Breadth of indications matters One drug for multiple indications

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1 Breadth of indications matters One drug for multiple indications Sylvia Haas, MD, PhD Formerly of the Technical University of Munich Munich, Germany Disclosures: Sylvia Haas 1

2 Novel oral anticoagulants: phase III studies Apixaban Dabigatran Edoxaban Atrial fibrillation AVERROES ARISTOTLE RE-LY RELY-ABLE ENGAGE AF TIMI 48 ROCKET AF J-ROCKET AF (Japan only) VTE prevention ADVANCE-1 ADVANCE-2+3 ADOPT (med.) RE-NOVATE I+II RE-MODEL RE-MOBILIZE STARS studies (Japan only) RECORD1 4 MAGELLAN (med) VTE therapy and secondary prevention AMPLIFY AMPLIFY-EXT RE-COVER RE-COVER II RE-SONATE RE-MEDY HOKUSAI EINSTEIN DVT EINSTEIN EXT EINSTEIN PE ACS APPRAISE-2 ATLAS ACS 2 TIMI 51 Green: primary endpoint positive Red: Primary endpoint negative Blue: Ongoing Clinical development of rivaroxaban Preclinical studies Indication VTE prevention VTE treatment Atrial fibrillation ACS Phase IIa ODIXa HIP Phase IIb ODIXa HIP ODIXa HIP2 (bid) ODIXa KNEE (bid) EINSTEIN DVT ODIXa DVT (bid) ODIXa DVT (bid) EINSTEIN DVT ATLAS ACS TIMI 46 (od, bid) Phase III MAGELLAN RECORD1 HIP RECORD3 KNEE EINSTEIN DVT (bid+od) EINSTEIN PE (bid+od) ROCKET AF ATLAS ACS TIMI 51 (bid) RECORD2 HIP RECORD4 KNEE EINSTEIN EXT Phase IV XAMOS XALIA XANTUS 2

3 Different indications and different dose regimens for the same drug A) Confusion? B) Benefit? Dosing of novel oral anticoagulants for VTE prevention Anticoagulant Dosing First dose Dabigatran etexilate 220 mg or 150 mg once daily 1 4 h postoperative with half daily dose 10 mg once daily 6 10 h postoperative Apixaban 2.5 mg twice daily h postoperative 1. Pradaxa SmPC, 2013; 2. Xarelto SmPC, 2012; 3. Eliquis SmPC,

4 Incidence Incidence Comparison of efficacy: RECORD1 4 pooled versus XAMOS 2,0 1,5 1,0 0,5 Pooled RECORD1 4, Total treatment duration 1, * 0,6 Symptomatic VTE N=12,383 1,3 0,7 Propensity score adjusted 2 Symptomatic VTE N=16,516 (rivaroxaban vs SOC) N=14,616 (rivaroxaban vs LMWH) 1,1 1,0 0,0 Enoxaparin LMWH SOC *Different treatment duration in RECORD and XAMOS 1. Turpie et al, 2011; 2. Turpie et al, 2012 Comparison of bleeding: RECORD1 4 pooled versus XAMOS 9,0 8,0 7,0 6,0 5,0 4,0 3,0 2,0 1,0 0,0 Pooled RECORD1 4, Total treatment duration 1, * 0,4 0,2 Enoxaparin LMWH SOC Major bleeding (RECORD) 2,2 1,8 Major bleeding (EMA) 7,0 6,5 Any bleeding Propensity score adjusted 2 0,4 0,3 0,3 Major bleeding (RECORD) 1,9 1,5 1,5 Major bleeding (EMA) 4,9 3,4 3,3 Any bleeding *Different treatment duration in RECORD and XAMOS. All events treatment emergent 1. Turpie et al, 2011; 2. Turpie et al,

5 VTE: disease phases and conventional anticoagulation treatment strategies Phases of the disease Acute Intermediate Long term Types and intensity of conventional anticoagulation treatment UFH, LMWH, fondaparinux Initial, parenteral therapeutic dose At least 5 days VKA INR Early maintenance/secondary prevention At least 3 months VKA INR or Long-term maintenance anticoagulation/ secondary prevention >3 months/years/indefinite* *With re-assessment of the individual benefit risk at periodic intervals Kearon et al, 2008; Schellong et al, 2009 Dosing of rivaroxaban for VTE treatment and secondary prevention Dosing 15 mg twice daily (3 weeks), followed by 20 mg once daily Dosing during initial treatment phase Initial treatment with rivaroxaban in higher dose (15 mg twice daily for 3 weeks), then dose reduction to 20 mg once daily Xarelto SmPC,

