Edoxaban. Domenico Prisco Dipartimento di Medicina Sperimentale e Clinica Università di Firenze SOD Patologia Medica, AOU Careggi, Firenze

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1 Edoxaban Domenico Prisco Dipartimento di Medicina Sperimentale e Clinica Università di Firenze SOD Patologia Medica, AOU Careggi, Firenze Bologna 8 novembre 2013 Disclosures: DP has received research support and honoraria by GSK, Bayer, Daiichi Sankyo, BMS, Boehringer Ingelheim

2 What does the name Edoxaban mean? EDO Xa BAN 2

3 Features of novel oral anticoagulants Dabigatran 1 Rivaroxaban 1,2 Apixaban 1,3 Edoxaban 4 6 Target IIa (thrombin) Xa Xa Xa Hours to Cmax CYP metabolism None 32% Minimal <4% Bioavailability 6% 80% 60% 62% Transporters P gp P gp/bcrp P gp/ BCRP P gp Protein binding 35% 93% 87% 50% Half life h (BD) 7 11 h (QD/BD) 8 15 h (BD) 8 10 h (QD) Renal elimination 80%* 33% # 25% # 35% # BCRP, breast cancer resistance protein CYP, cytochrome P450; P-gp, P-glycoprotein NR, not reported * Of absorbed substance # Of ingested substance 1. Eriksson et al. Clin Pharmacokinet 2009;48:1-22; 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011; 3. ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK; 4. Ruff et al. Hot Topics in Cardiology 2009;18:1-32; 5. Matsushima et al. Am Assoc Pharm Sci 2011; abstract; 6. Ogata et al. J Clin Pharmacol 2010;50:743-53

4 A single 60 mg dose of edoxaban inhibits thrombin generation for >24 hours in HV 40 Mean change from baseline thrombin (mean ± SD) (A) Edoxaban (B) Enoxaparin Time (Hours Post Dose) Mendell J et al. The effect of administration of edoxaban with enoxaparin or 12 hours post-enoxaparin on the pharmacokinetics, pharmacodynamics, and tolerability of edoxaban. Presented at 21 st International Congress on Thrombosis; Jul 6-9, 2010; Milan

5 Phase II data Atrial Fibrillation

6 Edoxaban study 018: Dose Finding Study in Atrial Fibrillation Study design: Randomized, double blind edoxaban dose regimens, open label warfarin, parallel treatment groups Primary Objective: Evaluation of safety of four fixed dose regimens of Edoxaban vs. Warfarin in patients with atrial fibrillation (CHADS 2 2) Primary endpoints: Occurrence of major and/or clinically relevant non major bleeding, elevated hepatic enzymes and/or bilirubin Edoxaban 30 mg QD Edoxaban 60 mg QD Screening Edoxaban 30 mg BID Edoxaban 60 mg BID* Follow up assessment N= days Day 1 Active control (Warfarin, INR ) 3 month randomized treatment period +30 days after last dose *Stopped prematurely QD, once daily; BID, twice daily; INR, International Normalized RatioWeitz et al. Thromb Haemost 2010;104:

7 Edoxaban study 018: major and clinically relevant non major bleeding 12 ** Bleeding incidence (%) * 0 Warfarin Edoxaban 30 mg QD Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID n/n 8/250 7/235 11/234 19/244 19/180 *p<0.05, **p<0.01, vs warfarin QD, once daily; BID, twice daily Weitz et al. Thromb Haemost 2010;104:633-41

8 Edoxaban phase II dose finding study in atrial fibrillation: exposure and bleeding C max AUC C min ng/ml Ng*h/mL ng/ml QD 60 QD 30 BID 60 BID 30 QD 60 QD 30 BID 60 BID 0 30 QD 60 QD 30 BID 60 BID AUC, area under the plasma concentration-time curve from 0 to 24 hours at steady-state; C max, maximum steady-state plasma concentration; C min, minimum steady-state concentration; QD, once daily; BID, twice daily Bleeding incidence, % QD Edoxaban 60 QD 30 BID 60 BID Weitz et al. Thromb Haemost 2010;104:633-41

