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.

Figure 1

Absolute risk of a breakthrough hereditary angioedema (HAE) attack vs. C1‐esterase inhibitor functional activity (C1‐INH(f)) (%). Blue dots represent the model predicted hazard vs. C1‐INH(f) (%) in each patient.

Figure 2

The relationship between cumulative probability of a breakthrough hereditary angioedema (HAE) attack and time of normalized attacks per month. The solid blue and green lines represent the cumulative probability of the observed HAE attacks (normalized by month). The blue and green bands reflect the 90% prediction intervals (without uncertainty based on estimation) based on 500 simulations based on the final model. C1‐INH, C1‐esterase inhibitor.

Figure 3

Predicted absolute risk of an hereditary angioedema (HAE) attack vs. C1‐esterase inhibitor functional activity (C1‐INH(f)) (%) stratified by age. The blue solid line represents the absolute risk of HAE attack at the median age (40 years old) of the patient population in the study. The blue dotted lines represented the 5th and 95th (20–60 years old) confidence interval of the age of the patient population in the study.

Figure 4

Simulated relationship between the relative risk of a breakthrough hereditary angioedema (HAE) attack and C1‐esterase inhibitor functional activity (C1‐INH(f); relative to the geometric mean baseline C1‐INH(f) of 25.4%) with predicted C_trough values expected after administering C1‐esterase inhibitor (C1‐INH (SC)). Box plots represent the range of observed baseline C1‐INH(f) values (baseline) and steady‐state final population pharmacokinetic model‐predicted C_trough after 40 IU/kg and 60 IU/kg doses of C1‐INH (SC), respectively. Black lines within the box represent the median value, the red circle represents the geometric mean, and these numbers are listed above the box. The red dashed line is the median of the simulation. The pink shaded area represents the prediction intervals (SEs in the parameter estimates only). The blacked dashed lines represent 50%, 70%, and 90% reductions in relative risk of a breakthrough HAE attack. Longhurst, H.J. et al.6 Prevention of hereditary angioedema attacks with subcutaneous C1 inhibitor. N. Engl. J. Med. 376, 1131–1140 (2017). Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.