6 Cumulative event rate (%) 30-day observation after treatment cessation EINSTEIN DVT and EINSTEIN PE (non-inferiority studies) Confirmed acute symptomatic DVT without symptomatic PE 1 N= mg bid 20 mg od Confirmed acute symptomatic PE with or without symptomatic DVT 2 R N=4832 Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start 48 hours, target INR range Day 1 Day The EINSTEIN Investigators, 2010; 2. The EINSTEIN PE Investigators, 2012 EINSTEIN pooled: primary efficacy outcome Enoxaparin/VKA N= N= Intention-to-treat population Time to event (days) Number of patients at risk Enoxaparin/VKA Büller,

7 Cumulative event rate (%) EINSTEIN pooled: major bleeding Enoxaparin/VKA N= N= Safety population Time to event (days) Number of patients at risk Enoxaparin/VKA Büller, 2012 for treatment of VTE Phases of the disease Acute Intermediate Long term treatment for VTE 15 mg twice daily for the initial treatment of acute VTE for the first 3 weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE Xarelto SmPC,

8 Dosing of novel oral anticoagulants for stroke prevention in non-valvular atrial fibrillation Anticoagulant Dabigatran etexilate 1 2 Apixaban 3 Dosing 150 mg twice daily (110 mg* twice daily in patients >80 years old and patients receiving concomitant verapamil) 20 mg once daily (15 mg once daily in patients with creatinine clearance ml/min) 5 mg twice daily (2.5 mg twice daily in special patient populations) *Not registered by FDA 1. Pradaxa SmPC, 2013; 2. Xarelto SmPC, 2012; 3. Eliquis SmPC, 2012 ROCKET AF: study design 20 mg daily (15 mg for CrCl ml/min) Atrial fibrillation Randomized double-blind, double-dummy (N=14,264) Warfarin INR target inclusive Monthly monitoring Adherence to standard of care guidelines Risk factors CHF Hypertension Age 75 years Diabetes (At least 2 or 3 required*) OR Stroke, TIA or systemic embolus Primary endpoint: stroke or systemic embolism *Enrollment of patients without prior stroke, TIA or systemic embolism and only two risk factors capped at 10% Patel et al,

9 Cumulative event rate (%) ROCKET AF: primary efficacy endpoint (intention-to-treat population) Stroke or systemic embolism HR 0.88 ( ) p<0.001 (non-inferiority) p=0.12 (superiority) Warfarin Days since randomization Number of subjects at risk Warfarin Intention-to-treat population = all patients randomized Patel et al, 2011 ROCKET AF: bleeding analysis Parameter (N=7111) n (% per year) Warfarin (N=7125) n (% per year) HR (95% CI) Principal safety endpoint 1475 (14.9) 1449 (14.5) 1.03 ( ) HR and 95% CIs Major bleeding 395 (3.6) 386 (3.4) 1.04 ( ) Haemoglobin drop ( 2 g/dl) 305 (2.8) 254 (2.3) 1.22 ( )* Transfusion 183 (1.6) 149 (1.3) 1.25 ( )* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 ( )* Intracranial haemorrhage 55 (0.5) 84 (0.7) 0.67 ( )* Fatal bleeding 27 (0.2) 55 (0.5) 0.50 ( )* Non-major clinically relevant bleeding 1185 (11.8) 1151 (11.4) 1.04 ( ) Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001* Safety population on-treatment analysis. *Statistically significant Patel et al, Favours rivaroxaban Favours warfarin 9

10 Anti-Factor Xa activity (change from baseline; ng/ml enoxaparin) Regarding the safety/efficacy profile of rivaroxaban, would you prefer a) Once-daily dosing? b) Twice-daily dosing? : similar onset of action to enoxaparin 4 Enoxaparin 40 mg 10 mg Time (hours) Kubitza et al,

11 ETP-peak (collagen) ETP-peak (TF) dose-dependently inhibits peak thrombin generation up to 24 hours Intrinsic coagulation pathway Extrinsic coagulation pathway Placebo (n=4) 5 mg rivaroxaban (n=8) 30 mg rivaroxaban (n=8) Time (hours) Time (hours) ETP, endogenous thrombin potential; TF, tissue factor Adapted from Harder et al, 2003; Graf et al, 2007 From a patient s perspective, which dose regimen seems preferable? For long-term anticoagulation, once-daily dosing is a significant advantage 11

12 An effective treatment combines efficacy, tolerability, adherence and convenience Efficacy Efficacy at preventing VTE in MOS, preventing stroke in AF and at treating DVT or PE Adherence Taken as instructed for the prescribed period of time Treatment goal Safety/tolerability Safety/tolerability profile similar to control treatment or placebo, respectively Convenience Easy to take and to administer Conclusion has proven to be efficacious with a good safety profile in several indications Multiple indications for the same drug offer a clear benefit Standard dosing simplifies patient management: 10 mg once daily for VTE prevention 20 mg once daily for long-term therapy (VTE treatment or stroke prevention in patients with AF) The only exceptions to these doses are: The intensified VTE treatment phase (15 mg twice daily for 3 weeks) Stroke prevention in patients with AF with moderate (CrCl ml/min) or severe (CrCl ml/min) renal impairment (15 mg once daily) 12