ISTH 2017 • • • • • • • PCC, prothrombin complex concentrate; tranexamic TXA, acid. Abbreviations: biomarkers; EB, exploratory PD, pharmacodynamics; PK, ; Figure (A) 1. Study design and (B) schematic of blinded treatments. • • • • Methods • • • • • • • Introduction A Randomized Study of 4-Factor Prothrombin Complex Concentrate and Authors: Jerrold H. Levy, MD Punch Biopsies in Rivaroxaban Treated Subjects With Supratherapeutic Drug Levels After Pharmacodynamics Tranexamic and Generation, , on Acid 5 States; United Jersey, New 1 MS Marcsisin, S. Victoria 343--PB Duke University School of Medicine, Durham, North Carolina, United States; McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada Ontario, Hamilton, Institute, Research Atherosclerosis and Thrombosis and University McMaster td endpoints Study criteria: Inclusion/exclusion This taglineisforinformationonly; 7057 Figur Descriptive statistics of BD and BV values (and change from baseline) and PK and PD The analysis of variance (ANOVA) procedure was used to compare the mean values of The primary endpoints for the statistical analysis were the log-transformed BD and BV – – – study the throughout evaluated were tolerability and Safety Serial blood samples for pharmacokinetics (PK) and pharmacodynamics (PD) A second punch biopsy was performed on Day 4after administration of 4F-PCC, TXA, – After their morning dose on Day 4, subjects were randomized to to 3cohorts receive A baseline punch biopsy was conducted on Day –1 (baseline). Rivaroxaban was given – study 1 phase randomized, parallel-group, double-blind, a was This – The rivaroxaban dosing regimen chosen was 20 mg twice daily (BID) so as to better Objective: to examine the potential utility for of 4F-PCC rivaroxaban and TXA reversal – an antifibrinolyticUse of TXA, agent, has also been suggested in patients with – Recent studies in healthy volunteers have assessed the utility of both 3-factor PCC Currently, there are no therapies approved for reversing oral inhibitors, FXa but Reversal of the of inhibitors FXa effects is important in the event of Oral factor Xa (FXa) inhibitors, including rivaroxaban, are replacing parameters were summarized by treatment group treatment by summarized were parameters BD and BV for the post-treatment over baseline values for each treatment group. group treatment each for values hours for PK and up to 168 hours for PD assessments were collected after rivaroxaban administration on Day 4for up to 72 were measured (BV) volume (BD) bleeding duration and Bleeding dose. rivaroxaban final the after or saline control no earlier than 4hours and no later than 4hours and 15 minutes or saline4F-PCC, ( TXA, meal on Days 1through 3, to achieve steady state (SS) at adose of 20 mg every 12 hours within 30 minutes after starting astandardized the elderly or in patients with renal impairment) mimic reversal when potentially higher levels of rivaroxaban might be found (eg, in volunteers healthy in bleeding rivaroxaban-associated rivaroxaban of effects anticoagulant the reverse to 4F-PCC and purpose this for suggested 4-factor prothrombin concentrate (4F-PCC) and tranexamic have acid (TXA) been bleeding relevant clinically indications thromboembolic many for warfarin as such antagonists DO NOTPRINT Exploratory endpoints included levels of factors (FII, FVII, FIX, The secondary endpoint was the PK of rivaroxaban at SS, along with the safety The primary endpoints to assess the on of rivaroxaban 4F-PCC effects and TXA at Subjects received 50 International Units (IU)/kg 4F-PCC at amaximum rate Healthy men or women, 18 to 55 years of age, with body mass index (BMI) This regimen also covered the exposures expected with the BID 15-mg dosing Although in reversing of the TXA efficacy anticoagulant is unclear, effects is TXA Results demonstrated partial to complete reversal of the of rivaroxaban effects thrombin-antithrombin complexes (TAT) complexes thrombin-antithrombin generation, including levels of prothrombin fragment 1.2 (F1.2), D-dimer, and ProteinFX, and C, Protein S) and biomarkers reflective of increased thrombin rivaroxaban of tolerability