Subcutaneous (SC) vs Intravenous (IV) C1-esterase-inhibitor (C1-INH) Replacement Treatment For The Prevention Of Attacks Of Hereditary Angioedema (HAE): A Population-based Exposure‑response Analysis

RATIONALE: C1-INH replacement therapy is well established for the prevention of HAE attacks. Two FDA approved treatments studied in independent randomized placebo‑controlled clinical trials are available: Cinryze® (1000 IU IV twice weekly) and Haegarda® (C1-INH(SC) 60 IU/kg). A population-based exposure-response analysis (PK/PD modelling) was performed to compare the relative efficacy of C1-INH IV vs SC based on the COMPACT studies.

METHODS: The C1-INH functional activity (C1-INH[f]) data, obtained after administration of C1-INH (prophylaxis SC and on‑demand IV) from 1 study in healthy volunteers (n=16) and 2 studies in HAE subjects (n=108), were pooled to develop a population PK model (PopPK). Using the PK/PD model, the relative risk of an HAE attack in a model patient weighing 80 kg, treated with IV vs SC C1-INH was determined.

RESULTS: The C1-INH(f) over time was described by a linear one-compartment model with first‑order absorption and elimination. The PopPK model simulations revealed higher C_trough with 60 IU/kg (47.0%) compared with 1000 IU IV (28.3%) and a lower peak-to-trough ratio with a more consistent elevation of the C1-INH(f) for 60 IU/kg SC doses compared with 1000 IU IV dose. The time to event model revealed an inverse relationship between C1-INH(f) and breakthrough attacks. Based on the PK/PD model for an 80 kg model patient, the 60 IU/kg SC dose predicted an additional 73.0% risk reduction of HAE attacks compared with 1000 IU IV twice weekly dosing.

CONCLUSIONS: Based on PK/PD modeling data C1-INH(SC) is predicted to provide a superior preventive effect compared with C1-INH(IV) in the majority of patients.