Summary Basis of Decision for Takhzyro

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 Takhzyro is located below.

Recent Activity for Takhzyro

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

Post-Authorization Activity Table (PAAT) for Takhzyro

Updated:

2020-09-30

The following table describes post-authorization activity for Takhzyro, a product which contains the medicinal ingredient lanadelumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02480948 - 300 mg/2 mL, solution, subcutaneous injection

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
Drug product (DIN 02480948) market notificationNot applicableDate of first sale:
2018-10-31
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 2387832020-04-03Issued NOL
2020-07-29
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change testing procedures for the drug substance.
NDS # 2139202018-02-22Issued NOC
2018-09-19
NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Takhzyro

Date SBD issued: 2019-02-18

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

Lanadelumab
300 mg/2 mL, solution, subcutaneous injection

Drug Identification Number (DIN):

  • 02480948

Shire Pharma Canada ULC

New Drug Submission Control Number: 213920

On September 19, 2018, Health Canada issued a Notice of Compliance to Shire Pharma Canada ULC for the drug product Takhzyro.

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 Takhzyro is favourable for the routine prevention of attacks of hereditary angioedema (HAE) in adolescents and adults.

Takhzyro is not intended for acute treatment of HAE attacks.

1 What was approved?

Takhzyro, a monoclonal antibody inhibitor of plasma kallikrein, was authorized for the routine prevention of attacks of hereditary angioedema (HAE) in adolescents and adults.

Takhzyro is not intended for acute treatment of HAE attacks.

The safety and efficacy of Takhzyro were evaluated in 23 pediatric patients (12 to 17 years old). Results of the subgroup analysis were consistent with results in adult patients (Number of adult patients [n] = 115).

The safety and efficacy of Takhzyro in pediatric patients less than 12 years of age have not been studied.

The safety and efficacy of Takhzyro were evaluated in 11 geriatric patients (≥65 years of age). Results of the subgroup analysis were consistent with results observed in adult patients.

Takhzyro 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.

Takhzyro 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.

Takhzyro (300 mg/2 mL lanadelumab) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient lanadelumab, the solution also contains citric acid, L-histidine, polysorbate 80, sodium chloride, sodium phosphate, and water for injection.

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

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

2 Why was Takhzyro approved?

Health Canada considers that the benefit-risk profile of Takhzyro is favourable for routine prevention of attacks of hereditary angioedema (HAE) in adolescents and adults.

Takhzyro is not intended for acute treatment of HAE attacks.

Hereditary angioedema is a rare genetic disorder resulting from deficiency or dysfunction of C1 esterase inhibitor protein. The deficiency or dysfunction of C1 esterase inhibitor protein results in an excessive production of bradykinin, which causes episodic increases in vascular permeability and angioedema. Hereditary angioedema is clinically characterized by unpredictable episodes of painful angioedema without pruritus or urticaria, which most often affects the skin or mucosal tissues of the face, upper respiratory tract, gastrointestinal tract, extremities, and/or genitals. Episodes may be associated with notable functional impairment, decreased quality of life, and mortality due to asphyxiation in the case of laryngeal swelling.

Patients with sufficiently frequent or severe episodes of angioedema may require long-term prophylaxis treatment of HAE aimed to reduce frequency, duration, and severity of HAE attacks and maintain an acceptable quality of life. Therapeutic agents approved in Canada that are indicated for long-term prophylaxis of HAE include intravenous Cinryze (C1 esterase inhibitor [human]), subcutaneous Haegarda (C1 esterase inhibitor [human]), and antifibrinolytic agents.

Lanadelumab is a fully human monoclonal antibody (immunoglobulin G subclass 1 [IgG1] / kappa [κ]-light chain) that binds plasma kallikrein and inhibits its proteolytic activity, subsequently inhibiting the production of bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE.

