Regulatory Decision Summary for Andembry

This New Drug Submission (NDS) was filed to obtain market authorization for Andembry (garadacimab injection) for the routine prevention of attacks of hereditary angioedema (HAE) in adult and pediatric patients (aged 12 years and older).

The submission was reviewed using the international review work-sharing model with the ACCESS Consortium between Australia (TGA), Switzerland (SMC), the United Kingdom (MHRA), and Canada. MHRA, SMC and TGA led the review of Module 3 (quality), Module 4 (non-clinical) and Module 5 (clinical) provided in this submission, respectively. Health Canada’s assessment was principally based on a peer review of their primary assessments.

A single randomized, double-blind, placebo-controlled study (Study 3001) evaluating Andembry (garadacimab injection) in the prevention of hereditary angioedema (HAE) attacks in adult and adolescent patients (aged 12 years and older) with confirmed HAE with C1-esterase inhibitor deficiency (C1-INH HAE) and a history of recurrent HAE attacks was submitted as the pivotal support for the efficacy and safety of Andembry in this patient population.

In this clinical trial, those assigned to Andembry (n = 39) demonstrated substantial evidence of HAE attack reduction with a statistically significant and clinically meaningful lower HAE attack rate per month during the 6-month treatment period compared with placebo (n = 25); the mean HAE attack rate per month was 0.27 with Andembry vs. 2.01 with placebo (p < 0.001), corresponding with an 86.51% reduction in the relative difference in the means of time-normalised number of HAE attacks per month for Andembry vs. placebo.

The safety of Andembry was characterized by the pivotal study (Study 3001), an open-label extension (Study 3002), and a Phase II study (Study 2001). The most frequent adverse events (> 10%) reported during treatment with Andembry were COVID-19 (35.5%), nasopharyngitis (18.1%), headache (11.4%), and upper respiratory tract infection (10.2%). The rate of serious adverse events was low and no deaths were observed during the HAE development program. The above risks were adequately described in the Product Monograph with appropriate risk mitigation strategies.

The recommended posology for Andembry in HAE is a fixed subcutaneous (SC) dose of 200 mg (1.2 mL) administered once a month beginning 1 month after an initial loading dose of 400 mg (i.e. two 200 mg SC injections). This posology was used in the pivotal Study 3001. Adolescents received the same dosing regimen as adults. The observed data from Study 3001, together with the data derived from pharmacometric analyses support the recommended dose.

There is residual uncertainty regarding the benefit/risk profile of Andembry in both HAE with normal C1-INH function and in adolescent patients due to the small sample sizes of these populations in the clinical development program. However, based on biological plausibility and disease similarity, respectively, these uncertainties are not deemed to be major concerns.

Routine pharmacovigilance will be conducted by the sponsor and additional pharmacovigilance activities have also been proposed to further characterize the risks presented in the Risk Management Plan.

Overall, the benefit-risk profile was favourable for Andembry (garadacimab), administered as an initial loading dose of 400 mg SC followed by a monthly dose of 200 mg SC, for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

A Notice of Deficiency (NOD) was issued by Health Canada due to the identification of a major quality deficiency that had the potential to impact the sterility of the drug product. In response to the NOD, the sponsor submitted an updated drug product process and supporting validation which addressed the objections regarding the risk to sterility.

An updated Risk Management Plan (RMP) for Andembry was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Andembry has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

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