and biopsy punch a wereSS bleeding variables (BD and BV) and PD parameters (PT and ETP) following intravenously all of 210 IU/min administered or 1.0 gTXA over 10 minutes or saline control, (aPTT) time thromboplastin of 18 to 30 kg/m (PE) embolism pulmonary regimen used in the initial treatment of acute deep vein thrombosis (DVT)/ surgery and in those with trauma well tolerated and has been shown to reduce blood loss in patients undergoing reversal rivaroxaban for PCC of utility potential the for support initial on prothrombin time (PT) and endogenous thrombin potential (ETP), providing e 1draft1.4 B A Randomization riv (las Explor Biomark ar Baseline 20 mg PD & t dose) ox Da ator aban er y –1 y s Baseline biop punch riv Times basedon 2 , normal renal function, and normal PT and activated partial partial activated and PT normal and function, renal normal , sy ar Jerrold Levy Management ofBleeding&Trauma ox Figure 1 Figure Pr Da A B C aban dose: e-dose/Tr y 1toDa Riv 20 mgBID (4-F (4-F Saline Con Saline Con ar 4-F ox actor PCC) actor PCC) actor PCC aban ) ough PK 3 y 3 University of Pittsburgh, Pittsburgh, Pennsylvania, United States; United Pennsylvania, Pittsburgh, Pittsburgh, of University Study 3 hr PK, PD tr tr Pr 3 infusion ol ol End of Riv e-dose , 45min 20 mgBID (comple ar , EB ox Pa punch biop (4 hr Da Adminis Po aban y 4 rt 2,Da te st , 15min) -dos d by4hrpos Saline Con Saline Con tr ation of:PCC,TX e 2 sy PK, PD Po (TXA) (TXA) ; Jay Ariyawansa, MS TXA st Da y 4 -dos infusion End of , EB y 5toDa 4 hr t las tr tr e ol ol t ri 1 ; Kenneth T. 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• • • Results (BV) mean ratio post-infusion vs baseline. vs (BV) post-infusion ratio mean (saline control) (Group C) on (A) bleeding duration (BD) and (B) bleeding volume Figure of treatment Effect 2. with (Group 4F-PCC (Group A), TXA B), or placebo Error bars represent 95% confidence intervals. represent 95%Error bars confidence Abbreviations: 4F-PCC, 4-factor prothrombin complex concentrate; tranexamic TXA, acid. a t concentration; CV, coefficient of variance; PK, pharmacokinetics; SD, standard deviation; steady SS, state; (AUC (t) SS at interval dosing a during curve 4F-PCC, 4-factor prothrombin complex concentrate; AUC concentrate; complex prothrombin 4-factor 4F-PCC, AUC t C C Parameter PK at Steady State (PK Data Analysis Set) Rivaroxaban of Parameters Pharmacokinetics of Table Summary 2. All subjects who received at least 1dose of rivaroxaban were included in the safety analysis set. acid. tranexamic TXA, deviation; SD, standard Abbreviations: 4F-PCC, 4-factor prothrombin complex concentrate; BMI, body mass index; BMI, kg/m Weight, mean kg, (SD) (SD) mean years, Age, Non-Hispanic/Latino Hispanic/Latino % Ethnicity, Asian Black/African American White Race, % Male Female % Sex, Set) Analysis (Safety Table Characteristics Baseline and Demographic 1. Median (min-max). Median max,ss max,ss max,ss trough This taglineisforinformationonly; 2 7057 Figur Mean trough plasma concentration values demonstrate that rivaroxaban reached SS – – – BD and BV: Subject characteristics were comparable between the ( 3cohorts theOf 147 subjects enrolled (49 in each of the 3cohorts), 145 (98.6%) completed Day 4are presented in concentrations by Day 3of the study. Plasma PK parameters for rivaroxaban at on SS the study the , time to maximalconcentration at steady state. τ,ss ; Jeffrey I. Weitz, MD , h , ng/mL , , ng/mL , , ng, DO NOTPRINT a The majority of subjects enrolled were male (70.1%) and white (66.0%), with a Compared with saline control, there were no differences observed in either the The mean values for BD on Day 4represented slightly less than adoubling of the median age of 28.0 years and amean BMI of 25.0 kg/m baseline adjusted BD or BV after receiving ( 4F-PCC and TXA generally consistent with the BD changes for all 3treatment groups mean baseline (Day –1) BD values for all treatment groups. The BV changes were 2 B A e 2draft1.2  Janssen Pharmaceuticals, Janssen Scientific Affairs, Titusville, Titusville, Affairs, Scientific Janssen Pharmaceuticals, Janssen 2 h/mL

