Engagement of the STING pathway is involved in spontaneous and treatment-induced anti-cancer immunity. Activation of STING with a specific agonist, as a monotherapy or in combination with anti-PD1 therapy, may be a promising novel anticancer strategy. Here we report the first-in-human results for the STING agonist BI 1387446 alone (Arm A) and in combination with ezabenlimab (Arm B). The phase 1, open-label, multicenter, dose-finding study 1426.1 (NCT04147234) evaluated BI 1387446 ± ezabenlimab in patients with advanced or metastatic solid tumors. In Arms A and B, BI 1387446 was given intratumorally starting at 50 μg (Cycles 1–3: Days 1, 8, 15; Cycle ≥4: Day 1). Patients in Arm B received ezabenlimab 240 mg intravenously on Day 1 in 21-day cycles. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Eligibility criteria included: ECOG PS 0 or 1, ≥1 lesion suitable for injection, and exhausted standard treatment options. Primary endpoint was maximum tolerated dose (MTD) based on number of dose-limiting toxicities (DLTs). Secondary and further endpoints included safety, efficacy, pharmacokinetics, and pharmacodynamics. Overall, 41 patients were treated (Arm A n=26; Arm B n=15). In Arm A, median age was 63 years and 46.2% had ECOG PS 1. In Arm B, median age was 56 years and 73.3% had ECOG PS 1. Maximum BI 1387446 dose was 400 μg in Arm A and 200 μg in Arm B. Median duration of BI 1387446 treatment was 1.8 months and 2.4 months in Arms A and B, respectively. DLTs were reported in 1 patient in Arm A receiving BI 1387446 200 μg (grade 3 fatigue and myalgia). No DLTs were reported in Arm B. The MTD was not reached. Safety and efficacy are summarized in the Table. Best response was stable disease (per RECIST v1.1 Arm A 46.2%, Arm B 53.3%). BI 1387446 monotherapy and in combination with ezabenlimab was well tolerated. MTD for either regimen could not be determined. Table (334/600).

Essentials Idarucizumab, a monoclonal antibody fragment, binds dabigatran with high affinity and specificity. In this phase 1 trial, healthy Japanese males received idarucizumab alone or with dabigatran. Idarucizumab achieved immediate, complete and sustained reversal of dabigatran anticoagulation. Idarucizumab was well tolerated and demonstrated no pro‐coagulant effects.

Idarucizumab, a humanised monoclonal antibody fragment, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a 1-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples. Measures were made before and 15 min after the end of infusion in Caucasian subjects, as well as pre dose, 15 min, 4 h and 8 h in Japanese subjects. The levels of the thrombosis markers D-dimer and prothrombin fragment 1 + 2 (F1.2) were assessed over time in plasma samples up to 72 h after the end of infusion of idarucizumab and placebo. Idarucizumab had no apparent effect on endogenous thrombin formation as measured by CAT. D-dimer and F1.2 levels were highly variable in all dose groups but did not increase when compared with placebo or pre-dose levels. In conclusion, idarucizumab had no effect on endogenous thrombin generation. Additional markers of thrombosis, F1.2 and D-dimer, did not differ between placebo and idarucizumab, indicating a lack of procoagulant properties of idarucizumab.

Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy.

Idarucizumab is a specific reversal agent that rapidly neutralizes dabigatran’s anticoagulant activity [(1–3)][1]. We investigated restoration of dabigatran anticoagulation 24 h after idarucizumab treatment and the safety and effectiveness of a second idarucizumab treatment. Six male and 6

Background Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1: 1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study.Methods In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18.5-29.9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3: 1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2.5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC 2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830.Findings Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2.5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2.5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC 2-12 to day 3 AUEC 2-12 for dTT was 1.01 with placebo, 0.26 with 1 g idarucizumab (74% reduction), 0.06 with 2 g idarucizumab (94% reduction), 0.02 with 4 g idarucizumab (98% reduction), and 0.01 with 5 g plus 2.5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.Interpretation These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress.

SummaryIdarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18–45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ∼45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.Clinical trial registration: http://clinicaltrials.gov/ct2/show/NCT01688830?term=NCT01688830&rank=1 (NCT01688830).