9 C min,ss is best predictor of bleed probability Probability of all bleeds mg QD 60 mg QD 30 mg BID 60 mg BID AUC, area under the plasma concentration-time curve from 0 to 24 hours at steady-state C max, maximum steady-state plasma concentration C min, minimum steady-state concentration P-gp, P-glycoprotein PRT-018 observed C max AUC C min Predicted incidence C min,ss most closely matched observed bleeding 1,2 Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg oncedaily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors in the ENGAGE AF-TIMI 48 trial 2 1. Giugliano RP et al. Presented at ISTH congress 2009, Boston, USA 2. Salazar et al. Thromb Haemost 2012;107. Epub ahead of print

10 Impact of renal impairment and concomitant P glycoprotein inhibitors on edoxaban exposure C min,ss ratio 50% 20% Increase in exposure CL CR 80 ml/min CL CR 50 ml/min CL CR 30 ml/min Keto, ketoconazole; Quin, quinidine; Ery, erythromycin; Amio, amiodarone; Verap, verapamil; CL CR, creatinine clearance; C min, ss, trough concentration at steady state. Salazar et al. Thromb Haemost 2012;107:

11 Simulation of dosage adjustment scenarios for Phase III subpopulations Without dose adjustment With dose adjustment 0.14 Incidence of all bleeding events All bleeds rate in warfarin group 0.00 Base 60 mg Renal Verap Ren+Ver Renal Verap Ren Ver 60 mg od 30 mg od **Horizontal yellow line denotes observed all bleeds rate in NCT (study 018, dose finding) warfarin group od, once daily Salazar et al. Thromb Haemost 2012;107:

12 Edoxaban Phase III development programme VTE prophylaxis orthopaedic surgery Stroke prevention in atrial fibrillation VTE Treatment / secondary prophylaxis JAPAN / ASIA GLOBAL GLOBAL

13 HOKUSAI VTE Great Wave at Kanagawa. Katsushika Hokusai (25.4 x 37.1 cm) color woodblock print from Hokusai's series Thirty-six Views of Mount Fuji, which are the high point of Japanese prints. The Hokusai-VTE Investigators. N Engl J Med 2013 Hokusai-VTE clinical study protocol. Version 5.0, 16 April Daiichi Sankyo

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15 N=8, sites in 37 countries Hokusai VTE: study design Randomized, double blind, event driven study Edoxaban 60 mg (30 mg) * Objectively confirmed VTE Stratified randomization: DVT / PE Dose of edoxaban Risk factors R Sham INR INR All patients followed for 12 months regardless of treatment duration Day 1 5 Day 6 12 Warfarin (INR ) 3 mo 12 mo Edoxaban Placebo Edoxaban Warfarin Placebo Warfarin Low molecular weight heparin / UFH *Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding due to potential overanticoagulation by predefined criteria During days 6 12 edoxaban or placebo edoxaban was started once heparin was stopped Raskob et al. J Thromb Haemost 2013;11: The Hokusai-VTE Investigators. N Engl J Med 2013

16 Dosing regimens in Hokusai VTE Edoxaban dose was 60 mg once daily with or without food Edoxaban dose was halved to 30 mg once daily with or without food At randomization: Permanent: CrCl ml/min Body weight 60 kg Temporary: Concomitant potent P gp inhibitor use, only while on these medications: quinidine, verapamil During study: Permanent: CrCl ml/min and >20% drop from baseline Body weight 60 kg and >10% drop from baseline Temporary: Concomitant potent P gp inhibitor use, only while on these medications: quinidine, verapamil, erythromycin, azithromycin, clarithromycin, ketoconazole, itraconazole The Hokusai-VTE Investigators. N Engl J Med 2013 Hokusai-VTE clinical study protocol. Version 5.0, 16 April Daiichi Sankyo

