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(12) Patent Application Publication (10) Pub. No.: US 2015/0025011 A1 SINHA Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0025011 A1 SINHA Et Al US 2015.0025O11A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0025011 A1 SINHA et al. (43) Pub. Date: Jan. 22, 2015 (54) UNIT DOSE FORMULATION OF ANTIDOTES (60) Provisional application No. 61/225,887, filed on Jul. FOR FACTORXANHIBITORS AND 15, 2009. METHODS OF USING THE SAME (71) Applicant: PORTOLA PHARMACEUTICALS, Publication Classification INC., SOUTH SAN FRANCISCO, CA (US) (51) Int. Cl. CI2N 9/64 (2006.01) (72) Inventors: UMASINHA, SAN FRANCISCO, CA A638/48 (2006.01) (US); GENMIN LU, BURLINGAME, (52) U.S. Cl. CA (US); ATHIWAT CPC .......... CI2N 9/6432 (2013.01); A61 K38/4846 HUTCHALEELAHA, REDWOOD (2013.01); C12Y 304/21006 (2013.01) CITY, CA (US); STANLEY J. USPC ......................................................... 514/14.4 HOLLENBACH, SOUTH SAN FRANCISCO, CA (US) (57) ABSTRACT (21) Appl. No.: 14/320,199 (22) Filed: Jun. 30, 2014 The present invention relates unit dose formulations of anti dotes to anticoagulants targeting factor Xa. Disclosed herein Related U.S. Application Data are methods of stopping or preventing bleeding in a patient (63) Continuation of application No. 12/836,536, filed on that is currently undergoing anticoagulant therapy with a Jul. 14, 2010. factor Xa inhibitor. Patent Application Publication Jan. 22, 2015 Sheet 2 of 30 US 2015/0025O11 A1 3OOOOO TF N TF+VIla (50 nM) 2OOOOO N TF+VIla (100 nM) D N %Z NTF+VIla (200 nM) Y 1OOOOO NNNEN % E.% N % 2 NNYNN,2 2 O N N W 2 N 2 a a O.OO 31.25 62.5O 125.OO 25O.OO Betrixaban (nM) 2.4 nM Xa O 2.4 nM Xa-12.5 nM g Betrixaban s A Buffer C SS O 1OO 200 300 Gla anhydro-FXa (nM) FIG. 5 Patent Application Publication Jan. 22, 2015 Sheet 3 of 30 US 2015/0025O11 A1 Thrombin Generation in PPP 2% WZ z 77 115 Gla anhydro-FXa (nM) Digestion 1.0 o Omin A 15 min D 3O min O 5 O.O O 25 50 75 100 Time (s) FIG. 7 Patent Application Publication Jan. 22, 2015 Sheet 4 of 30 US 2015/0025O11 A1 Xa: .25 nM SpXa: 100 uv. 75 - o On M. Betfixaban s A 1.25 nM Betrixaban g 5 M Betrixaban s s s des-Gia anhydro-FXa (nivl) FG. 8 3OOOOO I. No Antidote 2680 V Artidote 2OOOOOH 1 OOOOO Betrixaban (ny) FG. 9 Patent Application Publication Jan. 22, 2015 Sheet 5 of 30 US 2015/0025O11 A1 Betrixaban: 250 nM 750 E 500 as 250 O O ... ... PPP O 152 304. 