Takhzyro has been shown to be efficacious for the routine prevention of hereditary angioedema (HAE) attacks in adolescents and adults. The market authorization was based on one Phase III, multicentre, randomized, double-blind, placebo-controlled study (HELP Study; DX-2930-03). The double-blind study was followed by an open-label, uncontrolled extension study (HELP Study Extension; DX-2930-04). The primary efficacy endpoint in the study was the number of investigator-confirmed HAE attacks during the 26 week treatment period. Results from the study at the recommended dose of 300 mg every 2 weeks showed Takhzyro reduced the rate of HAE attacks by 86.9% compared to placebo. In addition, Takhzyro reduced the rate of HAE attacks requiring acute treatment by 87.3% and reduced the rate of HAE attacks categorized as moderate to severe by 83.4%. Regarding exploratory endpoints, the proportion of patients who achieved a 100% reduction in HAE attack rate (i.e., attack-free) over the 26 week treatment period was 44.4% of patients receiving Takhzyro and 2.4% for patients receiving placebo. The proportion of subjects who achieved a ≥50% reduction in HAE attack rate over the 26 week treatment period was 100% of patients receiving Takhzyro 300 mg every 2 weeks (q2wks) and 31.7% of patients receiving placebo. Additionally, the proportion of patients who achieved improvement in quality of life as measured by the angioedema quality of life (AE-QoL) questionnaire (minimally important clinical difference ≥6 in the AE-QoL total score) was 80.8% Takhzyro 300 mg administration q2wks and 36.8% for placebo, respectively.

The incidence of adverse events was similar when comparing Takhzyro to placebo. The most common adverse reactions associated with Takhzyro were injection site reactions, including injection site pain, injection site erythema, and injection site bruising. Most of these reactions, however, were of mild intensity and resolved within one day after onset.

As with all therapeutic proteins, there is the potential for developing immunogenicity. In the overall clinical program, there were 11.4% of patients who developed anti-drug antibodies and 3.2% with neutralizing antibodies, however, there was no association seen between antibodies and safety profile.

A Risk Management Plan (RMP) for Takhzyro was submitted by Shire Pharma Canada ULC 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 Takhzyro Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.

Overall, Takhzyro has been shown to have a favourable benefit-risk profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate patient monitoring. Appropriate warnings and precautions are included in the Takhzyro 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 Takhzyro?

The drug submission for Takhzyro was reviewed under the Priority Review Policy. Takhzyro is indicated for use in the treatment of a serious and rare disease, and is considered to provide an improved benefit-risk profile compared to existing therapies for hereditary angioedema, a condition that is not adequately managed by drugs currently marketed in Canada.

Submission Milestones: Takhzyro

Submission MilestoneDate
Pre-submission meeting:2017-10-03
Request for priority status
Filed:2018-01-10
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics:2018-02-06
Submission filed:2018-02-22
Screening
Screening Acceptance Letter issued:2018-03-23
Review
Review of Risk Management Plan complete:2018-08-30
On-Site Evaluation:2018-09-10 - 2018-09-14
Quality Evaluation complete:2018-09-06
Clinical Evaluation complete:2018-09-17
Labelling Review complete:2018-09-14
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2018-09-19

The Canadian regulatory decision on the non-clinical and clinical review of Takhzyro was based on a critical assessment of the data package submitted to Health Canada.

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.

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

Lanadelumab, the medicinal ingredient in Takhzyro, is a fully human monoclonal antibody (immunoglobulin G subclass 1 [IgG1]/ kappa [κ]-light chain) that binds plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with hereditary angioedema (HAE). In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, uncontrolled increase in plasma kallikrein activity results in angioedema attacks. Lanadelumab decreases plasma kallikrein activity to control bradykinin generation in patients with HAE.

The pharmacological properties of Takhzyro were characterized based on two Phase I studies, one Phase III (pivotal) study, and one open-label extension study. The pharmacokinetics of Takhzyro was approximately dose proportional in the dose range of 150 mg every 4 weeks (q4wks), 300 mg q4wks, and 300 mg every two weeks (q2wks). Following administration of a single dose, complete drug absorption was expected in 8 days. Steady state was expected to be achieved in approximately 70 days. The typical clearance and elimination half-life values were 0.0249 L/h and 14.8 days, respectively. Concentration dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of Takhzyro 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks in patients with HAE.

