Exposure-response model of subcutaneous C1-inhibitor concentrate to estimate the risk of attacks in patients with hereditary angioedema

Abstract

Subcutaneous C1-inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)-approved, highly concentrated formulation of a plasma-derived C1-esterase inhibitor (C1-INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low-Volume Subcutaneous C1-inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time-to-event model to characterize the timing and frequency of HAE attacks as a function of C1-INH activity, and then develop an exposure-response model to assess the relationship between C1-INH functional activity levels (C1-INH(f)) and the risk of an attack. The C1-INH(f) values of 33.1%, 40.3%, and 63.1% were predicted to correspond with 50%, 70%, and 90% reductions in the HAE attack risk, respectively, relative to no therapy. Based on trough C1-INH(f) values for the 40 IU/kg (40.2%) and 60 IU/kg (48.0%) C1-INH (SC) doses, the model predicted that 50% and 67% of the population, respectively, would see at least a 70% decrease in the risk of an attack.