Andexanet alfa in Factor Xa Inhibitor-Associated Acute Major Bleeding

Transcription

1 Andexanet alfa in Factor Xa Inhibitor-Associated Acute Major Bleeding Stuart J. Connolly, M.D., Truman J. Milling, Jr., M.D., John W. Eikelboom, M.D., C. Michael Gibson, M.D., John T. Curnutte, M.D., Ph.D., Michele D. Bronson, Ph.D., Patrick Yue, M.D., Genmin Lu, Ph.D., Pamela B. Conley, Ph.D., Peter Verhamme, M.D., Ph.D., Jeannot Schmidt, M.D., Saskia Middeldorp, M.D., Alexander T. Cohen, M.D., Jan Beyer-Westendorf, M.D., Pierre Albaladejo, M.D., Jose Lopez-Sendon, M.D., Andrew Demchuk, M.D., Shelly Goodman, B.S.N., Janet Leeds, Ph.D., Deborah M. Siegal, M.D., Elena Zotova, Ph.D., Brandi Meeks, M.Sc., Juliet Nakamya, Ph.D., Balakumar Swaminathan, M.Sc., Mark Crowther, M.D. on behalf of the ANNEXA-4 investigators

2 Background Factor Xa (FXa) inhibitors reduce thrombotic events, but can precipitate major bleeding >100,000 bleeding hospitalizations per year in the US Fatality rate of 15-20% Andexanet alfa was developed as a specific reversal agent for all direct and indirect FXa inhibitors It rapidly and safely reversed anti-fxa activity in healthy volunteers Truven Health Analytics, 12 months ending December 31, 2016 for Commercial, Medicare, and Medicaid patients Held C et al, Eur Heart J 2015; 36: Piccini JP et al, Eur Heart J 2014; 35:

3 Insights from the ARISTOTLE Trial: Clinical Outcomes and Management Associated with Major Bleeding in Patients with Atrial Fibrillation Treated with Apixaban or Warfarin Randomized trial of apixaban and warfarin in 18,200 patients ISTH major bleeding occurred in 5% of patients 30 day mortality after bleeding was 15% 43% mortality after ICH ICH Non ICH European Heart Journal (2015) 36, doi: /eurheartj/ehu463 3

4 ARISTOTLE: Risk of Thrombotic Events (without andexanet) after Bleeding 71% OAC interrupted 54% resumed For ICH 91% interrupted 11% resumed 22- and 13-fold increase in stroke/mi after ICH and non-ich bleeding, respectively European Heart Journal (2015) 36, doi: /eurheartj/ehu463 4

5 ANNEXA-4 Study Design Patient with acute major bleeding Patient Screening Within 18 hours of last dose of FXa inhibitor Assessments: IV Bolus Bleeding and Laboratory Assessment Andexanet 2-hour IV Infusion Day 1 After end of infusion 1 hr 4 hr 8 hr 12 hr Safety follow-up visit Day 3 Day 30 Efficacy Outcomes Change in anti-fxa activity Clinical hemostatic efficacy through 12 hours Safety Measurements Thrombotic events Antibodies to FX, FXa, andexanet 30-day mortality 5

6 Baseline Characteristics Includes all patients as of October 20, 2017 Safety Population N=227 Efficacy Population N=137 Age (yr), mean ± SD 77(±11) 77 (±12) Male 117 (52%) 70 (51%) Time from presentation until Andexanet (hrs) 4.7 ± ± 3.1 Estimated creatinine clearance < 30 ml/min 21 (9%) 13 (10%) Indication for anticoagulation Atrial fibrillation 178 (78%) 104 (76%) Venous Thromboembolic Disease 52 (23%) 38 (28%) Atrial fibrillation and VTE 8 (4%) 6 (4%) Medical History Myocardial infarction 32 (14%) 15 (11%) Stroke 47 (21%) 32 (23%) Heart Failure 52 (23%) 36 (26%) Diabetes mellitus 67 (30%) 42 (31%) 6

7 Site of Initial Bleeding Safety Population N=227 Efficacy Population N=137 Intracranial Bleeding 139 (61%) 78 (57%) Glasgow Coma Scale, mean ± SD 13.9 ± ± 1.70 Intracerebral site 74 (52%) 44 (54%) Sub-dural site 45 (32%) 24 (30%) Subarachnoid site 23 (16%) 13 (16%) Gastrointestinal Bleeding 62 (27%) 43 (31%) Other Bleeding site 26 (12%) 16 (12%) 7