The 300 mg q2wks dose regimen was shown to result in the highest response based on the exposure response models. A dosing interval of q4wks may be considered if the patient is well controlled (e.g., attack free) for more than 6 months. Body weight was identified as a significant covariate describing the variability of clearance and volume of distribution. In addition, the overall drug exposure in adolescents (12 to 17 years of age) was approximately 37% higher relative to that in adults. Yet, dose adjustment is not required based on consistent efficacy and safety observed across the entire study population.

Overall, the clinical pharmacological data support the use of Takhzyro for the recommended indication.

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

Clinical Efficacy

The efficacy of Takhzyro in preventing acute attacks in patients with Type I or Type II HAE was supported primarily by the results of one pivotal, multicentre, randomized, double-blind, placebo-controlled Phase III study (DX-2930-03). Additional efficacy results were obtained from the pivotal study's open label extension (DX-2930-04).

Study DX-2930-03

In study DX-2930-03, 115 adults and 10 adolescents with Type I or Type II HAE were randomized in a 3:2:2:2 ratio (placebo, Takhzyro 150 mg q4wks, Takhzyro 300 mg q4wks, or Takhzyro 300 mg q2wks; all administered by subcutaneous injection) for a 26-week treatment period. Randomization was stratified by baseline attack rate observed during the run-in period into the following groups: 1 to <2 attacks per 4 weeks, 2 to <3 attacks per 4 weeks, and ≥3 attacks per 4 weeks. Patients were required to discontinue other long-term prophylactic HAE treatments prior to the study run-in period. The use of rescue medications for treatment of acute HAE attacks, including C1 esterase inhibitors, were allowed during the study.

During the study, patients (or caregivers in the circumstance that a patient was <18 years of age) were instructed to notify and report details of an attack to the study site within 72 hours of the onset of an HAE attack. Patients were asked to provide specific details characterizing the attack, including severity and whether the attack required acute treatment.

The primary efficacy endpoint was the number of investigator-confirmed HAE attacks during the treatment period (Day 0 through Day 182). Key secondary endpoints included the number of investigator-confirmed HAE attacks requiring acute treatment during the treatment period (Day 0 through Day 182), and the number of moderate to severe investigator-confirmed HAE attacks during the treatment period (Day 0 through Day 182). Additional exploratory endpoints that are clinically relevant included a responder analysis (e.g., the proportion of patients who achieved a ≥50% reduction in HAE attack rate), proportion of patients that were attack-free (e.g., the proportion of patients with a 100% reduction in HAE attack rate), and the proportion of patients who achieved an improvement in quality of life as measured by the Angioedema Quality of Life questionnaire (AE-QoL).

Regarding patient demographics, 90.4% of patients enrolled in the study had Type I HAE. A history of laryngeal angioedema attacks was reported in 64.8% (81/125) of patients and 56.0% (70/125) were on prior long-term prophylaxis. During the study run-in period, attack rates of ≥3 attacks/month were observed in 52.0% (65/125) of patients overall.

The efficacy analysis was performed on the intention-to-treat (ITT) population, which included all randomized patients who received any exposure to the investigational product.

Results obtained from the DX-2930-03 study demonstrated Takhzyro 300 mg q2wks reduced the rate of investigator-confirmed HAE attacks by 86.9% (95% confidence interval [CI]; 76.2, 92.8) (rate ratio: 0.131 [95% CI; 0.072, 0.238]; p<0.001) compared to placebo following 26 weeks (182 days) of treatment in patients with Type I or Type II HAE who experienced at least one investigator-confirmed HAE attack per 4 weeks during the run-in period. Additionally, Takhzyro 300 mg q2wks reduced the rate of HAE attacks requiring acute treatment by 87.3% [95% CI; 75.2, 93.5] (rate ratio: 0.127 [95% CI; 0.065, 0.248]; p<0.001) and reduced the rate of HAE attacks categorized as moderate to severe by 83.4% ([95% CI; 67.1, 91.6] (rate ratio: 0.166 [95% CI; 0.084, 0.329]; p<0.001).