BV Mean Ratio, % BD Mean Ratio, % , mean (SD) Post to Baseline Post to Baseline 300 300 100 150 200 250 100 150 200 250 50 50 0 0 2 ; Matthew D. Neal, MD Mean 2,217 130 351 4F-PCC (Group4F-PCC A) 3.75 (1.00-4.50) Rivaroxaban + + Rivaroxaban Table 2 Table 4F-PCC 4F-PCC n =48 4 30.2 645 121 SD University of Vermont, Burlington, Vermont, United States; Rivaroxaban Rivaroxaban 76.0 (11.9)76.0 (Group A) (Group 25.4 (3.0) 25.4 29.8 (9.6) 29.8 + 4F-PCC + 4F-PCC t SS DOI: 10.3252/pso.eu.ISTH2017.2017 n =49 30.6 14.3 24.5 79.6 69.4 69.4 ); C ); CV% 40.6 34.6 29.1 0 max,ss Tr Tr eatment Gr eatment Gr , maximal concentration at steady state; C

Mean 2,357 Rivaroxaban + TXA TXA + Rivaroxaban 131 375 TXA TXA τ,ss 3.00 (2.00-4.60) 3.00 Rivaroxaban Rivaroxaban , area under the plasma concentration-time 72.8 (12.2)72.8 31.0 (10.3) 31.0 (Group B) (Group 24.3 (3.1) 24.3 5 (Group B) (Group n =49 + TXA + TXA oup oup 30.6 22.4 91.8 71.4 69.4 n =48 2.0 6.1 32.2 104 602 SD

CV% Saline Saline 25.6 41.0 27.8 Rivaroxaban Rivaroxaban 2 76.4 (11.8)76.4 + Placebo Placebo + (Group C) (Group 25.4 (3.2) 25.4 29.8 (9.5) n =49 28.6 71.4 83.7 32.7 57.1 Figure 2 Figure Mean 8.2 2.0 2,178 Comple Comple 344 130 Table 1 Table Placebo (GroupPlacebo C) 3 4.25 (1.00-5.02) 4.25 ; David Schneider, MD David ; Rivaroxaban + + Rivaroxaban te te

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n =49 ) 96.5 26.5 ) 522 SD trough 75.1 (12.0)75.1 rs rs 30.2 (9.8) 25.0 (3.1) 25.0 N =147 al al Total , trough trough , 66.0 85.0 26.5 29.9 70.1 1.4 9.5 Poster Monday, July 10 CV% 28.0 23.9 34.7 ISTH2017