8 Anti-factor Xa Activity (ng/ml) Anti-factor Xa Activity: Rivaroxaban n = Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr Median Percent Change -88% -87% -42% -49% -60% (95% CI) (-92 to -82) (-89 to -82) (-46 to -33) (-53 to -45) (-65 to -53) 8

9 Anti-factor Xa Activity (ng/ml) Anti-factor Xa Activity: Apixaban n = Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr Median Percent change -91% -91% -36% -30% -35% (95% CI) (-92 to -90) (-92 to -90) (-41 to -29) (-36 to -25) (-41 to -32) 9

10 Effective Hemostasis at 12 Hours Post Andexanet Number of Major Bleeds Adjudicated Number of Patients who Achieved Excellent or Good Hemostasis Percent of Patients who Achieved Excellent or Good Hemostasis 95% Confidence Interval % 76% - 89% 10

11 Clinical Hemostatic Efficacy Subgroup No. of Patients Excellent or Good (95% CI) Total Efficacy Patients ( ) Drug Rivaroxaban ( ) Apixaban ( ) Enoxaparin ( ) Sex Male ( ) Female ( ) Site of bleeding Gastrointestinal ( ) Intracranial ( ) Other ( ) Age <65 yr ( ) yr ( ) >75 yr ( ) Andexanet dose Low ( ) High ( )

12 Safety Assessment Thrombotic events occurred within 3 days of andexanet in 6 (2.6%) patients and by 30 days in 24 (11%) Anticoagulation re-started in 129 patients (57%) by 30 days Therapeutic anticoagulation was re-started in only 9 patients before a thrombotic event occurred 27 deaths occurred by 30 days (12%), of which 11 were cardiovascular 12

13 Proportion with an Event Thrombotic Events All events Events after re-start of anticoagulation % 0.12 Data as of: 20OCT2017 # Unrefuted TE after restart of AC among those restarted AC: 7 / % Days of Follow-up Days Since Re-start of AC No. at risk:

14 Thrombosis/Mortality Rates in Bleeding Patients in Recently Completed Studies Study ANNEXA-4 * (2018) REVERSE-AD (2017) Sarode (2013) Sarode (2013) Reversal Agent Anticoagulant Andexanet FXa Inhibitors Idarucizumab Dabigatran 4F-PCC Warfarin Plasma Warfarin Number Hemostatic Efficacy (95% CI) Thrombotic Event Rate (95% CI) Mortality (95% CI) Total % ICH Total ICH Total ICH Total ICH % (76-89) 81% (72-90) 11% (7-16) % a NR b 5% (3-8) % (64-81) 65% (56-75) 42% (15-72) 58% (28-85) 8% (3-15) 6% (3-13) 12% (7-19) 6% (2-13) NR NR 12% (8-18) 14% (10-18) 6% (2-12) 5% (2-10) 12% (7-20) 16% (10-25) NR NR Ezekwudo (2017) None VKA 60%/FXai 35% N/A N/A 15% (9-23) 15% (9-23) 45% (36-54) 45% (36-54) 4F-PCC = Four factor prothrombin complex concentrate; CI = Confidence interval; ICH = Intracranial hemorrhage; N/A = Not applicable; NR = Not reported a 68% had investigator-determined, non-adjudicated time to hemostasis within 24 hours b Time to hemostasis not calculated in ICH patients 14

15 Conclusions Andexanet rapidly reverses anti-fxa activity Effective hemostasis achieved in 83% of patients Thrombotic events/mortality rates consistent with the high risk profile of the patients Andexanet reversal of FXa inhibitor-bleeding has similar efficacy and safety as reported with other approved reversal agents 15