Regarding exploratory endpoints, the proportion of patients who achieved a ≥50% reduction in HAE attack rate over the 26 week treatment period (e.g., responder) was 100% of patients receiving Takhzyro 300 mg q2wks compared to 31.7% of patients receiving placebo. The proportion of patients who achieved a 100% reduction in HAE attack rate (i.e., attack-free) over the 26 week treatment period was 44.4% of patients receiving Takhzyro 300 mg q2wks compared to 2.4% of patients receiving a placebo. Additionally, the proportion of patients who achieved an improvement in quality of life as measured by the AE-QoL questionnaire (minimally important clinical difference ≥6 in the AE-QoL total score) was 80.8% for Takhzyro patients who received 300 mg q2wks and 36.8% for placebo patients.

Similar results were observed with Takhzyro 300 mg q4wks dosage regimen, although numerically less than results observed with the more frequent dosing posology. Pharmacokinetic and pharmacodynamic analysis indicates that exposure-response relationship (e.g., number of HAE attacks per month) plateaus by 6 months, with no notable difference in HAE attack rates between Takhzyro 300 mg q2wks and q4wks, respectively. A less frequent dosing interval of 300 mg q4wks may be considered by health care professionals if the patient is well-controlled (e.g., attack free) for more than 6 months on the recommended dose of 300 mg q2wks.

Patients who completed the treatment period in the DX-2930-03 study were then given the opportunity to enroll in the open-label extension study DX-2930-04. Patients who consented to participate in the DX-2930-04 study received their first open-label dose following the completion of all double-blind assessments scheduled on Day 182.

Study DX-2930-04

The DX-2930-04 study extension was an open-label, uncontrolled study designed to evaluate the long-term safety and efficacy of Takhzyro for prevention of HAE attacks in patients with Type I or Type II HAE. A total of 212 adult and adolescent (≥12 years) patients received at least one dose of 300 mg q2wks Takhzyro in the study extension, including 109 patients who entered as rollover patients from the original DX-2930-03 study. Rollover patients, regardless of randomization group in the DX-2930-03 study, received a single dose of Takhzyro 300 mg at study entry and did not receive additional treatment until the occurrence of an HAE attack. After the first HAE attack, all patients received open-label treatment with Takhzyro 300 mg q2wks. The majority of patients self-administered Takhzyro over 10 to 60 seconds (64.4% of 929 injections).

Results from the study extensions demonstrated at week 4 post-dose, 80.0% of patients who had been in the 300 mg q2wks treatment group (number of patients [n] = 25) in the DX-2930-03 study remained attack-free. These exploratory results should be interpreted with caution, however, as they reflect a select cohort that completed 26-weeks of exposure to Takhzyro and selectively enrolled in the open-label extension study.

Based on results derived from the pivotal clinical study (i.e., DX-2930-03) and supported by the extension study (i.e., DX-2930-04) Takhzyro 300 mg q2wks demonstrated the greatest numerical magnitude of efficacy compared to the other assessed dosing posologies. The robustness of these data supports a posology of Takhzyro 300 mg q2wks.

Indication

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

  • Takhzyro (lanadelumab injection) is indicated for routine prevention of attacks and control of the symptoms of hereditary angioedema (HAE) in adolescents and adults.

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Takhzyro (lanadelumab injection) is indicated for routine prevention of attacks of hereditary angioedema (HAE) in adolescents and adults.
  • Takhzyro is not intended for acute treatment of HAE attacks.

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

Clinical Safety

The safety assessment of Takhzyro included pooled safety data from two Phase I studies in addition to two Phase III studies (DX-2930-03 and DX-2930-04) previously described in the Clinical Efficacy section. Further safety data was also consulted in reference to external assessments of pediatric data, electrocardiogram (ECG), and hepatic data from Phase III studies.

