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Potential Utility of rNAPC2 in ACS: Phase 2 Heparin Replacement Trial

This study evaluates the potential of rNAPC2 as a heparin replacement in acute coronary syndromes (ACS). Results suggest that rNAPC2 may reduce ischemia in patients with ACS, providing a novel treatment option.

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Potential Utility of rNAPC2 in ACS: Phase 2 Heparin Replacement Trial

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  1. Potential Utility of rNAPC2 in ACS: Phase 2 Heparin Replacement Trial Evaluating RNAPc2 In Acute Coronary SyndromesRobert P. Giugliano, MD, SM, Associate Physician, Cardiovascular DivisionBrigham and Women's HospitalAssistant Professor in Medicine Harvard Medical SchoolBoston, MA

  2. Novel Tissue Factor / Factor VIIa Inhibitor Reduces Ischemia in Patients with NSTE-ACS: Results of the Dose-Ranging and Heparin De-Escalation Phases of the ANTHEM-TIMI 32 Trial RP Giugliano1, SD Wiviott1, DI Simon2, MJ Schweiger3, MA Leesar4, PH Stone1, R Bach5, A Skene6, SR Deitcher7, E Braunwald1 on behalf of the ANTHEM-TIMI 32 Investigators (1) Brigham & Women’s Hospital, Boston, MA. (2) University Hospitals – Case Medical Center, Cleveland, OH. (3) Baystate Medical Center, Springfield, MA. (4)U of Louisville, Louisville, KY. (5) Washington U School of Medicine, St. Louis, MO. (6) Nottingham Clinical Research Limited, Nottingham, UK. (7) Nuvelo, Inc., San Carlos, USA

  3. Accumetrics, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals Baxter Bayer Healthcare LLC Beckman Coulter, Inc. Biosite Incorporated Bristol-Myers Squibb CardioKinetix CV Therapeutics, Inc. Eli Lilly and Company FoldRx GlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corp Integrated Therapeutics Corp KAI Pharmaceuticals Merck & Co., Inc. Millennium Pharmaceuticals, Inc. Novartis Pharmaceuticals Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics Corporation Roche Diagnostics GmbH Sanofi-Aventis Sanofi-Synthelabo Recherche Schering-Plough St Jude Medical The National Institutes of Health Disclosures The TIMI Study Group received research/grant support in the last 2 yrs through Brigham & Women’s Hospital from (alphabetical order): MJ Schweiger, MA Leesar, R Bach, and A Skene received research grant support from Nuvelo; SR Deitcher is an employee of Nuvelo

  4. Background • Exposure of tissue factor (TF) initiates coagulation at sites of vascular injury (plaque rupture, PCI) • rNAPc2 is a recombinant, modified version of NAPc2 (derived from the hookworm) that provides potent factor X(a)-dependent inhibition of the TF/fVIIa complex • rNAPc2 prevented new thrombin generation in a dose-dependent manner in phase 2 studies of elective knee surgery and elective PTCA • Ischemia during continuous ECG monitoring identifies patients with ACS at high risk of adverse cardiac events • Enoxaparin was associated with less ischemia based on continuous ECG and better clinical outcomes than UFH, suggesting more proximal inhibition may be more effective than distal inhibition of the coagulation cascade

  5. Trial Design: Dose Ranging nSTE ACS -> Early Catheterization ASA, Enox or UFH, GP IIb/IIIa*, clopidogrel* Blinded Randomized 4:1 rNAPc2 (n=163) IV bolus q 48h 8 escalating doses (1.5, 2, 3, 4, 5, 7.5, 10† mcg/kg) Placebo IV q 48h n = 40 Major Endpoints Safety Major/Minor Bleed Efficacy F1+2, PT, PK Holter Ischemia PK, PD: pre-dose, 2-6h, 48h, d7, d42 Continuous ECG x 7 days Clinical f/u to 6 months * Encouraged per current practice guidelines † 10 mcg/kg dose panel repeated

  6. Heparin De-Escalation (HDE) Design (n=52) Unblinded ASA GP IIb/IIIa* clopidogrel* nSTE ACS Early Cath rNAPc2 10 mcg/kg 2 Sequential Panels 1 ½ Std† UFH (n=26) 2 No UFH (n=26) Endpoints Major/Minor Bleed Thrombotic Bailout‡ F1+2, PT, PK Holter Ischemia PK, PD, Cont ECG, 6 mth clinical Angiograms reviewed by Core Lab Thrombosis monitored by Investigators * Encouraged per current practice guidelines † 30 U/kg bolus (max 2500 U); 6 U/kg/h (max 600 U/h) ‡ Defined as use of open-label anticoagulant to manage a thrombotic complication

  7. R Aspirin 75-325 mg daily x 6 mths Entry Criteria and Study Schema Inclusion: Age 18-75, rest sx > 5min w/i 48h c/w ACS + markers or ST deviation or TIMI Risk Score > 3 Planned early invasive strategy Exclusions: STEMI, creatinine > 4, bleed risk, planned CABG <7d in hospital Angio +/- PCI IV GP IIb/IIIa (encouraged) Clopidogrel 300/75 (encouraged) Enox q 12h or UFH 0 48h 96h 144h 192h (8d) rNAPc2/ placebo (rNAPc2/ placebo) (rNAPc2/ placebo) Up to 3 doses administered as determined by clinical circumstances and length of hospitalization