17 Flexible treatment duration Prior to study start investigators chose a target length of therapy based on guidelines 1 Study start Minimum treatment period After 3 months, proposed treatment period could be varied by investigator based on patient s clinical features: risk of recurrent VTE, risk of bleeding, patient s preference 2 3 months >3 12 months 1. Hokusai VTE clinical study protocol. Version 5.0, 16 April Daiichi Sankyo Inc 2. Raskob et al. J Thromb Haemost 2013;11:

18 Efficacy and safety outcome measures Primary efficacy: symptomatic recurrent VTE Defined as composite of DVT, non fatal or fatal PE during the 12 month period Principal safety: clinically relevant bleeding Defined as composite of major or clinically relevant nonmajor bleeding during treatment or within 3 days of stopping or interrupting study treatment All primary efficacy and principal safety outcomes were adjudicated by a Clinical Events Committee Raskob et al. J Thromb Haemost 2013;11:

19 Inclusion criteria Inclusion criteria Adult ( 18 years) patients presenting with acute symptomatic DVT involving the popliteal, femoral or iliac veins, or acute symptomatic PE, or both, confirmed by appropriate diagnostic imaging Raskob et al. J Thromb Haemost 2013;11: The Hokusai VTE Investigators. N Engl J Med 2013

20 Characteristic Mean age (years±sd) Age 75 years, n (%) Overall patient characteristics Edoxaban (N=4118) 55.7± (13.6) Warfarin (N=4122) 55.9± (13.2) Male sex, n (%) 2360 (57.3) 2356 (57.2) Weight, n (%) 60 kg >60 kg >100 kg Creatinine clearance, n (%) ml/min >50 ml/min Patients dosed with 30 mg edoxaban (or placebo) at randomization, n (%) Race, n (%) Caucasian Asian Black or African American Other SD=standard deviation 524 (12.7) 3594 (87.3) 611 (14.8) 268 (6.5) 3850 (93.5) 519 (12.6) 3603 (87.4) 654 (15.9) 273 (6.6) 3849 (93.4) 733 (17.8) 719 (17.4) 2867 (69.6) 866 (21.0) 156 (3.8) 220 (5.3) 2895 (70.2) 861 (20.9) 144 (3.5) 215 (5.2) The Hokusai-VTE Investigators. N Engl J Med 2013;

21 Characteristic Overall patient characteristics (cont.) Causes of DVT or PE, n (%) Unprovoked Temporary risk factor * History of cancer Active cancer Previous VTE Actual duration of treatment with study drug, n (%) 3 months >3 to 6 months >6 months 12 months Edoxaban (N=4118) 2713 (65.9) 1132 (27.5) 378 (9.2) 109 (2.6) 784 (19.0) 485 (11.8) 1076 (26.1) 2557 (62.1) 1661 (40.3) Warfarin (N=4122) 2697 (65.4) 1140 (27.7) 393 (9.5) 99 (2.4) 736 (17.9) 528 (12.8) 1084 (26.3) 2510 (60.9) 1659 (40.2) Duration of study drug, mean days±sd / median 250.3±111.8 / ±112.6 / 261 Total patient years on study drug Total patient years of follow up off study drug * Temporary risk factors include: recent surgery, trauma, immobilization or estrogen use SD=standard deviation The Hokusai-VTE Investigators. N Engl J Med 2013;

22 Treatment The median duration of heparin treatment after randomization was 7 days Overall treatment duration was similar between the two groups 250.3±111.8 days (mean±sd) for edoxaban treated patients 248.4±112.6 days for warfarin treated patients Adherence to edoxaban was 80% in 99% of patients as measured by pill counts The INR was in the therapeutic range for 63.5% of the time, above 3.0 for 17.6% of time, and below 2.0 for 18.9% of time The Hokusai-VTE Investigators. N Engl J Med 2013

