PS110 GSTM1 Null Genotype Isn’t Associated With Increased Risk of Chronic Heart Failure Among Patients With Diabetes Mellitus

Abstract

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.The primary objective was to evaluate safety. Assessments of pharmacokinetics, pharmacodynamics and subcutaneous concizumab immunogenicity were secondary objectives.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 (F1 + 2) levels. explorer™3 was completed after investigation of three dose cohorts (0.25, 0.5 and 0.8 mg kg−1, 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.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 F1 + 2 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.explorer™3 data support further clinical development of concizumab for use in people with hemophilia, with or without inhibitors.