Poster presented: WA-ACEP 2015 Summit to Sound Northwest Emergency Medicine Assembly, Seattle, Washington, USA, April 22-24, 2015. (previously presented at the American Heart Association, Dallas, TX, USA, November 16–20, 2013)

Idarucizumab infusion led to immediate, complete, and sustained reversal of dabigatran anticoagulant activity.

Idarucizumab had no prothrombotic effect as indicated by ETP ex vivo.

Infusion of up to 8 g idarucizumab was well tolerated and showed a positive safety profile, both alone and in combination with dabigatran.

Idarucizumab fulfills the requirements for a fast-acting and specific reversal agent to dabigatran with a favorable safety profile; a Phase III clinical trial with idarucizumab is ongoing.

CONCLUSIONS

ACKNOWLEDGMENTS The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).

The authors received no direct compensation related to the development of the poster.

Writing, editorial support, and formatting assistance for this poster was provided by Daniella A. Babu, PhD, of Envision Scientific Solutions, which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), for these services.

BIPI was given the opportunity to review the poster for medical and scientific accuracy as well as intellectual property considerations.

Disclosures: S. Glund, J. Stangier, M. Schmohl, M. De Smet, D. Gansser, B. Lang, V. Moschetti, S. Norris, and P. A. Reilly are employees of Boehringer Ingelheim, the developer of dabigatran etexilate and idarucizumab; S. Ramael was an employee of SGS Life Science Services, which was contracted by Boehringer Ingelheim for this study.

Idarucizumab, a Specific Reversal Agent for Dabigatran: Immediate, Complete, and Sustained Reversal of Dabigatran Induced Anticoagulation Shown in Healthy Male Volunteers

Stephan Glund1, Joachim Stangier2, Michael Schmohl2, Marina De Smet3, Dietmar Gansser2, Benjamin Lang4, Viktoria Moschetti1, Steven Ramael5, Stephen Norris6, Paul A. Reilly6

1Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss and Ingelheim, Germany; 2Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 3Clinical Operations, SCS Boehringer Ingelheim Comm. V., Brussels, Belgium; 4Clinical Biostatistics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 5Clinical Pharmacology Unit, SGS Life Science Services, Antwerpen, Belgium; 6Clinical Development & Med Affairs, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA

REFERENCES1. Weitz JI, et al. Circulation. 2012;126:2428–2432.

2. Majeed A, et al. Circulation. 2013;128:2325–2332.

3. Glund S, et al. Circulation. 2013;128:A17765.

4. Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151.

Potential conflict of interest may exist. Please

refer to the Acknowledgments and Disclosures.

BACKGROUND and OBJECTIVE

The new oral anticoagulants are effective alternatives for warfarin, but specific reversal agents are not yet available for these agents.

Current options for management of bleeding patients receiving dabigatran treatment include1,2: – Interruption of treatment – Supportive care – Volume replacement/blood product transfusions/prothrombin complex concentrate – Hemodialysis.

A specific reversal agent may provide an additional option for patient management during emergency situations. Idarucizumab, a specific reversal agent for dabigatran, is in Phase III clinical trial (RE-VERSE ADTM); a biologics application has been submitted to the US Food and Drug Administration, and accelerated approval has been requested.

The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses of idarucizumab (Part I), and the effectiveness of idarucizumab in reversing dabigatran anticoagulant activity (Part II).

Study Population The study enrolled healthy male volunteers who met the following criteria:

– Aged 18–45 years – Body mass index 18.5 to 29.9 kg/m2.

Study Design This was a Phase I, randomized, double-blind, placebo-controlled within dose groups proof-of-concept study (NCT01688830).

Dose selection: – 1:1 molar binding of idarucizumab to dabigatran was assumed.3

– Dabigatran etexilate (DE) 220 mg twice daily (bid) was administered in healthy male volunteers to achieve median concentrations equivalent to those observed in the RE-LY® study4 in the patients who were treated with DE 150 mg bid.

– Idarucizumab 2 g (single infusion) was calculated to be equimolar to the total body load of dabigatran after administration of DE 220 mg bid in healthy volunteers.

Part I: Male volunteers (N = 110) were randomized (6:2) to receive single intravenous doses of idarucizumab or placebo:

– A 1-hour infusion was administered to volunteers in each of the 10 groups that were assigned to a different dose of idarucizumab (from 20 mg to 8 g; n = 86).

– A 5-minute infusion was administered to volunteers in each of the 3 groups that were assigned to a dose of 1, 2, or 4 g of idarucizumab (n = 24).

Part II: Male volunteers (n = 35) were randomized (9:3) to receive idarucizumab intravenous infusions or placebo in the presence of dabigatran (Figure 1):

– Volunteers were pre-treated with DE 220 mg bid for 3 days and 1 dose in the morning of day 4. – A 5-minute infusion was administered to volunteers in each of the 3 groups that were assigned to a dose

of 1, 2, or 4 g of idarucizumab.

d1 d2 d3 d4 d5 d6 d7

DE 220 mg bid Idarucizumab/plc IV ~2 hours after day 4 DE morning dose

PK/PD sampling:12-hour profile day 3

PK/PDsampling

3-monthADA follow-up

Figure 1: Study design (Part II)

Endpoints The safety and tolerability of idarucizumab administered alone (Part I) or at steady-state of dabigatran (Part II) was assessed primarily via the reporting of adverse events (AEs).