23 Kaplan Meier curves of efficacy outcomes overall analysis Edoxaban Warfarin Overall On Rx TTR : 63.5% Number at Risk: Edoxaban Overall Warfarin Overall Edoxaban On-tx Warfarin On-tx The Hokusai-VTE Investigators. N Engl J Med 2013

24 Primary efficacy outcome (recurrent VTE) Outcome All patients, n (%) Overall study period On treatment period Edoxaban (N=4118) 130 (3.2) 66 (1.6) Warfarin (N=4122) 146 (3.5) 80 (1.9) Patients with index DVT, n (%) 2468 (59.9) 2453 (59.5) Overall study period On treatment period 83 (3.4) 48 (2.0) 81 (3.3) 50 (2.0) Patients with index PE, n (%) 1650 (40.1) 1669 (40.5) Overall study period On treatment period 47 (2.8) 18 (1.1) 65 (3.9) 30 (1.8) Relative risk (95% CI) 0.89 ( ) * 0.82 ( ) * 1.02 ( ) 0.96 ( ) 0.73 ( ) 0.60 ( ) * P<0.001 for non inferiority The Hokusai-VTE Investigators. N Engl J Med 2013

25 Efficacy outcomes Subgroup analysis: 30 mg # Characteristic Edoxaban (N=733) Warfarin (N=719) Relative risk (95% CI) Efficacy Recurrent VTE 22 (3.0) 30 (4.2) 0.73 ( ) # At randomization and for overall (12-month) treatment period regardless of treatment duration The Hokusai-VTE Investigators. N Engl J Med 2013

26 Cumulative Event Rate (%) Kaplan Meier curves of principal safety Edoxaban Warfarin outcome Time to Event (days) Number of patients at risk warfarin edoxaban The Hokusai-VTE Investigators. N Engl J Med 2013

27 Principal safety outcomes Patients (%) HR 0.81, 95% CI, P=0.004 for superiority HR 0.80, 95% CI, % P=0.004 for superiority 8.5% 8.9% 7.2% HR 0.84, 95% CI, P=0.35 for superiority 1.4% 1.6% The Hokusai-VTE Investigators. N Engl J Med 2013

28 Other safety outcomes Outcome Adverse events, n (%) Any treatment emergent event Any serious adverse event (SAE) Any SAE leading to permanent discontinuation Any drug related AE leading to permanent discontinuation Death, n (%) overall study period VTE related Myocardial infarction Ischemic stroke Other cardiac death Cancer Infectious disease Other Edoxaban (N=4118) 2821 (68.5) 503 (12.2) 121 (2.9) 41 (1.0) 132 (3.2) Warfarin (N=4122) 2928 (71.0) 544 (13.2) 105 (2.5) 51 (1.2) 126 (3.1) The Hokusai-VTE Investigators. N Engl J Med 2013; Daiichi Sankyo, data on file.

29 Cardiovascular events On treatment period, n (%) Edoxaban (N=4118) Warfarin (N=4122) Acute coronary event Cerebrovascular event Systemic embolism 20 (0.5) 26 (0.6) 4 (<0.1) 13 (0.3) 26 (0.6) 0 (0.0) 30 day post study treatment period Edoxaban (N=4061) Warfarin (N=4077) Acute coronary event Cerebrovascular event Systemic embolism 1 (<0.1) 2 (<0.1) 1 (<0.1) 3 (<0.1) 8 (0.2) 2 (<0.1) The Hokusai-VTE Investigators. N Engl J Med 2013

30 Liver function tests On treatment period, n (%) Edoxaban n/n (%) Warfarin n/n (%) ALT 3x ULN 81/3901 (2.1) 90/3903 (2.3) ALT 5x ULN 26/3901 (0.7) 28/3903 (0.7) ALT or AST 3x ULN + bilirubin 2x ULN 9/3878 (0.2) 4/3865 (0.1) ALT or AST 3x ULN+ concurrent bilirubin 2x ULN 6/3878 (0.2) 3/3865 (<0.1) Number of subjects with events satisfying Hy s Rule per adjudication (pure drug effect) 0/3878 2/3865 (<0.1) Liver failure 0/4118 1/4122 ALT=alanine transaminase; AST=aspartate transaminase; ULN=upper limit of normal The Hokusai-VTE Investigators. N Engl J Med 2013

