A	B	C
1	Main
2		Brand Name	Xarelto, fka BAY 59-7939
3		Generic Name	rivaroxaban
4		Mechanism	Factor Xa inhibitor, reversible anticoagulant. Inhibits platelet-bound Factor Xa, clot-bound Xa and free Xa.
5		PK	Cmax 1-4 hours, 80% F, 5-13h T1/2, oxazolidinone chemical class. Little dose response, but more bleeding at higher doses.
6		Administration	Oral
7		Economics	US only. Bayer in Europe.
8		Indication	Stroke and thrombosis prevention.
9			1.3 million people in the US get a DVT or receive hip/knee replacement.
10		IP	2020 - DB
11		Competition	PFE/BMY apixaban. BI's Pradaxa (dabigatran). GSK's odiparcil, betrixaban, edoxaban, eribaxaban, LY517717, TAK-442, YM150. In VTE/PE: Lovenox, fondaparinux.
12			Pradaxa has very low bioavailability? Schulman et al.
13		Timeline	Was file in 2009, now file in Q110. Filed 7/08, PDUFA extended. Refiling seems dependent on ROCKET.
14			11/4/2011: Approved.
15			11/13/2011: ATLAS ACS results.
16			12/29/2011: Submits sNDA for ACS.
17		Papers	Oral factor Xa inhibitors for thromboprophylaxis in major orthopedic surgery: a review. Imberti et al.
18			Rivaroxaban in orthopedic surgery - a change of paradigm? Schulman et al. Clin Appl Thromb Hemost 2009.
19		Safety	Very clean non-bleed safety profile.
20		PI	Sam Schulman, McMaster University.
21		Clinical Trials
22			Phase III ATLAS ACS 2 n=15526 - Started 11/08 - Published NEJM 2011
23			8.9% death, MI, stroke versus 10.7% for placebo.
24
25			Phase III "ROCKET" - Stroke prevention in A-Fib vs warfarin. N=14,226. Enrollment complete 7/2009. Results November 2010?
26			20mg 18 month? dosing. Co-primary of bleeding/stroke events. Event-driven study (405 events).
27			1.7% event rate versus 2.2% event rate for warfarin, p=0.015.
28			2.1% event rate versus 2.4% event rate for warfarin for non-inferiority.
29			14.9% bleeding versus 14.5% for warfarin, p=0.442.
30
31			Phase III "RE-LY" - Stroke prevention in A-Fib: Pradaxa vs warfarin. Pradaxa versus warfarin - n=18,113.
32			110mg or 150mg daily vs warfarin. Open-label?
33			1.69% events per year in warfarin, 1.53% in low-dose, 1.11% in high-dose.
34
35			RECORD-3 Phase III - VTE prevention in total knee replacement surgery n=2531 ex-US
36			Superior to Lovenox (enoxaparin) and similar safety profile.
37			DVT, non-fatal PE, all-cause mortality was 18.9% for enoxaparin vs 9.6% for rivaroxaban, a 49% reduction.
38			Bleeding was nearly identical 7 for riva and 6 for Lovenox.
39
40			RECORD-1 Phase III - VTE prevention in total hip replacement surgery n=4541 ex-US
41			3.7% events for Lovenox vs 1.1% for riva. 6 bleeds for riva vs. 2 for Lovenox.
42
43			RECORD-2 Phase III - VTE prevention in total hip replacement surgery n=2509 WW
44			9.3% events for Lovenox vs. 2.0% events for riva. 1 bleed for each group.
45
46			RECORD-4 Phase III - VTE prevention in total knee replacement surgery n=3148 WW
47			Prevention of VTE following total knee replacement surgery. 6.9% vs 10.1% for Lovenox.
48			Major bleeding 0.7% vs 0.3% for Lovenox.
49
50			Phase II dose-finding studies ODIXa-knee/hip n=2817 total in 4 studies
51
52			Phase II EINSTEIN - Treatment of VTE
53
54			Phase III EINSTEIN - Treatment of VTE
55
56			Phase III EINSTEIN - Treatment of DVT
57
58			Phase III EINSTEIN-Extension n=1107 - Prevention of recurrent DVT/PE.
59
60			Phase II ATLAS ACS TIMI 46 n=3000 - presented AHA 2008
61			45% RR reduction
62
63
64			Phase III MAGELLAN - Prevention of VTE in medically ill patients. N=8000