Summary Basis of Decision for Andembry

Clinical Pharmacology

The clinical pharmacokinetic data for garadacimab, the medicinal ingredient in Andembry, were obtained from three Phase I, one Phase II, and two Phase III clinical studies. Together, the observed data from these studies, along with pharmacometric analyses, including population pharmacokinetic/pharmacodynamic modeling and exposure-response analyses, were used to characterize the pharmacokinetics and pharmacodynamics of garadacimab.

The clinical pharmacokinetic data for garadacimab are limited due to the small number of patients studied. Serial pharmacokinetic samples were collected in the Phase I studies in healthy subjects and in a Phase II study in patients with hereditary angioedema (HAE). Sparse pharmacokinetic samples were collected in the Phase III studies in patients with HAE. To address these limitations, the sponsor has provided extensive pharmacometric analyses to further characterize the pharmacokinetic profile of garadacimab and to support dosing recommendations.

Based on a population pharmacokinetic analysis, following the subcutaneous administration of garadacimab, peak plasma concentration is reached within approximately 6 days and the terminal elimination half-life is approximately 19 days. Steady state garadacimab exposure was achieved after the initial subcutaneous loading dose of 400 mg (administered as two 200 mg subcutaneous injections).

The pharmacokinetics in adolescents (aged 12 to 17 years) was found to be consistent with the pharmacokinetics in adults. Pharmacometric analyses further validate the efficacy of this dosing strategy, confirming that age does not influence the pharmacokinetic profile of garadacimab, thereby eliminating the need for age-based dose adjustments in patients aged 12 years and older. Although body weight was identified as a covariate in the population pharmacokinetic model, exposure-response analysis showed no variation in monthly attack rates across different weight groups, supporting the recommendation of a fixed dose without weight-based adjustments.

Across studies, garadacimab demonstrated a dose-dependent inhibition of Factor XIIa-mediated kallikrein activity, with adolescents showing similar responses to adults.

Evidence supports the comparative bioavailability of garadacimab when administered via a pre-filled pen and pre-filled syringe in healthy subjects. The pharmacokinetic parameters between the two presentations met the bioequivalence criteria. Additionally, garadacimab administered subcutaneously with either device was safe and well tolerated in this study.

Treatment with garadacimab has been associated with the development of low-titre treatment-emergent anti-drug antibodies (ADAs) in 5 out of 172 (2.9%) treated patients during the clinical development program. The development of ADAs against garadacimab did not affect the pharmacokinetics, pharmacodynamics, or safety of garadacimab, nor did it affect the clinical response to garadacimab.

The potential effects of neutralizing antibodies on garadacimab exposure, efficacy, pharmacodynamics, and safety have not been evaluated, as no standalone neutralizing antibody assay has been developed.

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

Clinical Efficacy

The efficacy of Andembry in the prevention of HAE attacks in adult and adolescent patients (aged 12 to 17 years) was established in Study 3001, a multicentre, randomized, double-blind, placebo-controlled study. The study enrolled patients aged 12 years and older with confirmed HAE and C1-esterase inhibitor deficiency (C1-INH HAE), and a history of recurrent HAE attacks. Overall, the study included 64 randomized patients treated with either Andembry (39 patients) or placebo (25 patients). A small number of adolescent patients were enrolled in the study (6 patients).

The majority of patients were female (38 [59.4%] patients) and White (55 [85.9%] patients) and not of Hispanic or Latino ethnicity (60 [93.8%] patients). There were 6 (9.4%) patients identified as Asian-Japanese, 1 (1.6%) patient identified as Black or African American, and 1 (1.6%) patient identified as Native Hawaiian or Other Pacific Islander. The mean (standard deviation [SD]) overall age of all patients was 41.2 (15.92) years, with patients ranging from 12 to 69 years of age. The mean (SD) overall body mass index of all patients was 28.05 (6.612) kg/m², with patients ranging from 18.7 to 52.7 kg/m². Demographic characteristics of all patients were comparable between treatment arms.

Andembry was administered at a dosing regimen of 200 mg subcutaneously once a month following an initial 400 mg subcutaneous loading dose (i.e., two 200 mg subcutaneous injections). The duration of the treatment period was 6 months.

The primary endpoint was the difference between Andembry and placebo in time-normalized number of HAE attacks from Day 1 to Day 182 (6 months). Substantial evidence of HAE attack reduction was demonstrated in the Andembry arm, with a statistically significant and clinically meaningful lower HAE attack rate per month during the 6-month treatment period compared to placebo (mean attack rate per month: 0.27 in the Andembry arm versus [vs.] 2.01 in the placebo arm; p<0.001). This corresponded to an 86.51% relative difference (reduction) in the means of time-normalized number of HAE attacks per month for Andembry compared to placebo.

The secondary efficacy endpoints demonstrated that during the 6-month treatment period, the majority of patients in the Andembry arm (94.9%) were responders with a 50% or greater reduction in the time-normalized number of HAE attacks (vs. 33.3% in the placebo arm). Overall, 61.5% of Andembry-treated patients were attack free during the 6-month treatment period (vs. 0.0% of patients in the placebo arm). During the first 3 months of treatment, 71.8% of patients in the Andembry arm were attack free (vs. 8.3% of patients in the placebo arm).

Other secondary efficacy endpoints quantifying and analyzing both objective (i.e., investigator-defined HAE attacks) and subjective (i.e., quality of life) measures associated with HAE were all supportive of Andembry compared to placebo from a statistical significance and clinical meaningfulness perspective. Efficacy results from an open-label extension study (Study 3002), in which the median duration of exposure is over 1 year, are supportive of the sustained efficacy of Andembry in the prevention of HAE attacks.