31 Safety outcomes Subgroup analysis: 30 mg Characteristic Safety Primary: First major or clinically relevant non major bleeding, n (%) Edoxaban (N=733) Warfarin (N=719) Relative risk (95% CI) 58 (7.9) 92 (12.8) 0.62 ( ) Major bleeding, n (%) 11 (1.5) 22 (3.1) 0.50 ( ) Clinically relevant non major bleeding, n (%) 47 (6.4) 70 (9.7) The Hokusai-VTE Investigators. N Engl J Med 2013

32 Subgroup of patients with pulmonary embolism

33 Primary efficacy outcome (recurrent VTE) HR= % CI P<0.001 * 3.5% 3.2% HR= % CI % 3.3% HR= % CI % HR= % CI P<0.001 * 1.6% 1.9% HR= % CI %2.0% 2.8% HR= % CI % 1.1% * for non-inferiority The Hokusai-VTE Investigators. N Engl J Med 2013; e-pub ahead of print

34 Subgroup analysis in PE patients with NT probnp 500 pg/ml HR=0.52 (95% CI, ) 6.2% 3.3% 15/454 30/484 The Hokusai-VTE Investigators. N Engl J Med 2013

35 Subgroup analysis in Hokusai VTE Approximately 90% of PE patients had a baseline NT probnp level measured In PE patients with NT probnp levels 500 pg/ml recurrent VTE occurred in 15 of 454 patients (3.3%) who received edoxaban and in 30 of 484 patients (6.2%) given warfarin (HR 0.52 [ ]) Of the 1002 random sample of patients measured by CT, approximately 35% had RV dysfunction Similar results were observed in patients with RV dysfunction on CT as in those with NT probnp levels 500 pg/ml (HR 0.42 [ ]) The Hokusai-VTE Investigators. N Engl J Med 2013

36 NOAC VTE trials: Anatomic extent of qualifying PE EINSTEIN PE 1 AMPLIFY 2 Hokusai VTE 3 Patients with PE ± DVT, n Anatomic extent of qualifying PE, n (%) Limited: 25% of vasculature of a single lobe 608 (13) 168 (9) 251 (8) Intermediate 2816 (58) 787 (43) 1361 (41) Extensive: 2 lobes with 25% of entire vasculature 1173 (24) 683 (37) 1521 (46) Not assessable 235 (5) 198 (11) 186 (6) Dabigatran RE COVER trial anatomic extent of qualifying PE not reported Extensive: 2 lobes with 50% of vasculature for each lobe 1. EINSTEIN PE Investigators. N Engl J Med 2012;366: Agnelli et al. N Engl J Med doi: /nejmoa The Hokusai-VTE Investigators. N Engl J Med 2013

37 Edoxaban 60 mg regimen: Conclusions Non inferior to standard therapy for preventing recurrent VTE Statistically significant reduction of clinically relevant bleeding Results consistent across a broad range of patients including: those receiving patient specific dosing with 30 mg edoxaban patients with severe PE The Hokusai-VTE Investigators. N Engl J Med 2013

38 Unique study features Hokusai VTE Largest single study in VTE Once daily dosing Dynamic dose adjustment Flexible treatment duration (3 12 months) Simulate usual clinical practice Active INR feedback to sites regarding TTR Follow up of all patients for 12 months Primary efficacy analysis at 12 months regardless of duration of therapy Raskob et al. J Thromb Haemost 2013; e pub ahead of print Daiichi Sankyo Inc. Data on file