16 Biomarker Reversal vs. Hemostatic Efficacy of Andexanet Compared to Approved Reversal Agents Study N Reversal Agent Biomarker % with Full Biomarker Reversal Hemostatic Efficacy Excellent/Good Poor/None ANNEXA-4 * 137 Andexanet Anti-fXa 88% a 83% 17% REVERSE-AD 123 Idarucizumab DTT ECT 98% b 89% b 68% c 32% Sarode F-PCC INR 88% 72% 28% 104 Plasma INR 58% 65% 35% 4F-PCC = Four factor prothrombin complex concentrate; CI = Confidence interval; DTT = Diluted thrombin time; ECT = Ecarin clotting time; INR = International normalized ratio a Percentage of patients with a post-treatment nadir in anti-fxa activity of < 75 ng/ml b Percentage of patients as documented in BLA c Percentage of patients with investigator-determined hemostasis at 24 hours (only indicated at study completion) * Based on 228 patient data cut 20 Oct

17 Recent Publications of the APEX Trial: Betrixaban for VTE Prevention in Hospital to Home for Acute Medically Ill Patients

18 More Major Bleeding Event Rate (%) VTE Events Previous VTE Prophylaxis Studies Failed Due to Significant Increase in Major Bleeding and Limited Efficacy 6 EXCLAIM (Failed Interim Futility) Enoxaparin* vs. Extended Enoxaparin N=5,963 MAGELLAN Enoxaparin vs. Rivaroxaban N=8, % RRR=22.8% ARR=1.31% P= % 4.4% 3.3% 3.3% 2.5% 2.4% % P< % Standard Enoxaparin (6-14d)* Extended Enoxaparin (24-32d) 0.4% P< % Standard Enoxaparin (6-14d) Extended Rivaroxaban (31-39d) EXCLAIM efficacy analysis based on revised eligibility criteria and enrollment after DSMB stopped trial for futility. * Patients in both study arms received open label enoxaparin for 6-14 days followed by placebo or extended duration enoxaparin. Cohen AT et al. N Eng J Med. 2013;368(6): ; Hull RD et al. Ann Intern Med. 2010;153(1):

19 mitt Analysis; Primary Efficacy and Safety Outcomes (80 mg and 40 mg population) VTE and VTE Death DAY 42 Major Bleeding DAY 42 7% 6% 5% 4% 3% Enoxaparin/Placebo Betrixaban 6.0% 223/3720 RRR=25% ARR=1.56% P=0.003 NNT=65 4.4% 165/3721 7% 6% 5% 4% 3% Enoxaparin/Placebo Betrixaban RR=1.2 P=0.54 2% 1% 0% 2% 1% 0% 0.6% 0.7% 21/ /3716 mitt=modified intent-to-treat; RRR=relative risk reduction BEVYXXA [Package Insert], Portola Pharmaceuticals, Inc. 19

20 VTE-related Death (%) Reduction in VTE-Related Death (mitt population) New results published last month in The American Heart Journal VTE-Related Death (80 mg) HR = 0.46 (95% CI: ) p = ARR = 0.45% NNT = 223 Enoxaparin 0.79% Betrixaban 0.34% Gibson et al. Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients. Am Heart J. 2018; 198:

21 Probability of Rehospitalization (%) Reduction in VTE-Related Rehospitalizations 1.50 VTE-Related Rehospitalizations (80 mg) (mitt population) % % 0.75 P= NNT= ENOXAPARIN P= NNT= % Chi G et al. Circulation. 2018; 137(1): % Time (days) BETRIXABAN 21

22 Probability of Ischemic Stroke (%) Time to Ischemic Stroke in Patients With Ischemic Stroke or CHF as Index Event Time to Ischemic Stroke (Post hoc, 80 mg and 40 mg doses) % 1.0 P=0.014 ENOXAPARIN 0.63% BETRIXABAN HR = 0.45 (0.24, 0.87) ARR = 0.75% NNT = 133 HR = 0.45 (0.24, 0.87) ARR = 0.75% NNT = Time (days) The results presented by the APEX investigators highlight the urgent need for more effective secondary prevention therapies in these patients and provide the first evidence that a NOAC 22 may reduce stroke in this population. - Editorial Gibson CM et al. Circulation. 2017;135(7):

23 Reduction of VTE in Patients with a History of VTE Composite VTE (mitt population) 20% 16% 18.9% RRR = 43% P=0.006 NNT = 12 12% 10.4% 8% 4% 0% 55/291 32/307 Standard Enoxaparin (6-10d) Extended Betrixaban (36-42d) Gibson et. al. ISTH SSC 2016 May 27, 2016 Yee et al 2017 J Thromb Thrombolysis 23

24 Thank You