Introduction Oral anticoagulation is an effective therapy to prevent and treat thromboembolic events. So far, Vitamin K antagonists have been the main drug of choice. Recently, the advent of the direct oral anticoagulants (DOAC) has changed medical practice significantly; nevertheless all anticoagulants are associated with an increased risk of bleeding. Bleeding management can be achieved through established therapies; however specific antidotes are not yet available for these agents to further facilitate patient management in cases needed. Previously the dabigatran antidote (idarucizumab) has demonstrated immediate, complete and sustained reversal of dabigatran induced anti-coagulation in healthy male volunteers. In the present study it was determined whether and to what extent doses of up to 5 g idarucizumab would reverse the anticoagulant effects of dabigatran in male and female healthy mid-aged, elderly and renally impaired volunteers. In addition, it was tested whether oral intake of dabigatran etexilate 24 hrs after idarucizumab treatment could restore dabigatran related anticoagulation. It was further tested if a second administration of idarucizumab 2 months later was safe and well tolerated. Methods Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab were investigated in a randomized, double-blind, placebo controlled two-way cross-over study in 46 male and female volunteers. Dabigatran etexilate (DE), 220 mg bid in healthy subjects and 150 mg bid in subjects with mild or moderate renal impairment (CLCR60 to <90 or 30 to <60 [mL/min], respectively) was given over 4 days to achieve the steady state conditions. Idarucizumab doses of 1 g, 2.5 g, 5 g or 5 g given as 2x2.5 g one hour apart were administered as 5 min i.v. infusion 2 hrs after the last dose of DE. Concentrations of unbound dabigatran were determined as a measure of pharmacologically active dabigatran. The anticoagulant effect of dabigatran and its reversal were assessed by coagulation time measurements, including diluted Thrombin Time (dTT, Hemoclot® DTI assay), Ecarin Clotting Time (ECT) and activated Partial Thromboplastin Time (aPTT). Results All administered doses of idarucizumab were safe and well tolerated. PK measurements of unbound dabigatran indicated that idarucizumab binding and thus reversal of the anticoagulant effect of dabigatran occurred immediately after end of infusion. Prolongation of clotting times induced by dabigatran was reversed to baseline at the end of the 5 minute infusion of the antidote. This was consistently demonstrated by all clotting assays. Sustained reversal over the entire observation period was observed for idarucizumab doses of 2.5 g, 5 g and 2x2.5 g. For the 1g dose, there was partial return of dabigatran induced anticoagulation around 2-4 hours after i.v. infusion. Also a second administration of idarucizumab (two months after the first) was safe and resulted in complete reversal. In addition, PD and PK measurements at selected time points and in comparison to placebo treatment confirmed that effective dabigatran anticoagulation could be re-established 24 hours after administration of idarucizumab. Conclusions The dabigatran antidote, idarucizumab, was well tolerated under all conditions tested. The administration of 5 g or 2x2.5 g led to sustained reversal of dabigatran induced anticoagulation in male and female subjects of different age and renal function. In addition, idarucizumab administered 2 months apart achieved the same degree of reversal. Dabigatran anticoagulation could be re-established 24 hrs after idarucizumab dosing. These results support the use of a total dose of 5 g idarucizumab as an effective dose in further clinical testing. Disclosures Glund: Boehringer Ingelheim: Employment. Off Label Use: Idarucizumab, a specific antidote for dabigatran, is in clinical development.. Stangier:Boehringer Ingelheim: Employment. Schmohl:Boehringer Ingelheim: Employment. Moschetti:Boehringer Ingelheim: Employment. Haazen:SGS Life Science Services (contracted by Boehringer Ingelheim to conduct the study): Employment. De Smet:SCS Boehringer Ingelheim Comm. V.: Employment. Gansser:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Lang:Boehringer Ingelheim: Employment. Reilly:Boehringer Ingelheim: Employment.

Introduction: Dabigatran etexilate is an oral direct thrombin inhibitor. Although routine anticoagulation monitoring with dabigatran is not usually required, a simple and precise laboratory test to measure dabigatran concentrations in patient plasma may be useful in certain clinical circumstances, such as emergency situations. The HEMOCLOT (R) Thrombin Inhibitors assay has demonstrated accurate and precise determination of dabigatran concentrations within a range of 50-500 ng/ml. The objective of this study was to assess comparability of dabigatran concentrations determined by HEMOCLOT (R) and by liquid chromatography/tandem mass spectrometry (LC-MS/MS) in plasma samples from human volunteers with end-stage renal disease (ESRD) undergoing regular haemodialysis (HD) during a Phase I study.Materials and Methods: Overall, 304 plasma samples were obtained from seven ESRD patients in dabigatran steady-state for measurement by HEMOCLOT (R) (calibrated diluted thrombin time [dTT]) and by LC-MS/MS. Agreement of dabigatran concentrations was assessed by regression analysis and difference plots.Results: The measurements of calibration standards of the HEMOCLOT (R) assay showed excellent precision with coefficients of variation <5%. Accuracy determined by analysis of two quality control samples was 90% and 111%. HEMOCLOT (R)-derived dabigatran plasma concentrations paralleled those obtained by LC-MS/MS. The mean ratio of the LC-MS/MS and dTT-derived concentrations was 0.955 (67% limits of agreement: 0.771-1.18).Conclusions: The HEMOCLOT (R) Thrombin Inhibitors assay is suitable for measuring dabigatran plasma concentrations in volunteers with ESRD undergoing haemodialysis. The agreement between dabigatran concentrations determined by the HEMOCLOT (R) assay and the LC-MS/MS reference method met bioanalytical acceptance criteria. (C) 2015 Elsevier Ltd. All rights reserved.

INTRODUCTION: The new oral anticoagulants are effective alternatives for warfarin but specific antidotes are not yet available for these agents to manage life-threatening bleeding or when emergency surgery is necessary. A specific antibody fragment (Fab) is being developed which binds dabigatran with high affinity and thereby prevents dabigatran inhibition of thrombin. For the first time in human volunteers, we determined whether equimolar doses of Fab would reverse the anticoagulant effects of dabigatran. METHODS: Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the Fab were investigated in a randomized, double-blind, placebo controlled study in 145 healthy male volunteers. In part I of the study, subjects received single rising i.v. doses of up to 8 g Fab. In part II, Fab doses of 1 g, 2 g and 4 g were administered as 5 min i.v. infusion in the presence of dabigatran (220 mg bid for 4 days). Concentrations of unbound dabigatran were determined as a measure of pharmacologically ac...