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on 4F-PCC (Group4F-PCC (Group A), TXA B), and placebo (saline control) (Group C). potential (ETP) mean on absolute values baseline change treatment from for with Figure 3. Time course of (A) prothrombin time (PT) and (B) endogenous thrombin Haemostasis (ISTH); July 8-13, 2017; Berlin, Germany. Abstract PB 343. PRESENTED AT: 2017 Congress of the International on Society Thrombosis and [email protected] contact: E-mail Vinay We thank Inc. Pharmaceuticals, Janssen by provided was assistance editorial medical for support Financial Acknowledgments Ionis Pharmaceuticals, Janssen, Merck, Portola, Novartis, and Pfizer. JIW is aconsultant for and received honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, JA is employed by Janssen. VSM is employed by Janssen. DS received grant and honorarium from Janssen. MDN receives research support from Janssen and is aconsultant/scientific advisor for Janssen and Behring. CSL is employedKTM by Janssen. Ingelheim, Behring, CSL Grifols, Instrumentation Laboratories, Janssen, Leading Biosciences, and Pfizer. JHL serves on research steering committees, data safety monitoring boards, and/or advisory boards for Boehringer- This research was supported by Janssen Scientific Affairs, LLC. Disclosures and Funding 4. 3. 1. References • • ETP: • PT: • concentration-time tranexamic curve; TXA, acid; TGA, thrombin generation assay. plasma the under area AUC, concentrate; complex prothrombin 4-factor 4F-PCC, Abbreviations: 2. This t

7057 Figur : • • • • Conclusions agline isf at B A Pasupuleti, – All treatments were well tolerated Following the infusion of 4F-PCC, F1.2 levels increased, whereas D-dimer levels did – – – – prothrombin complex concentrate.prothrombin complex Zahir H, Brown Vandell KS, et al. A, Edoxaban on bleeding effects following punch biopsy and reversal by a4-factor Cochrane Database Syst Rev. Perel P, Ker K,Morales Uribe CH, et al. Tranexamic acid for reducing in emergency mortality and urgent surgery. 2014;12(9):1428-1436. prothrombin concentrate. complex factor Barco S, Whitney Cheung Y, Coppens M, et al. In vivo reversal of the anticoagulant of rivaroxaban effect with four or salineof TXA control (data not shown) not. In contrast, the levels of F1.2 and D-dimer were unchanged after administration concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. volunteers. healthy in rivaroxaban of effects anticoagulant the of reversal regarding concentrates Levi M, Moore KT, Castillejos CF, et al. Comparison of three TGA (ETPAUC) DO NO Additional studies assessing the utility of 4F-PCC alone or in combination with – Interestingly, however, our data are not in agreement with arecent report The clinical relevance of these findings is uncertain; nevertheless, the PD changes – – This study demonstrates that neither reverses 4F-PCC nor TXA punch biopsy punch biopsy model as well as other bleeding models may be warranted on bleedingTXA associated with lower therapeutic doses of rivaroxaban in this biopsy bleeding in subjects given edoxaban, another oral inhibitor FXa wherein the same dose of 4F-PCC as used in the present study attenuated punch observed with 4F-PCC administration are consistent with previous studies rivaroxaban of doses supratherapeutic receiving subjects in bleeding or info

e 3dr T PRINT There were no discontinuations because of adverse events and no deaths or Following the infusion of 4F-PCC, fully ETP reversed, whereas had no effect TXA Following the administration of rivaroxaban 20 mg BID, with the final dose on the Following the infusion of 4F-PCC, partially PT reversed, whereas had no TX effect Following the administration of rivaroxaban 20 mg BID with the final treatment-emergent serious adverse events adverse treatment-emergent serious ( morning of Day 4, values ETP decreased in all 3treatment groups ( groups treatment 3 all dose on the morning of Day 4, the maximum value PT increased for Mean Absolute Values, nmol/L*second PT Mean Absolute Values, seconds Figure 3, Panel B Figure 3, Panel A 100 rmaon only; 20 40 60 80 15 20 25 Differences in dosing regimens of supratherapeutic rivaroxaban versus versus rivaroxaban supratherapeutic of regimens dosing in Differences Although 4F-PCC partially reversed and PT completely reversed ETP, Neither had 4F-PCC any nor on BD TXA effect or BV divergence therapeutic edoxaban (60 mg) could provide one explanation for this TXA did not affect these variables these affect not did TXA a 1.4

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