What evidence is there that variable clinical responses to PK parameters exist for NOACs? What conclusions can we draw from these data?

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1 Is There A Role For Pharmacokinetic/Pharmacodynamics Guided Dosing For Novel Anticoagulants? The Heart House, Washington, DC, 3 December 2015 What evidence is there that variable clinical responses to PK parameters exist for NOACs? What conclusions can we draw from these data? Review of data from edoxaban Michele Mercuri, MD, PhD, FAHA Daiichi Sankyo for SAVAYSA / LIXANA (edoxaban) 3 December 2015 Daiichi Sankyo 1

2 Disclosures Employment Yes Entity: Daiichi Sankyo Pharma Development, Daiichi Sankyo, Inc. Compensation: Significant (>$10K or 5%) Ownership Interest Stock option equivalent is part of the compensation plan Research Grant or Other Research Support None Speakers' Bureau No speaking engagements to disclose Honoraria No honoraria to disclose. Consultant or Advisory Board No consultant or advisory relationship to disclose Expert Witness No expert testimony to disclose

3 Outline Which PK/PD factors are associated with bleeding and thrombotic events? What patient factors are associated with stroke/thrombotic events? What is the extent of intra-individual PK variability? Can PK/PD be used as a guide for dosing? 3 December 2015 Daiichi Sankyo 3

4 Question N. 1 Which PK/PD factors are associated with bleeding and thrombotic events? 3 December 2015 Daiichi Sankyo 4

5 edoxaban Pharmacokinetic and Pharmacodynamic Profiles what do we know? edoxaban has been extensively tested in vitro, ex vivo, in healthy volunteers and in patients with Atrial Fibrillation and Venous Thrombo-Embolism as well in those who underwent various orthopedic surgeries 3 December 2015 Daiichi Sankyo 5

6 ENGAGE AF-TIMI 48 Time to First Event Modeling Parametric time-to-event analysis (Exponential, Weibull or Gompertz distributed times-to-event evaluated) warfarin and edoxaban treatments modeled separately Stepwise covariate model (SCM) building (p<0.05 forward, p<0.05 backwards) for warfarin arm, backwards (p<0.05) for edoxaban arm Two exposure response models (C min and C av ) for each efficacy and safety endpoint In collaboration with the University of Uppsala and the Pharmetheus Group 3 December 2015 Daiichi Sankyo 6

7 ENGAGE AF-TIMI 48 Risk Factors Included in Exposure Response Analyses Risk Factor Efficacy Safety Age (as continuous value) X X Age 75 X X Female sex X Body weight X X Congestive heart failure X X Hypertension requiring medication X X Diabetes mellitus X X Prior stroke or TIA X X X Composites of CHADS 2 scores (CHADS vs 4-6) X X Anemia X History of any bleeding X Serum creatinine 1.5 mg/dl or CrCL X History of cancer X Prior stroke X VKA-naïve vs VKA-experienced X X Concomitant use of aspirin or antiplatelet agent X Concomitant use of NSAID X X Ethnicity X X Race X X Diuretics X Dyslipidemia X Concomitant use lipid lowering therapy X In collaboration with the University of Uppsala and the Pharmetheus Group 7

8 Which PK/PD factors are associated with bleeding and thrombotic events? Average Drug Concentration (C av ) could be used to adequately describe the exposure-response relationship in the Phase 3 Program 3 December 2015 Daiichi Sankyo 8

9 Predicted probability within 1 year (%) THE ENGAGE AF TIMI 48 TRIAL Average Concentration vs. Clinical Outcomes % Range 4.0 Major Bleeding Stroke or SEE Life Threat / Fatal Bleeding edoxaban 60-mg QD C av (ng/ml) Predicted outcomes using ~10,000 samples from ~5,000 ENGAGE AF TIMI 48 patients 3 December 2015 Daiichi Sankyo 9

10 Question N. 2 What patient factors are associated with stroke/thrombotic events? 3 December 2015 Daiichi Sankyo 10

11 Observed Cumulative Hazard Rates (All Patients) Stroke/Systemic Embolism P< % Adjusted HR: <65 vs. 75: 1.38 (1.11, 1.72) <65 vs : 1.13 (0.93, 1.38) Adjusted for weight, gender, HTN, Dyslipidemia, DM, Smoking, Prior PCI, Prior stroke or TIA, Congestive HF, treatment arms, type of AF, CrCl, Race, Region, History of increased risk of falling, History of neuropsychiatric, and dose reduction Adapted from Kato et al., AHA 2014; Courtesy of the TIMI Study Group 11