Assessment of the pharmacokinetics of idarucizumab and dabigatran was a secondary endpoint. Other secondary endpoints included the assessment of pharmacodynamic parameters to evaluate the reversal of dabigatran induced anticoagulation with idarucizumab.

METHODS

AnalysesPharmacokinetics

Idarucizumab concentrations were measured by enzyme-linked immunosorbent assay. Concentrations of dabigatran and unbound dabigatran were measured by high performance liquid chromatography-tandem mass spectrometry:

– For this study, dabigatran refers to the total amount of dabigatran plus the amount of dabigatran metabolites (glucuronides).

– Unbound dabigatran refers to the fraction of dabigatran that is not bound to either idarucizumab or plasma proteins.

Pharmacodynamics Biomarkers of blood coagulation were assessed in parallel to pharmacokinetic sampling.

– Central analysis of dabigatran diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), thrombin time (TT), and endogenous thrombin potential (ETP); dTT and ETP are presented here, and ECT, aPTT, and TT are summarized.

– ETP is a measurement of the potential of a plasma sample to generate thrombin (clotting was initiated with tissue factor); evaluated at pre-dose and 15 minutes after idarucizumab infusion.

Anti-drug antibodies were determined at baseline and up to 3 months post-treatment administration (results are summarized).

Safety Safety analysis was based on the number (%), type, and severity of AEs. The investigators determined whether AEs with idarucizumab or placebo were drug related. Assessments of safety included physical examination, vital signs, 12-lead and continuous electrocardiogram, pO2 monitoring, laboratory tests, and local tolerability.

Statistical Evaluation Safety outcomes and pharmacodynamic endpoints were evaluated descriptively.

Of 145 volunteers, all completed the study per protocol and were included in the pharmacologic and safety analyses.

Pharmacokinetic/Pharmacodynamic AnalysesPharmacokinetics

The mean initial half-life was short, ~45 minutes, and the terminal half-life ranged from a mean of 4.5 to 9 hours (Figure 2).

There was a substantial contribution of renal excretion and catabolism to idarucizumab elimination.

– This is mainly based on the amounts of idarucizumab found in urine and in the literature data on fragment antibody binding.

Dabigatran pre-treatment had no obvious effect on idarucizumab pharmacokinetics.

RESULTS

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DE + 1 g idarucizumab (day 4) (n = 9)DE + 2 g idarucizumab (day 4) (n = 9)DE + 4 g idarucizumab (day 4) (n = 8)

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)Figure 2: Idarucizumab plasma concentration-time curves (geometric mean)

The measurement of unbound dabigatran approximates the amount of pharmacologically active dabigatran in plasma.

Idarucizumab infusion reduced unbound dabigatran concentrations to or below the lower limit of quantification (Figure 3).

Idarucizumab 2 g and 4 g doses resulted in a sustained reduction of mean unbound dabigatran concentrations. Idarucizumab infusion resulted in ~5.5 to 6.5-fold increase in mean dabigatran plasma levels (data not shown).

– At the same time anticoagulant activity of dabigatran was reduced, demonstrating that idarucizumab binding to dabigatran reverses its activity.

Pharmacodynamics

Dabigatran prolonged clotting times as determined by dTT (Figure 4), ECT, aPTT, and TT. Mean clotting times were reversed to baseline immediately after the end of the idarucizumab infusion. Idarucizumab 2 g and 4 g doses resulted in a sustained reduction in dTT.

DE + placebo (n = 9)DE + 1 g idarucizumab (day 4) (n = 9)DE + 2 g idarucizumab (day 4) (n = 9)DE + 4 g idarucizumab (day 4) (n = 8)LLOQ (1 ng/mL)

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Figure 3: Unbound dabigatran concentration after idarucizumab infusion

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Figure 4: Reversal of dabigatran clotting time with idarucizumab

ETP (AUC) Lag time

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Figure 5: Endogenous thrombin potential of idarucizumab

15 minutes after idarucizumab 4 g or 8 g infusions, idarucizumab had no effect on endogenous thrombin formation (Figure 5).

Safety and Tolerability No clinically relevant drug-related AEs or relevant changes in safety parameters were observed in this study. No persistent newly developed anti-drug antibodies or AEs indicative of immunogenic reactions were observed. A dose-dependent, transient increase in urine protein and low-weight proteins was observed:

– Values returned to normal range within 4–12 hours after end of infusion. – These findings suggest saturation of tubular uptake/catabolism processes that mediate the reabsorption of

small (≤ ~70 kilodaltons) proteins from the filtrate.

ADA, anti-drug antibodies; DE, dabigatran etexilate; IV, intravenous; PD, pharmacodynamic; plc; placebo; PK, pharmacokinetic

conc., concentration; DE, dabigatran etexilate

DE, dabigatran etexilate; LLOQ, lower limit of quantification; SD, standard deviation

‘Normal upper reference limit’ refers to (mean+2*SD) of 86 pre-dose measurements from a total of 51 subjects DE, dabigatran etexilate; dTT, diluted thrombin time; SD, standard deviation; SEM, standard error of the mean

AUC, area under the curve; ETP, endogenous thrombin potential