  8. Baseline Characteristics rNAPc2 Placebo No. of patients 215 40 Age (median) 58 yrs 56 yrs Age > 65 yrs 28 18 Women 34 20 nSTE-MI 53 50 ST dev > 0.5mm 47 45 Diabetes 34 33 Mean TIMI Risk Score (0-7) 3.5 3.7 Data shown are % of patients All p = NS

  9. Concomitant Treatments rNAPc2 Placebo (n=215)(n=40) # Study drug doses: 1 85 83 2 14 18 3 1 0 *Enoxaparin / UFH 71 / 33 75 / 33 Clopidogrel 81 85 GP IIb/IIIa inhibitor 53 53 Treatment Strategy: PCI 45 58 CABG 11 3 Medical 44 40 Data shown are % of patients * Excludes 52 patients in the heparin de-escalation phase All p = NS

  10. 1° Study Endpoint: Adjudicated TIMI Major or Minor Bleeding Dose- Ranging Phase HDE All rNAPc2 p-value for trend = 0.23 p = NS for each pairwise comparisons with placebo *p = 0.50 for comparison with placebo (1° endpoint) 7.5 5.0 5.0 4.8 4.8 3.8 3.7* 2.5 4 # bleeds -> 1 1 0 0 1 1 1 3† 0 1 4† Dose of rNAPc2 (mcg/kg) # patients: 40 21 21 20 21 20 20 40 26 26 215 †3/4 major bleeds were CABG-related 2-3 days post dose

  11. Other Safety Endpoints rNAPc2 Placebo (n = 215) (n = 40) P-value Minimal Bleeding 9.8 10.0 NS Provoked by procedure 8.4 5.0 NS Spontaneous 1.4 5.0 NS RBC Transfusion 5.6 2.5 NS Fresh Frozen Plasma 1.4 2.5 NS Platelet Transfusion 0.5 2.5 NS Recombinant FVIIa (antidote) 0 0 -- Serious Adverse Events 30 33 NS rNAPc2 Antibody @ 42d 13* 0 0.01 Data shown are % of patients * No allergic symptoms, anaphylaxis, or clinical manifestations were reported

  12. Plasma Concentration of rNAPc2 (Dose Ranging Phase) rNAPc2 (ng/mL) rNAPc2 dose Trend p <0.0001 at 2-6h and 48h

  13. Median International Normalized Ratio (INR) – Dose Ranging INR rNAPc2 dose Trend p <0.0001 Trend p = 0.02

  14. Correlation of Log Conc and INR 2-6 hours post dose 5 Adjusted r2 = 0.26 correlation coefficient = 0.51 p < 0.0001 4 INR 3 2 1 3 4 5 6 log(rNAPc2 concentration µg/kg)

  15. F1+2 Concentration: A Measure of New Thrombin Generation (All Pts) %D in Median F1+2 from Randomization rNAPc2 dose 2-6h 48h Randomization * 7d post ** *p = 0.04 vs. placebo ** p = 0.005 vs. placebo ***p = 0.002 vs. placebo † p = 0.08 vs. placebo p = NS for all others † ***

  16. Incidence of Ischemia by Dose % pts Trend p = 0.013 • Median duration of recording was 6.7 days • Continuous ECGs were interpreted by a blinded central core laboratory 7/34 6/18 4/19 5/19 7/19 3/18 2/18 7/79 Dose of rNAPc2 in mcg/kg

  17. Incidence of Ischemia 3-way p = 0.007 % pts p = 0.12 p = 0.64 p = 0.002 7/34 25/93 9/97

  18. Heparin De-Escalation Results Unblinded HDEDouble-blind rNAPc2 dose (mcg/kg) 10 10 10 placebo Heparin Dose None ½Std Std Std (n=26) (n=26) (n=40) (n=40) Major/Minor Bleed, % 3.8 0 7.5 2.5 • D Median F1.2 from rand. At 2-6 hours -8% -17* -23* -1 At 48 hours -5% -28%* -9* +31 % Holter ischemia 4† 13 10 21 % Thrombotic Bailout 19‡ 0 -- -- *p < 0.05 vs placebo † p = 0.12 vs placebo ‡ p = 0.051 vs ½ Std heparin. Note: TBO was prospectively assessed only during heparin de-escalation, 1 case was retrospectively identifiedin patients receiving 10 mcg/kg rNAPc2 + standard heparin

  19. Clinical Endpoints at 42 Days rNAPc2 placebo (n=215) (n = 40) All-cause Mortality 0 0 New Myocardial Infarct* 2 3 Clinical Rec Ischemia* 8 8 D / MI* / RI* 10 10 Holter ischemia* 0-7 days 18 21 Revasc post discharge 10 13 Stroke 0.5 0 Any of the above 30 38 Data shown are % of patients * Central blinded adjudicated All p = NS

  20. Summary and Conclusions • rNAPc2 did not increase bleeding despite dose-related increase in INR • Higher dose rNAPc2 (> 7.5 mcg/kg) suppressed new thrombin generation and these doses  ischemia by 50% • Some heparin may be necessary to avoid procedure-related thrombosis • These proof of concept data warrant larger-scale evaluation to determine if rNAPc2 improves clinical outcomes

  21. Question & Answer

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