456 608 760 Antidote (n) I No Antidote 50 +Antidote (563 nM) - 4.0 it 3.0 re 2.0 - for Enoxaparin (fm) F.G. 11 Patent Application Publication Jan. 22, 2015 Sheet 6 of 30 US 2015/0025O11 A1 Ola (5 nM) la (5 nM)+Argatroban (50 nM) Š? Š?. s. O 90 79 269 359 448 538 Antidote (n) F.G. 12 Berixaban-Artidote Control+Antidote Antidote nM) F.G. 13 Patent Application Publication Jan. 22, 2015 Sheet 7 of 30 US 2015/0025O11 A1 GLA deletion PstI (6925) Pst (312) EF1a Promoter RVV deletion PstI (642O) X a triple mut ala419 Ban.HI (1255) Sac (1292) AB1-triple-mut Not I (1568) 73O3 bp Nico (1829) Sac (2221) DHFR Nico (2582) SV40E Poly(A) AMP Sac (2857) Patent Application Publication Jan. 22, 2015 Sheet 8 of 30 US 2015/0025O11 A1 FXa -Antidote FXa r-Antidote Anti-C at Anti-C at FIG. 15A Patent Application Publication Jan. 22, 2015 Sheet 9 of 30 US 2015/0025O11 A1 B C MK Xa r-Antidote MK Xa r-Antidote Xa r-Antidote S Anti-HC antibody Anti-LC antibody FIG. 15B FIG. 15C Patent Application Publication Jan. 22, 2015 Sheet 10 of 30 US 2015/0025O11 A1 -- 3&ixa 8 -e-Seixaaiii-pd-Antidote s a --- ; 3. s Sire ir FG. 6 Patent Application Publication Jan. 22, 2015 Sheet 11 of 30 US 2015/0025011 A1 600 aeE z 400 o s s s 2OO ai i O s O.O. "15 mg/kg 15 mg/kgr Antidote F.G. 17A F.G. 17B 5.0 Nor-Antidote 2508 Vir-Antidote 4.0 3.0 T 2.0 10 () 0.3125 (.625 125 Enoxaparin (fm) F.G. 18 Patent Application Publication Jan. 22, 2015 Sheet 12 of 30 US 2015/0025O11 A1 9 O 8O 70 60 50 40 30 Patent Application Publication Jan. 22, 2015 Sheet 13 of 30 US 2015/0025O11 A1 25 20 15 10 5 O III. FIG. 20 Patent Application Publication Jan. 22, 2015 Sheet 14 of 30 US 2015/0025O11 A1 FG. 21 Patent Application Publication Jan. 22, 2015 Sheet 15 of 30 US 2015/0025O11 A1 1500 1 OOO 500 FG.22A Atidotefetrixaba. FG. 22B Patent Application Publication Jan. 22, 2015 Sheet 16 of 30 US 2015/0025O11 A1 OnM 2.5 nM 5.0 nM 7.5 nM O 25 50 75 100 125 r-Antidote (nM) FIG. 23A e E ? O E D s s X O 25 50 75 100 125 r-Antidote (nM) FIG. 23B O 25 50 75 100 125 r-Antidote (nM) FIG. 23C Patent Application Publication Jan. 22, 2015 Sheet 17 of 30 US 2015/0025O11 A1 Control 1 M rivaroxaban D Control+Antidote Q Q Q (Q Q Q S S) SSt AS\ X 8°O S.S SS r-Antidote (nM) FIG. 24 8 Control D Control+Antidote 1.0 uM Apixaban 1.5uM Apixaban Q Q Q (Q &S 3CS as r-Antidote (nM) FIG. 25 Patent Application Publication Jan. 22, 2015 Sheet 18 of 30 US 2015/0025O11 A1 r-Antidote (nM) FIG. 26 Infusion of Rivaroxaban Infusion of -A Rivaroxaban + Vehicle (n=3) (0.25 mg/kg/hr) Age -(- Rivaroxaban + Antidote 1 mg (n=3) 4.5 D -V- Rivaroxaban + Antidote 3.4 mg (n=3) -O-Vehicle (n=3) 40 3. 3.5 3.0 d O g 2.5 o s 2.0- 15 1.O O 30 35 60 90 120 Time (min) FIG. 27 Patent Application Publication Jan. 22, 2015 Sheet 19 of 30 US 2015/0025O11 A1 Total and Unbound Plasma Concentration of Rivaroxaban: Rivaroxaban (0.25 mg/kg/hr, IV) +- Antidote (1 and 3.4 mg., IV) (n F3 per group) Infusion of Infusion of Antidote fxanhibitor -e- Riv Alone: Total • Riv + 1 mg AD: Total o Riv + 3 mg AD: Total X Riv Alone: Unbound 9 • Riv + 1 mg AD: Unbound Riv + 3 mg AD: Unbound 2 400 Z O s o 10 C O 8 6 w s 4 H 2 O O 10 20 30 : 40 50 60 70 80 go 100 110 120 Time:(min) Antidote