Regulatory Decision Summary for Firazyr

Firazyr (icatibant acetate) was indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase inhibitor deficiency. New interim clinical trial data were provided in this Supplemental New Drug Submission (SNDS) to support the safety and efficacy of Firazyr in the pediatric population. The proposed pediatric indication is similar to that in adults, and is supported by one population pharmacokinetic (PK) study (SHIR-RAS-003) and one Phase 3 study (HGT-FIR-086). HGT-FIR-086 is an open-label, nonrandomized, single-arm study to evaluate the PK, efficacy, and safety, including effects on reproductive hormones, of a single 0.4 mg/kg subcutaneous administration of Firazyr in pediatric subjects with HAE.

SHIR-RAS-003 included exposure-response modelling of data derived from five studies in adults and HGT-FIR-086, including 172 subjects. Firazyr exposure was reduced in pediatric compared with adult subjects but the clinical response was unaffected. Based on the PK findings the European Medicines Agency approved a 5 weight-band dosing regimen in 2017, which was also proposed in the SNDS to Health Canada.

Thirty-two (32) subjects were enrolled (11 prepubertal [children] and 21 pubertal/postpubertal [adolescent] subjects). All of the children and 11 adolescents received a single administration of Firazyr following an acute HAE attack. Ten adolescents received a dose of Firazyr in the absence of an attack. The primary efficacy endpoint, the time to the onset of symptom relief (TOSR), was achieved by 100% of subjects. The median TOSR was 1.0 hour (95% CI: 1.0, 2.0) and was similar between the children and the adolescents. Secondary efficacy endpoints were consistent with and supportive of the results of the primary efficacy endpoint.

The observed safety profile of Firazyr was consistent with the known safety profile in adult patients. There were 32 treatment-emergent adverse events (TEAEs) in nine subjects; gastrointestinal disorders and headache were most common. One subject experienced two mild TEAEs, dry mouth and fatigue, which were possibly related to Firazyr. The majority of subjects experienced injection site reactions but most were mild or moderate in intensity and had resolved by 6 hours post-dose.

The complexity of administration, a lack of long-term reproductive hormone concentrations data, and slight over-exposure in subjects at the lowest weight-band present uncertainty related to the safety of Firazyr, and there were data limitations in subjects under six years of age and in the treatment of laryngeal attacks. There is also uncertainty in the usability of Firazyr regarding self-administration in adolescent patients. Despite the uncertainties, the magnitude of the benefit of the TOSR in this rare patient population was substantial and access to Firazyr addresses an unmet need for many patients with HAE. Regarding self-administration, Shire established the OnePath Patient Support Program that distributes Firazyr and the required supplies, and offers training and education for patients. Furthermore, no changes in reproductive hormone concentrations have been reported post-approval in the European Union.

Relevant sections of the Product Monograph (PM) were updated to include data from the analysis of HGT-FIR-086 and a description of the OnePath Patient Support Program. Additions included a description of the paucity of data in very young children, in treating laryngeal attacks, and in the effects on the growth and development in pediatric patients with prolonged use. The instructions for use were updated in the PM.

With appropriate monitoring of reproductive hormone concentrations with frequent use, the benefits of Firazyr use in pediatric patients with HAE outweigh the risks when used in accordance with the updated, approved labelling.