorbent assay [ELISA]), the resulting functional activity and clotting activity were also measured.

Sufficient knowledge was demonstrated of both process‑ and product‑related impurities, as well as an understanding of the potential safety impact of these impurities on the patient. All process‑ and product‑related impurities were found to be adequately controlled and/or characterized. The nitrosamine risk assessment concluded that the risk of presence of nitrosamine impurities was low.

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

Etranacogene dezaparvovec is produced using the baculovirus expression vector system (BEVS) that utilizes a proprietary insect cell line derived from Spodoptera frugiperda Sf9 cells, with well-defined growth characteristics when cultured in a serum-free medium. The BEVS is composed of different recombinant baculoviruses, which serve to deliver the essential components to produce adeno-associated virus (AAV) containing the Padua variant of human FIX gene (hFIXco-Padua) in the insect cells.

The upstream stage of the drug substance manufacturing process begins with the expansion of insect cells from thawed working cell bank vials. Working seed virus vials for each baculovirus is thawed and amplified in the insect cells to generate inoculum for the production bioreactor. Within a production bioreactor, the expanded insect cells are co-infected with the recombinant baculovirus inocula, and cultured to generate the AAV product.

The downstream stage is initiated after the defined baculovirus infection period, and involves a series of purification steps. These include cell lysis and DNA degradation steps, followed by various filtration and chromatography steps, and concentration and diafiltration into formulation buffer by tangential flow filtration. Finally, polysorbate‑20 is added and the pool is filtered again to produce the drug substance (formulated bulk), etranacogene dezaparvovec. The drug substance is stored prior to manufacture of the drug product. No reprocessing is permitted.

The drug product manufacturing process involves preparation of the formulation buffer, thawing of the drug substance sterile filtration and drug product compounding, filling and finish, visual inspection, and bulk vial storage at 2 °C to 8 °C. The bulk drug product is shipped to another site for labelling, secondary packaging, and drug product storage.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of etranacogene dezaparvovec with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

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

The data reviewed demonstrate a sufficient knowledge of both process- and product-related impurities and an understanding of their potential safety impact on the patient. Routine testing is conducted for the majority of potential product- and process-related impurities as part of drug substance and drug product release, and they are deemed to be adequately controlled and/or characterized. The nitrosamine risk assessment concluded that the risk of presence of nitrosamine impurities was low.

Batch analysis results were submitted and all test results met the relevant acceptance criteria. Based on these data, the manufacturing process is considered to be adequately controlled and able to consistently yield drug substance and drug product of the required quality.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24‑month shelf life at 2 °C to 8 °C for Hemgenix is considered acceptable. The product must not be frozen and must be protected from light until the time of dilution and administration. Additional storage and special handling instructions are included in the Hemgenix Product Monograph.

Facilities and Equipment

A Virtual Evaluation of Process and Facility (VEPF) was conducted remotely at the drug substance/drug product manufacturing site. The evaluation focused on witnessing and assessing the manufacturing steps, quality control and testing, quality systems, the quality agreement with the sponsor, review-related topics, facility operations, and product development. The facility was issued a compliant rating with one observation, which was resolved. The results of the VEPF supported a positive recommendation following the review of the quality data package of the submission.

Adventitious Agents Safety Evaluation

The starting materials, including the working cell bank and baculovirus working virus seed banks, were developed and prepared using traceable materials of animal origin. The banks were qualified according to applicable guidelines.

Appropriate biological safety documentation was provided for the ancillary materials of biological origin used in the production of etranacogene dezaparvovec.

The drug substance manufacturing process includes multiple virus clearance steps. Virus clearance studies were conducted according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Overall, the control strategy concerning the recombinant baculoviruses used in the drug substance manufacturing process, and adventitious agents, was deemed acceptable.

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