12 %/Y % Stroke/TIA history is associated with a Higher Incidence of Vascular Events HR 0.86 ( ) 2.4% % Systemic embolism Hemorrhagic stroke Ischemic stroke HR 0.88 ( ) 1.2% warfarin (N=1991) edoxaban (N=1976) Yes, Prior Stroke/TIA (N=5973) 0.0 warfarin (N=5045) edoxaban (N=5059) No Prior Stroke/TIA (N=15,132) Adapted from Rost et al, World Stroke Conference 2014; Courtesy of the TIMI Study Group 12

13 The event rate in patients by APT (%/Y) Antiplatelet (ATP) use increases the risk of bleeding 5 4 HR 0.80, P=0.01 HR 0.82, P=0.10 HR 0.51, P<0.001 edoxaban warfarin P interaction> HR 0.56, P<0.001 HR 0.60, P<0.001 HR 0.50, P<0.001 HR 0.50, P=0.001 HR 0.27, P< No APT APT No APT APT Major Bleeding Fatal/life-threatening Bleeding Adapted from Xu et al, AHA 2014; Courtesy of the TIMI Study Group 13

14 Stroke or Systemic Embolism (%/Y) Stroke/Systemic Embolism by Exploratory Creatinine Clearance Subgroup Edoxaban* edoxaban (60-mg QD Or 30-mg QD if CrCl 50, BW 60 Kg or P-gp use) p-interaction = CrCl (ml/min) 50 >50-95 >95 N (%) 2740 (20) 8208 (58) 3123 (22) edoxaban Events Intention-to-treat Overall Study Period Adapted from Bohula et al, AHA 2015; Courtesy of the TIMI Study Group 14

15 Major Bleeding (%/Yr) Major Bleeding by Exploratory Creatinine Clearance Subgroup 4.0 CrCl (ml/min) 50 >50-95 >95 N (%) 2728(20) 8177 (58) 3119 (22) edoxaban Events edoxaban (60-mg QD Or 30-mg QD if CrCl 50, BW 60 Kg or P-gp use) p-interaction = 0.11 p-interaction = Safety Population On Treatment Period Adapted from Bohula et al, AHA 2015; Courtesy of the TIMI Study Group 15

16 Question N. 3 What is the extent of intra-individual PK variability? 3 December 2015 Daiichi Sankyo 16

17 ENGAGE AF TIMI 48: Pop-PK Modeling Estimated Intra-individual (Inter-occasion) Variability PK parameter Inter-occasion variability (% CV) Apparent oral clearance (CL/F) 9.78 Absorption rate constant (Ka) 101 Apparent volume of central compartment (Vc/F) December 2015 Daiichi Sankyo 17

18 Question N. 4 Can PK/PD be used as a guide for dosing? 3 December 2015 Daiichi Sankyo 18

19 Despite the good knowledge acquired from the edoxaban registration program, many critical questions remain to be answered. 3 December 2015 Daiichi Sankyo 19

20 PK measurements are impractical for clinical use outside controlled clinical trials due to technical complexity, intra- and inter-patients variability, and the key role of specific clinical characteristics on PK data interpretation. Standardization of methodology is lacking and shall be established before this approach can be further considered for wide clinical use. 3 December 2015 Daiichi Sankyo 20

21 Daiichi Sankyo continues to work with the large edoxaban PK/PD dataset, and to explore the possible use of other more common coagulation tests to further the available data interpretation, and to guide future hypothesis testing 3 December 2015 Daiichi Sankyo 21

22 Summary 1. Several PK/PD factors are associated with thrombotic and bleeding events Drug concentrations, Renal function/age 2. Several patient factors are associated with thrombotic and bleeding events History of Stroke/TIA, Renal function/age, Concomitant use of APT 3. PK measurements are still rather impractical for clinical use outside controlled clinical trials due to technical complexity, patients variability, and the key role of specific clinical characteristics on PK data interpretation 4. Daiichi Sankyo continues to work with the large edoxaban PK/PD dataset, and to explore the possible use of alternative coagulation tests to further the available data interpretation and to guide future hypothesis testing 3 December 2015 Daiichi Sankyo 22