Concizumab plasma concentration measurements for personalized dose adjustment in patients with Hemophilia A/B with and without inhibitors: Data from the Phase 3 explorer7 and explorer8 studies

Abstract Background Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody intended for patients with hemophilia A or B, with or without inhibitors. It is approved in the US, Europe and other countries for once-daily, subcutaneous prophylaxis in hemophilia A or B with inhibitors. Aim Describe the observed and modelled pharmacokinetics (PK) and bleeding outcomes from one-time concizumab dose adjustments in phase 3 concizumab studies. Methods In two prospective, multicenter, open-label, phase 3 concizumab studies, explorer7 (patients with inhibitors; NCT04083781) and explorer8 (patients without inhibitors; NCT04082429), male patients aged ≥12 years were randomized 1:2 to no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or allocated to non-randomized concizumab prophylaxis (arms 3 and 4). Following a study pause due to non-fatal thromboembolic events in 3 patients receiving concizumab, a revised dosing regimen was implemented with a 1.0 mg/kg loading dose on the first day of treatment, followed by an initial daily dose of 0.20 mg/kg. At week 4, concizumab plasma concentrations were measured with a clinical trial enzyme-linked immunosorbent assay for potential one-time dose adjustments to set the maintenance dose. The dose was increased to 0.25 mg/kg if concizumab plasma concentration was <200 ng/mL, decreased to 0.15 mg/kg if >4,000 ng/mL, or maintained at 0.20 mg/kg if between 200–4,000 ng/mL. Population PK modeling was used to simulate concizumab exposure and response. Efficacy outcomes based on dose adjustments from the primary analysis (explorer7) or confirmatory analysis (explorer8) cut-offs are presented. Results A total of 281 patients were assigned to one of four arms in explorer7 and explorer8 (62.3% White, 28.1% Asian, 4.6% Black/African American, 2.1% American Indian/Alaska native, 2.5% not reported, 0.4% other). Concizumab plasma concentration was measured in 218 of 226 concizumab-exposed patients in arms 2–4; 8 patients withdrew before maintenance doses were reported. Of the 218 patients measured, 153 (70.2%) continued with a maintenance dose of 0.20 mg/kg, 55 (25.2%) patients adjusted to 0.25 mg/kg and 10 (4.6%) patients adjusted to 0.15 mg/kg. The majority of patients (70.2%) had concizumab plasma concentrations between 200–4,000 ng/mL at week 4 and continued with maintenance dose at 0.20 mg/kg; mean concizumab plasma concentration in this group were 629 ng/mL and 608 ng/mL at week 4 and week 12, respectively. The proportion of patients with concizumab plasma concentrations <200 ng/mL at week 4 and adjusted to 0.25 mg/kg was 25.2%, consistent with the population model prediction of 21%. After dose adjustment to 0.25 mg/kg, the mean concizumab plasma concentration in the <200 ng/mL group increased from 119 ng/mL to 296 ng/mL from week 4 to week 12. The proportion of patients with concizumab plasma concentrations >4,000 ng/mL at week 4 and adjusted to 0.15 mg/kg was 4.6%, lower than the model prediction of approximately 10%. After dose adjustment to 0.15 mg/kg, the mean concizumab plasma concentration decreased from 5,525 ng/mL to 766 ng/mL from week 4 to week 12. Post-dose adjustment concizumab plasma concentrations aligned with modelled predictions. Based on simulated efficacy outcomes in the <200 ng/mL group, increasing the daily maintenance dose to 0.25 mg/kg would reduce the predicted annualized bleeding rate (ABR). Consistent with modelled predictions, observed mean ABR within the <200 ng/mL group was lower after dose adjustment vs before dose adjustment: 3.8 (standard deviation [SD]: 8.2; mean observation period 262 days) vs 7.2 (SD: 10.4; mean observation period 64 days), respectively. Mean ABR in the <200 ng/mL group after dose adjustment was similar to the 200–4,000 ng/mL group (3.1; SD: 6.5; mean observation period 287 days). For patients with >4,000 ng/mL plasma concizumab, observed mean ABR after dose adjustment was 3.8 (SD: 4.8; mean observation period 340 days), similar to the 200–4,000 ng/mL group (3.1; SD: 6.5; mean observation period 287 days). Conclusions These findings support the use of concizumab plasma concentration-guided dose adjustments to optimize prophylaxis in patients with hemophilia A or B, with or without inhibitors. Exposure-response analyses confirmed the validity of the selected lower (200 ng/mL) and upper (4,000 ng/mL) limits of concizumab plasma concentration and showed that dose adjustments can effectively personalize therapy to reduce bleeding rates.