A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A

Abstract

Essentials explorer™3 was a double-blinded, multiple-dose escalation trial of subcutaneous concizumab. A pharmacodynamic relationship for unbound TFPI and thrombin generation was confirmed. No serious adverse events and no anti-drug antibodies were observed. explorer™3 data support further clinical development of concizumab in people with hemophilia. SUMMARY: Background Concizumab is a humanized mAb targeting tissue factor pathway inhibitor (TFPI), leading to enhanced thrombin generation (TG) potential. explorer™3 (NCT02490787) was a phase 1b, double-blind, multiple-dose escalation trial of subcutaneous concizumab in people with severe hemophilia A without inhibitors. Objectives The primary objective was to evaluate safety. Assessments of pharmacokinetics, pharmacodynamics and subcutaneous concizumab immunogenicity were secondary objectives. Patients/Methods Adverse events (AEs), clinical assessments and bleeding episodes were recorded. Plasma concizumab levels and unbound TFPI levels were measured with ELISAs; residual TFPI activity was measured with a chromogenic assay. Standardized assays were used to assess TG, D-dimer and prothrombin fragment 1 + 2 (F ) levels. explorer™3 was completed after investigation of three dose cohorts (0.25, 0.5 and 0.8 mg kg , once every 4 days) had been completed. Twenty-four patients received 12 doses of concizumab or placebo in a 3 : 1 randomization over a 42-day period. Results No serious AEs and no anti-drug antibodies were observed. Fifty-four mild and two moderate AEs were observed in 19 patients. Concizumab exposure increased with dose in a non-linear manner, confirming target-mediated drug disposition. D-dimer and F levels were increased mostly in the highest dose cohort, in line with previous observations. The level of unbound TFPI decreased in a dose-dependent manner, and was accompanied by a residual TFPI activity decrease and an increase in peak TG. Although the trial was not powered to evaluate efficacy, a trend towards lower bleeding rates was observed in patients in the highest dose cohort. Conclusion explorer™3 data support further clinical development of concizumab for use in people with hemophilia, with or without inhibitors.

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data

“…In EXPLORER3, five escalating dose levels of sc concizumab (0.25, 0.5, 0.8, 1.1 and 1.5 mg/kg) were planned, but the trial was finalized after completion of the 0.8 mg/kg cohort based on coagulation and PK parameter changes that were observed in the 0.8 mg/kg cohort, as well as the high inter‐patient variation in the PK parameters and pro‐coagulant response to concizumab in this cohort. No serious adverse events were observed in the completed dose groups . Each patient in EXPLORER3 received the first two doses on two consecutive days to allow steady state to be reached rapidly, followed by subsequent administration once every 4 days.…”

“…No serious adverse events were observed in the completed dose groups. 13 Each patient in EXPLORER3 received the first two doses on two consecutive days to allow steady state to be reached rapidly, followed by subsequent administration once every 4 days.…”

“…In the primary analysis of EXPLORER3, no serious adverse events were seen in the completed cohorts, and a PK/pharmacodynamic (PD) relationship for concizumab dose, free TFPI and thrombin generation was confirmed. 13 Currently, concizumab is being assessed in phase 2 clinical trials in patients with severe haemophilia A without inhibitors (EXPLORER5; NCT03196297), as well as in patients with haemophilia A or B with inhibitors (EXPLORER4; NCT03196284).…”

Origins and organization of the NHLBI State of the Science Workshop: Generating a national blueprint for future research on factor VIII inhibitors

“…Novel non‐factor therapeutics to treat haemophilia in the presence of inhibitors are on the horizon . Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of FVIII, has recently been approved for use in PWHA with or without FVIII inhibitors .…”

“…19 Novel non-factor therapeutics to treat haemophilia in the presence of inhibitors are on the horizon. [20][21][22] Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of FVIII, has recently been approved for use in PWHA with or without FVIII inhibitors. 20,23 Gene therapy approaches are also in clinical development with phase III clinical trials underway for PWHA without inhibitors.…”