Mark Crowther, MD, MSc, FRCPC. Co-authors. Professor of Medicine, McMaster University, Canada

Transcription

1 Reversal of Enoxaparin-Induced Anticoagulation in Healthy Subjects by Andexanet Alfa (PRT064445), An Antidote for Direct and Indirect fxa Inhibitors A Phase 2 Randomized, Double-Blind, Placebo Controlled Trial Mark Crowther, MD, MSc, FRCPC Professor of Medicine, McMaster University, Canada Co-authors Gallia Levy 1, Genmin Lu 1, Pamela B. Conley 1, Janice Castillo 1, Stan Hollenbach 1, Janet Leeds 1, Joyce Lin 1, Lee Barron 1, Sandra Russell 1, Stuart Connolly 2, John Curnutte 1 1 Portola Pharmaceuticals employee; 2 Portola Pharmaceuticals consultant 1

2 Disclosures Presenter s Financial Disclosure Consultant, Portola Pharmaceuticals Dr Crowther discloses having sat on advisory boards for Janssen, Leo Pharma, Portola, and AKP America. Dr Crowther holds a Career Investigator award from the Heart and Stroke Foundation of Ontario, and the Leo Pharma Chair in Thromboembolism Research at McMaster University. Dr Crowther s institution has received funding for research projects from Leo Pharma. Dr Crowther has received funding for presentations from Leo Pharma, Bayer, Celgene, Shire and CSL Behring. Unlabeled/Unapproved Uses Disclosure The use of Andexanet Alfa (PRT064445) as an antidote for factor Xa inhibitors is investigational Portola Pharmaceuticals analyzed the data and participated in the preparation of this presentation 2

3 Rationale Unmet Medical Need NOACs Increased adoption of oral fxa inhibitors based on superior or comparable anticoagulant efficacy and/or safety versus warfarin LMWH s LMWH s are widely used for prevention and treatment of VTE and PE Reversal Agents for Anti-coagulated Patients Bleeding is the major risk for any anticoagulant No specific antidote for NOACs during episodes of major bleeding or prior to emergency surgery Unlike for heparin, protamine can only partially reverse (~60%) the effect of LMWH s (enoxaparin), but has no effect on fondaparinux 3

4 Andexanet: Designed to Reverse Activity of Factor Xa Inhibitors Nature Medicine (2013),19(4): Recombinant engineered version of human factor Xa produced in CHO cells Acts as a fxa decoy and retains high affinity for all direct fxa inhibitors Change of Serine to Alanine to eliminate catalytic activity and prevent prothrombin cleavage GLA domain removed to prevent anticoagulant effect Factor Xa inhibitor Factor Xa inhibitor S419 A419 Gla Gla S S Catalytic Domain S S Factor Xa Andexanet Alfa No known interaction with other coagulation factors except Tissue Factor Pathway Inhibitor (TFPI) Retains high affinity for Antithrombin III-inhibitor complex and can reverse ATIIIdependent anticoagulant effects of enoxaparin and fondaparinux in vitro and in vivo 4

5 MOA: Reversal of ATIII-dependent anticoagulants such as LMWHs (enoxaparin) and fondaparinux by andexanet AT H AT H + H AT H FXa-AT-H complex Inhibited FXa Free H AT-H complex AT H X Andexanet-AT-H complex H = Enoxaparin or Fondaparinux 5

6 Phase 2 Clinical Study Overview Double blind, randomized 2:1 (9 healthy subjects per cohort) fxa Inhibitor PRT064445/ Placebo IV Checkout Inpatient Unit Last Safety Follow up Days 1-6 (to steady state) Day 6 3h after last fxa inhibitor dose Day 13 Day 48 Study 3 - Enoxaparin Cohort 1: 40 mg enox/210 mg IV (frozen liquid formulation) Cohort 2: 40 mg enox/420 mg IV (frozen liquid formulation) Cohort 3: 40 mg enox/210 mg IV (lyophilized powder) Cohort 4: TBD this presentation Study 1: Apixaban 5 mg PO Q12 Study 2: Rivaroxaban 20 mg PO QD Study 3: Enoxaparin 40 mg SQ QD/1 mg/kg SQ Q12 Study 4: Edoxaban 60 mg PO QD 6

