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
Saturday, March 3, 2018
South Hall A2 (Convention Center)
Bruce L. Zuraw, MD, Marco Cicardi, MD, Timothy Craig, DO, FAAAAI, AOA, Hilary J. Longhurst, MD, William R. Lumry, Jonathan A. Bernstein, MD FAAAAI, Ying Zhang, Dipti K. Pawaskar, PhD

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 Ctrough 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.