Overall, a total of 233 HAE patients and 24 healthy volunteers were exposed to Takhzyro at doses up to 400 mg during clinical development. The majority of doses (93.1%) were 300 mg. Of the 233 HAE patients enrolled in the Phase 1b and Phase III studies, 23 (10%) of these patients were adolescents 12 to 17 years old and 11 (5%) were 65 years of age and older. The majority of patients that participated in the primary Phase III studies continued their participation in the open-label extension with a length of exposure to Takhzyro of 19.6 months.

There were no deaths or serious adverse events (SAEs) determined by investigators to be related to study treatment with Takhzyro. There were 89.1% of patients that had treatment-emergent adverse events (TEAEs), 53.6% that had adverse drug reactions (ADRs), 5.0% with SAEs, 12.3% with severe TEAEs, and 2.7% that discontinued due to TEAEs. The most commonly observed adverse reactions associated with Takhzyro in patients with HAE were injection site reactions (ISR) including injection site pain, injection site erythema and injection site bruising. Most were of mild intensity and resolved within one day after onset. There were 11.4% of patients with anti-drug antibodies and 3.2% with neutralizing antibodies. There was no association seen between antibodies and safety profile.

There were 5.5% of patients that had adverse events of special interest (AESIs) of hypersensitivity reactions or disordered coagulation adverse events. There was an increase in activated partial thromboplastin time (aPTT) seen in Takhzyro patients which the sponsor attributes to the effect of plasma kallikrein inhibition on the assay. These elevations were not associated with bleeding events. There were several patients with hypersensitivity reactions, and while none were anaphylactic reactions, they did lead to discontinuation in three cases. There were two cases of severe elevations of liver enzymes seen in Takhzyro-treated patients that led to discontinuation. Review of reports detailing independent expert assessments of ECGs, pediatric data, and hepatic event data did not identify increased risk of such events with Takhzyro treatment.

Hereditary angioedema is a rare disease making clinical study enrolment relatively challenging. With a relatively limited number of patients enrolled in the pivotal study, which is common for such rare diseases, there exists a degree of uncertainty related to the safety of Takhzyro in the overall HAE patient population, including in various demographic subgroups. There were few adolescent (i.e., 12 to 17 years of age; Number of patients [n] = 23) and geriatric (i.e., ≥65 years of age; n = 11) patients enrolled in the Phase III clinical program; however, no pronounced safety signals were identified in these patients. Additionally, long-term safety data reflective of the intended chronic prophylaxis treatment remains limited. These limited data preclude robust conclusions regarding the safety of long-term treatment with Takhzyro in the HAE population, and in the incidence of rare and/or latent adverse events.

Overall, based on the data evaluated as part of this submission, Health Canada considers there to be sufficient evidence at this time to conclude that the benefit-risk profile of Takhzyro for the routine prevention of HAE attacks in adolescents and adults is favourable. The identified safety risks are considered sufficiently mitigated by product labelling and routine pharmacovigilance activities.

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

7.2 Non-Clinical Basis for Decision

Lanadelumab (the medicinal ingredient in Takhzyro) was shown to bind to human plasma kallikrein and inhibit plasma kallikrein activity in vitro. Pivotal toxicology studies were conducted in cynomolgus monkeys. In a 6-month repeat-dose general toxicity study, no lanadelumab-related adverse effects were observed in animals at exposures 15-fold and 20-fold greater than the estimated human exposures for adolescents and adults, respectively. In addition, no adverse effects on male or female fertility-related endpoints were observed in a 13-week study at exposures 14-fold and 19-fold greater than the estimated human exposures for adolescents and adults, respectively. There were also no maternal or developmental adverse effects observed in an enhanced pre- and post-natal developmental toxicity study following maternal exposures 21-fold and 29-fold greater than the estimated human exposures for adolescents and adults, respectively. Exposure in infants was observed during the postnatal period, demonstrating that lanadelumab crosses the placental barrier. Low concentrations of lanadelumab were also excreted in the milk of lanadelumab-administered maternal animals (approximately 0.2% of plasma concentrations). Carcinogenicity and genotoxicity studies were not conducted.