7 Safety Blinded safety data for 27 subjects completing 48-day follow-up indicate: No severe or serious adverse events No premature discontinuations of andexanet One subject was discontinued prior to receiving andexanet due to rash from enoxaparin No thrombotic events Protocol-required repeated assessments during study 4 subjects with mild, reversible infusion reactions Self-limited without intervention No antibodies generated against endogenous fx or fxa 7

8 Andexanet (ng/ml) Andexanet PK from Phase II Study in presence of enoxaparin A comparison with Phase I Study Cohort mg Frozen Cohort mg Cohort mg Lyophilized Time (hr) Comparison of Andexanet PK from Phase I&II Studies Clinical Study Phase I (no inhibitor) Phase II (with enoxaparin) *Liquid formulation of Andexanet was used unless specified. Dose normalized AUC 0-inf for Phase I single ascending dose and Phase II studies. Dose* (mg) T 1/2 (h) NAUC 0-inf (ng*h/ml) ± ± ± ± ± ± (Lyo) 8.8± PK properties of the liquid and lyophilized formulations are similar PK properties of andexanet in the presence or absence of enoxaparin are similar Effect of andexanet on enoxaparin compared to direct fxa inhibitors -no redistribution of extra-vascular component with enoxaparin 8

9 Anti-fXa (IU/mL) Fast Onset of Action and Sustained Reversal of Enoxaparin-Induced Anti-fXa Activity by Andexanet End of bolus ** Placebo (Cohorts 1-3, n=9) 210 mg bolus only (Cohort 1, n=6) 420 mg bolus only (Cohort 2, n=6) 210 mg (Lyo) bolus only (Cohort 3, n=6) * Lower limit of detection Time after bolus (hr) AnXa vs. Placebo *p<0.0001; **p<

10 Thrombin Generation (RFU) Restoration of Thrombin Generation upon Andexanet Administration End of bolus mg bolus only (n=6) 420 mg bolus only (n=6) 210 mg lyo bolus only (n=6) Placebo (n=9) Baseline for Cohorts Baseline Time after bolus (hr) 10

11 Expected Effect on TFPI by Enoxaparin and Andexanet Enoxaparin increases whereas Andexanet decreases free TFPI Free TFPI (ng/ml) Free TFPI (ng/ml) Day1 Pre-Enox Day1 Pre-Enox Day5 Day5 Day6 Pre-Enox Day6 Pre-Enox Day6 3hr-Enox Day6 3hr-Enox Day6-0.16hr Day6-0.16hr Day6-0.5hr Day6-0.5hr Day6-1.5hr Day6-1.5hr Day6-2.5hr Day6-2.5hr Day6-4.5hr Day6-4.5hr Day6-6.5hr Day6-6.5hr Day6-8.5hr Day6-8.5hr Day7-0hr Day7-0hr Day7-12hr Day7-12hr Day8 Day8 Day9 Day9 Day10 Day10 Day11 Day11 Day13 Day13 Day20 Day20 Day34 Day34 Day48 Day48 Day 6 Pre- and Post-Andexanet mg bolus only (Cohort 2, n=6) Placebo (Cohorts 1-3, n=9) 0 11 Dashed lines represent the range of free TFPI in plasma from 20 healthy individuals

12 Conclusions Andexanet alfa administration was safe and well-tolerated in this study No antibodies generated against endogenous fx or fxa Transient increases in F1+2, TAT and D-dimer without clinical symptoms or signs Fast onset of action for reversal of anticoagulation demonstrated ex vivo Decrease of anti-fxa activity Restoration of thrombin generation No rebound of coagulation markers after discontinuation of enoxaparin 12

13 Clinical Study Summary Completed/Ongoing Studies Phase I Single Ascending Dose Study - Completed Results were presented at ATVB Conference [2013] Phase II with direct and indirect fxa inhibitors Completed/Ongoing Apixaban - Completed Results were presented at ISTH [2013] Rivaroxaban Completed Results were presented at ASH [2013] Enoxaparin Ongoing Results are presented at ISTH SSC [2014] Edoxaban Ongoing Betrixaban - Planned Phase 3 with Apixaban and Rivaroxaban - Ongoing 13