Indication

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

Andembry is indicated for routine prevention of attacks of hereditary angioedema (HAE) in adult and pediatric patients (aged 12 years and older).

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

Andembry (garadacimab injection) is indicated for routine prevention of attacks of hereditary angioedema (HAE) in adult and pediatric patients (aged 12 years and older).

Andembry is not intended for acute treatment of HAE attacks.

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

Clinical Safety

The clinical safety of Andembry was evaluated in a pooled safety analysis set consisting of 172 patients with HAE from the pivotal study (Study 3001; see Clinical Efficacy section), an open-label Phase III extension study (Study 3002), and a Phase II study (Study 2001).

Of the 166 patients who received the recommended dose of Andembry (200 mg), most had a cumulative exposure of 6 months or longer (160 patients [96.4%]), and the majority had a cumulative exposure of 12 months or longer (142 patients [85.5%]). The most frequent adverse events (occurring in 10% or more of patients) reported during treatment with 200 mg of Andembry were coronavirus disease 2019 (35.5%), nasopharyngitis (18.1%), headache (11.4%), and upper respiratory tract infection (10.2%). There were no deaths observed during the clinical development program. The incidence of serious adverse events was low and none were considered related to treatment with Andembry in the pooled safety analysis set. Notably, the frequency of reported treatment-emergent adverse events did not appear to increase with long-term treatment. Based on the safety data collected, Andembry demonstrated a consistent safety and tolerability profile across the clinical studies.

While data was limited due to the small sample size, the safety of Andembry in adolescents (aged 12 to 17 years) with HAE appeared to be similar to that of the entire study population.

Appropriate warnings and precautions are in place in the approved Product Monograph for Andembry to address the identified safety concerns.

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

Garadacimab is the medicinal ingredient in Andembry. It’s mechanism of action and proof of concept for treatment were demonstrated by in vitro studies and studies using animal models of disease, respectively. Some mice and monkeys administered garadacimab intravenously or subcutaneously developed immune-mediated anaphylactic responses in the repeat-dose toxicity studies, without additional toxicity. Garadacimab did not affect fertility in reproductive toxicology studies conducted with rabbits. Garadacimab did not produce maternal toxicity and was not teratogenic in developmental toxicology studies conducted with rabbits. Garadacimab crosses the placental barrier. Following in utero exposure, fetal plasma garadacimab concentrations can exceed maternal plasma concentrations at parturition.

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

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

Characterization of the Drug Substance

Garadacimab, the medicinal ingredient in Andembry, has a typical monoclonal antibody structure consisting of two heavy chains and two light chains, joined by disulfide bonds. The immunoglobulin G4 heavy chain constant region contains a single engineered serine-to-proline substitution to stabilize the hinge and prevent half antibody formation. The heavy chain also has an N-glycosylation site.

Garadacimab has been well characterized using a wide range of orthogonal methods to elucidate the primary and higher order structure, disulfide bonding pattern, molecular assembly, post-translational modifications, sialic acid content, charge and size heterogeneity, particle size distribution, isoelectric point, conformational stability, structure and function relationships, and biological activities. Process-related impurities and product-related substances and impurities were also well characterized.

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

The drug substance is manufactured in a Chinese hamster ovary expression system. The production of one batch of drug substance starts with the thawing of one vial of working cell bank, which is expanded through to a production bioreactor. Cell culture fluid is harvested from the production bioreactor by depth and 0.2 µm filtration. This is followed by downstream purification using affinity capture chromatography, low pH viral inactivation, anion exchange chromatography, cation exchange chromatography, and tangential flow filtration. Once the target concentration of the bulk purified protein is achieved, the drug substance is filtered into single-use bags and stored frozen.

The drug product is supplied in two presentations for subcutaneous administration: a pre-filled pen and a pre-filled syringe. The manufacturing process for the drug product involves thawing, pooling, and dilution of drug substance to the desired strength, followed by sterile filtration and filling into single-dose pre-filled syringes. The pre-filled syringes are assembled either into a pre-filled pen or with a needle safety device, then labelled, packaged, and stored.

A Notice of Deficiency was issued by Health Canada during the review cycle as the initially proposed drug product manufacturing process introduced unnecessary risk for compromising product sterility. To address this issue, the sponsor introduced an additional sterile filtration step. Health Canada determined that the issue was appropriately resolved.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. 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) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The Andembry control strategy includes control of raw materials, in-process and process parameter control during manufacturing, and release and stability specifications. Appropriate process parameters have been implemented and critical process parameters have been identified. This multi-level control strategy, as part of the overall process performance and product quality monitoring system, assures the consistent manufacture of acceptable product. The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

Andembry 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.

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 36-month shelf life at 5 °C for Andembry is considered acceptable, with a storage allowance of 2 months when stored up to 25 °C.

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

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The United Kingdom's Medicines and Healthcare products Regulatory Agency, the Swiss Agency for Therapeutic Products, and Australia’s Therapeutic Goods Administration served as the primary review agencies for this submission, as part of the Access Consortium: Access Consortium: New Active Substance Work-Sharing Initiative (NASWSI). Health Canada conducted a peer review of the review reports prepared by these agencies and therefore on-site evaluations (OSEs) of the facilities involved in the manufacture and testing of the drug substance and drug product were not recommended.

Adventitious Agents Safety Evaluation

Raw materials of animal and recombinant deoxyribonucleic acid origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.