Riv Ratio: 1 mg 1.1 0.54 0.19 0.10 3.4 mg 2.3 1.1 0.42 0.14 FIG. 28 Infusion of 5.0 RivarOxaban Bolus + Infusion of antidote (0.25 mg/kg/hr) (4 mg + 4 mg/hr) -A-Rivaroxaban +Vehicle (n=4) -V-Rivaroxaban +Antidote (n=5) -o-Vehicle (n=4) O 30 35 60 90 Time (min) *P-value < 0.001 (Antidote vs. RivarOxaban Alone) FIG. 29A Patent Application Publication Jan. 22, 2015 Sheet 20 of 30 US 2015/0025O11 A1 Infusion of 2.5 RivarOxaban Bolus + Infusion of antidote 0.25 mg/kg/hr (4 mg + 4 mg/hr) -A-Rivaroxaban+Vehicle (n=4) 2.0 -V-Rivaroxaban--Antidote (n=5) -O-Vehicle (n=4) 15 O 30 35 60 90 Time (min) *P-value < 0.01 (Antidote vs. Rivaroxaban Alone) FIG. 29B 7.0 -- 1 mg/kg Enoxaparin (n=2) -V-3 mg/kg Enoxaparin (n=4) 6.0 -A-6 mg/kg Enoxaparin (n=2) 5.0 4.0 3.0 2.0 1. O2 15 30 60 90 120 Time (min) Post Bolus injection of Enoxaparin FIG. 30 Patent Application Publication Jan. 22, 2015 Sheet 21 of 30 US 2015/0025O11 A1 Enoxaparin 3 mg/kg (M Bolus) Bolus + Infusion of antidote (5 mg + 5 mg/hr) 160- Or bolus of protamine (0.9 mg) 140 - A - Enoxaparin+Vehicle (n=4) 120 -V-Enoxaparin-Antidote (n=3) -(-Enoxaparin-Protamine (n=4) 1 OO -O-Vehicle (n=4) 60 40 20 O r- -- O 5 10 15 20 3O 40 50 60 70 Time (Min) Post Bolus injection of Enoxaparin "P-value < 0.04 (Enoxaparin-Vehicle vs. Enoxaparin+Antidote and Enoxaparin + Protamine) Infusion of 400- Betrixaban ; : Bolus + infusion of antidote 3.75- (11 mg/kg/hr)moikoih - (5 mg + 5 mg/hr) 350- R -A-Betrixaban-i-Vehicle nat4 3.25- : -V-Betrixaban-Antidote n=4 -O-Vehicle n=4 t O 30 35 60 90 Time (minutes) "P-values 0.05 (Betrixaban-i-vehicle vs. Betrixaban+Antidote) "P-watues 0.01 (8etrixaban+Vehicle vs. Betrixaban+ Antidote) FIG. 32 Patent Application Publication Jan. 22, 2015 Sheet 22 of 30 US 2015/0025O11 A1 100 x 1 O O O.O1 O 5 10 15 2O 25 Time (hr) FIG. 33 1 O 8 O 3O 6O 90 120 150 180 210 24O 270 300 330 360 390 Time (min) FIG. 34 Patent Application Publication Jan. 22, 2015 Sheet 23 of 30 US 2015/0025O11 A1 Antidote and Rivaroxaban Plasma Concentrations - - - - Plasma concentration of rivaroxaban following 20 mg PO 3.5 ----------------------------------------------------------------- Predicted two-fold increase in riwaroxaban concentration N following antidote administration 3 w N - - - Plasma concentration of antidote given a 400 mg IV bolus 8. 2.5 Y W 2 N N 1.5 n - O.5 O O 2 4 6 8 1O 12 Time (hr) Antidote and Rivaroxaban Plasma Concentrations - - - - Plasma concentration of rivaroxaban following 20 mg PO 3.5 -ray Predicted two-fold increase in riwaroxaban concentration 3 V following antidote administration - - - Plasma concentration of antidote given a 400 mg IV bolus 8 2.5 M followed by 500 mg IV infusion for 6 hours s w X as w it 5a 2 N o a W 2S n 3 E 1.5 as ? s s H Time (hr) FIG.
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