Overall, appropriate warnings and precautionary measures are in place in the Takhzyro Product Monograph to address the identified safety concerns.

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

7.3 Quality Basis for Decision

Takhzyro (lanadelumab) is a solution for subcutaneous injection provided in a single-use 5 mL glass vial. The sterile, preservative-free, ready-to-use solution contains 150 mg/mL of lanadelumab which is a recombinant, fully human, immunoglobulin G subclass 1 (IgG1), kappa (κ)-light chain, monoclonal antibody expressed in Chinese Hamster Ovary (CHO) cells. Lanadelumab is a highly potent inhibitor of active plasma kallikrein (pKa1), an enzyme which converts kininogen to bradykinin. Bradykinin is a vasodilator and excess bradykinin is associated with the characteristic HAE symptoms of localized swelling, inflammation, and pain. Therefore, the inhibition of pKa1 by lanadelumab leads to decreased HAE symptoms.

Characterization of the Drug Substance

Extensive characterization of the physicochemical, biological, and immunological properties of lanadelumab and confirmation of its purity were performed using methods selected in accordance with International Council for Harmonisation (ICH). The data demonstrate that lanadelumab has the structure expected of a recombinant humanized monoclonal antibody expressed in CHO cells. Product variants and process-related impurities were quantified and were consistent with those described for several other monoclonal antibody products.

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

Lanadelumab is produced in a recombinant suspension-adapted CHO cell line. The manufacturing process consists of a series of steps which include cell culture, harvest, purification stages, including viral inactivation/removal steps, and formulation. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable. Data from product quality assessments, non-clinical studies, and clinical studies demonstrate that lanadelumab produced by different manufacturing process versions during development is comparable and that there has been no significant impact on quality observed due to the associated process changes. The manufacturing process has been successfully validated with full-scale drug substance batches used to assess the removal of process-related impurities, product quality and process performance attributes, and to support the demonstration of process consistency.

The production of Takhzyro drug substance consists of thawing, pooling, and mixing the contents of the drug substance containers followed by sterile filtration and aseptic filling into 5 mL (300 mg dosage; 2.25 mL) sterile, single-use glass vials. Following filling, vials are stoppered, capped, lot printed, and then 100% visually inspected before bulk packaging, shipping, labeling, and packaging.

In-process control tests for the drug substance and drug product were established, corresponding analytical methods validated, and acceptance criteria justified. The manufacturing process is considered to be adequately controlled within justified limits.

Materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use.

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

Control of the Drug Substance and Drug Product

The purified bulk drug substance and drug product are tested against suitable reference standards to demonstrate strength, purity, potency, and identity. Analytical procedures have been carefully selected according to their ability to confirm the safety, efficacy, and activity of the lanadelumab drug substance and drug product. The methods were validated in full accordance with the ICH guidelines for method validation.

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 months shelf life at 5ºC±3ºC for Takhzyro is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An OSE of the facility involved in the manufacture of the drug substance was conducted from September 10 to 14, 2018 and obtained a satisfactory rating.

An OSE of the facility involved in the manufacture of the drug product was not conducted as it was not recommended based on the risk determination score.

Adventitious Agents Safety Evaluation

The lanadelumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Lanadelumab drug substance was manufactured without any materials of human or animal origins. The Master Cell Bank (MCB) and Working Cell Bank (WCB) were prepared using chemically defined media without any components derived from human or animal origin. However, fetal bovine serum (FBS) was used in the cryopreservation medium in generation of the host cell line and the parental cell bank. A Certificate of Analysis of the FBS including its origin and testing was provided, reviewed, and deemed acceptable. In addition, the MCB, WCB, and Post Production Cell Bank (PPCB) were evaluated in accordance with ICH Q5A and ICH Q5D guidelines and found to be free of viral and non-viral contamination.