Population Pharmacokinetic/Pharmacodynamic and Exposure-Response Modeling of Garadacimab in Healthy Volunteers and Patients With Hereditary Angioedema

Abstract

Hereditary angioedema (HAE) is a rare genetic disease that manifests as recurrent, unpredictable, and potentially life-threatening attacks of angioedema. Garadacimab is a first-in-class, fully human, monoclonal antibody targeting activated factor XII (FXIIa) that is under clinical development for the long-term prophylaxis of HAE attacks. We developed population pharmacokinetic (PK)/pharmacodynamic (PD)/exposure-response (ER) models using pooled data across clinical studies to quantify the relationship between garadacimab concentration and the relative risk of HAE attacks and to support the rationale for 200 mg once-monthly dosing. The PK of garadacimab was adequately characterized by a two-compartment model with first-order absorption and elimination. The PD, as analyzed by FXIIa-mediated kallikrein activity, was adequately characterized by a direct inhibitory response model. PK/PD parameters were generally consistent across multiple covariates. ER analysis based on a repeated-time-to-event model showed that administration of garadacimab 200 mg subcutaneously (SC) once monthly results in 75% of patients reaching the target therapeutic threshold (90% reduction in relative risk of attack vs. run-in). Use of a loading dose (two 200 mg SC injections) as the first administration achieved steady-state PK exposures and PD response, with 85% of patients having exposures surpassing the therapeutic threshold. The models support the use of garadacimab 200 mg SC once-monthly dosing in patients aged ≥ 12 years, with no need for dose adjustments, and indicate that, due to the achievement of garadacimab steady-state exposures after the first administration, the use of a loading dose may facilitate the early onset of protection against HAE attacks, as observed in clinical studies.

Keywords: exposure–response; garadacimab; hereditary angioedema; pharmacodynamics; pharmacokinetics.

FIGURE 1

PopPK final model: Univariate forest plot showing covariate effects on garadacimab AUC_tau,ss relative to a reference subject. The covariates in the model were visualized by varying single covariates individually while keeping all other conditions constant (ceteris paribus). Results are presented relative to a reference subject, i.e., a non‐Japanese, non‐Chinese, healthy volunteer with BL weight of 70 kg, BL sCR 0.75 mg/dL, BL ALT 25 U/L, and BL bilirubin 8 μmol/L. The circles represent the median and the solid horizontal lines represent the 95% confidence intervals. The reference range of 80%–125% within the two dashed lines was analogous to the region of practical equivalence. For continuous covariates, the upper and lower values used in the predictions were determined based on the 10th and 90th percentiles in the observed dataset. AUC_tau,ss, area under the concentration–time curve for a dosing interval at steady state; ALT, alanine aminotransferase; BL, baseline; CI, confidence interval; HAE, hereditary angioedema; sCR, serum creatinine.

FIGURE 2

Monthly HAE attack rate vs. time in the pivotal phase III (VANGUARD) study, stratified by quartiles of garadacimab AUC_tau,ss at 3 months. Lines represent the mean, 25th or 75th percentiles of the observed (solid) and predicted (dashed) data. The shaded region represents 95% confidence intervals. AUC_tau,ss, area under the concentration–time curve for a dosing interval at steady state; HAE, hereditary angioedema; Q, quartile.

FIGURE 3

Forest plots: Conditional predictions of monthly attack rates at 3 months with fixed covariate levels. Points and lines indicate the mean and 95% prediction interval, respectively, for the mean monthly attack rate. Results are presented relative to a reference subject (41 years of age, body weight of 79 kg, baseline monthly attack rate of 2.9, female sex, non‐Chinese and non‐Japanese ethnicity, HAE‐C1INH‐Type1/2, had not received any prior treatment). Covariates are fixed at the indicated levels in either HAEA, in which case PK assumes the reference subject, or in both the HAEA and PopPK model. PK is simulated at steady state with a loading dose of two 200 mg SC injections followed by 200 mg SC once monthly. Continuous covariate levels (age and weight) correspond to the 5th, 25th, 50th, 75th, and 95th percentiles of the covariate in the analysis population. CI, confidence interval; HAE, hereditary angioedema; HAEA, HAE attack model alone; HAE‐C1INH‐Type1/2, hereditary angioedema with deficiency or dysfunction of C1 inhibitor; PK, pharmacokinetics; Pop, population; SC, subcutaneous; SD, standard deviation.

FIGURE 4

PK/PD predictions: Model‐predicted (a) garadacimab concentration and (b) FXIIa‐mediated kallikrein activity, vs. time in patients aged ≥ 12 years. Dosing regimen: Loading dose of two 200 mg SC injections followed by 200 mg SC once monthly. N = 20,000. The solid lines represent the predicted median, and the shaded areas represent the predicted 5th and 95th percentiles. PD, pharmacodynamics; PK, pharmacokinetics; SC, subcutaneous.

FIGURE 5

Population predictions: Relative risk of HAE attack in the adolescent and adult populations by C _{min, ss}. The top graph shows the predicted mean relative risk of an HAE attack, shown as a solid line with an approximate 95% CI in the shaded areas. The bottom graph shows the density of predicted C _min,ss in which the boxplot indicates the 25th, 50th, and 75th percentiles, with whiskers extending to 1.5 × IQR. The dashed line indicates the exposure threshold corresponding to a ≥ 90% reduction in the relative risk of HAE attacks. CI, confidence interval; C _{min, ss}, minimum concentration in the dosing interval at steady state; HAE, hereditary angioedema; IQR, interquartile range.

FIGURE 6

Model‐predicted garadacimab plasma concentrations vs. model‐predicted HAE attack rate over (a) 300 days (~42 weeks) and (b) 4 weeks. The solid lines represent the predicted mean garadacimab concentration after the administration of the loading dose (two 200 mg SC injections) followed by 200 mg once monthly; bars represent predicted mean HAE weekly attack rates with associated 95% CIs. The dashed line shows the therapeutic threshold for C _min,ss at a garadacimab concentration of 6.00 μg/mL. CI, confidence interval; HAE, hereditary angioedema; SC, subcutaneous.