39 Study design N=21,105 AF on electrical recording < 12 mo Intended oral anticoagulant CHADS 2 > 2 R Low exposure strategy: edoxaban 30 mg QD High exposure strategy: edoxaban 60 mg QD Median duration of follow up 24 months Active control: warfarin (INR ) Primary objective Edoxaban: therapeutically as good as warfarin 1º endpoint = stroke or SEE (non inferiority boundary HR 1.38) 2º endpoint = stroke or SEE or all cause mortality Safety endpoints = major bleeding, hepatic function AF, atrial fibrillation, mo, months; QD, once daily; HR, hazard ratio SEE, systemic embolic event; INR, International Normalized Ratio Ruff et al. Am Heart J 2010;160:

40 Patients randomized to either of the two edoxaban groups anticipated to have an increased drug exposure received a 50% dose reduction (e.g. from 30 mg to 15 mg) Dose reductions occurred for one or more of the following: CrCl ml/min calculated with the Cockcroft Gault formula Body weight 60 kg Dosing strategy Concomitant administration of strong P gp inhibitors: verapamil, quinidine, or dronedarone Dose reduction can occur at randomization or any time during the trial CrCl, creatinine clearance; P gp, P glycoprotein Ruff et al. Am Heart J 2010;160:

41 End of Study Transition 1. Detailed protocol amendment, training 2. Required transition to open label A/C, unless absolute contraindication 3. Transition permitted to VKA or NOAC 4. If transitioning to open label VKA Transition Kit containing active edoxaban given until INR therapeutic Frequent INR testing (> 3) in first 2 weeks Use of approved VKA dosing algorithm req.

42 Baseline Characteristics in AF Trials RE-LY (Dabigatran) ARISTOTLE (Apixaban) ENGAGE AF-TIMI 48* (Edoxaban) ROCKET-AF (Rivaroxaban) # enrolled 18,113 18,201 21,105 14,264 Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78] Female 36% 35% 38% 40% CHADS 2 score 3 32% 30% 52% 87% VKA naive 50% 43% 41% 38% Paroxysmal AF 33% 15% 25% 18% Prior stroke/tia 20% 19% 18% / 12% 55%** Diabetes 23% 25% 36% 40% Prior CHF 32% 35% 56% 62% Hypertension 79% 87% 90% 91% *Preliminary data **includes prior systemic embolism Patel MR, et al. N Engl J Med 2011;Aug 10:[Epub] Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub] Granger CB, et al. N Engl J Med 2011 (doi /NEJMoa )

43 Phase III AF trials: dose comparisons RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban N 18,113 14,266 18,201 21,105 Dose (mg) 150, , 30 Frequency BID QD BID QD Initial Dose adj* No mg mg mg mg Dose adj (%) >25 Dose adj* after randomization No No No Yes Design PROBE 2x blind 2x blind 2x blind *Dose adjusted in patients with drug clearance, low body weight, concomitant p gp inhibitors PROBE, prospective randomized, open label, blinded end point evaluation Connolly et al. N Engl J Med 2009;361: Patel et al. N Engl J Med 2011;365: Granger et al. N Engl J Med 2011;365:

44 Edoxaban in Atrial Fibrillation What Will It Add to Current Knowledge? 1. The largest (21,105) RCT in AF with a NOAC with the longest follow up (median 2.8 yrs) 2. Two once daily dosing regimens (60 & 30 mg) 3. First study with continually dose adjustment (60 30 mg; mg) at and after randomization providing data on 3 doses spanning a 4 fold range 4. Benefit of hindsight: Minimizing missing data Transition on/off edoxaban/oacs Warfarin titration Wealth of ancillary studies exploring disease state, pharmacology and mechanism of action

45 Clinical Experience To date, over 34,000 subjects enrolled in the edoxaban clinical program Phase I: ~ 870 subjects Phase II DVT/VTE prophylaxis: ~1750 subjects Phase II Atrial Fibrillation: ~1500 subjects Phase III DVT/VTE prophylaxis: ~1300 subjects Phase III DVT/VTE treatment: ~8000 subjects Phase III Atrial Fibrillation: ~21,000 subjects