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

Evaluating RNAPc2 In Acute Coronary Evaluating RNAPc2 In Acute Coronary SyndromesSyndromes

Robert P. Giugliano, MD, SM, Associate Physician, Cardiovascular Division

Brigham and Women's HospitalAssistant Professor in Medicine

Harvard Medical SchoolBoston, MA

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

DisclosuresDisclosures

Accumetrics, Inc. Amgen, Inc. AstraZeneca PharmaceuticalsBaxterBayer Healthcare LLCBeckman Coulter, Inc. Biosite IncorporatedBristol-Myers SquibbCardioKinetixCV Therapeutics, Inc. Eli Lilly and CompanyFoldRxGlaxoSmithKlineINO Therapeutics LLCInotek Pharmaceuticals Corp

Accumetrics, Inc. Amgen, Inc. AstraZeneca PharmaceuticalsBaxterBayer Healthcare LLCBeckman Coulter, Inc. Biosite IncorporatedBristol-Myers SquibbCardioKinetixCV Therapeutics, Inc. Eli Lilly and CompanyFoldRxGlaxoSmithKlineINO Therapeutics LLCInotek Pharmaceuticals Corp

Integrated Therapeutics CorpKAI PharmaceuticalsMerck & Co., Inc.Millennium Pharmaceuticals, Inc. Novartis PharmaceuticalsNuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics CorporationRoche Diagnostics GmbHSanofi-AventisSanofi-Synthelabo RechercheSchering-PloughSt Jude MedicalThe National Institutes of Health

Integrated Therapeutics CorpKAI PharmaceuticalsMerck & Co., Inc.Millennium Pharmaceuticals, Inc. Novartis PharmaceuticalsNuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics CorporationRoche Diagnostics GmbHSanofi-AventisSanofi-Synthelabo RechercheSchering-PloughSt Jude MedicalThe National Institutes of Health

The TIMI Study Group received research/grant support in the last 2 yrs through Brigham & Women’s Hospital from (alphabetical order):

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

MJ Schweiger, MA Leesar, R Bach, and A Skene received research grant support from Nuvelo; SR Deitcher is an employee of Nuvelo

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

Trial Design: Dose RangingnSTE ACS -> Early Catheterization

rNAPc2 (n=163)IV bolus q 48h

8 escalating doses(1.5, 2, 3, 4, 5, 7.5, 10† mcg/kg)

PlaceboIV q 48hn = 40

ASA, Enox or UFH, GP IIb/IIIa*, clopidogrel*ASA, Enox or UFH, GP IIb/IIIa*, clopidogrel*

PK, PD: pre-dose, 2-6h, 48h, d7, d42Continuous ECG x 7 daysClinical f/u to 6 months

Major Endpoints

Safety

Major/Minor Bleed

Efficacy

F1+2, PT, PK

Holter Ischemia* Encouraged per current practice guidelines† 10 mcg/kg dose panel repeated

Blinded Randomized 4:1

nSTE ACS

Early Cath

nSTE ACS

Early Cath

Heparin De-Escalation (HDE) Design (n=52)

ASA

GP IIb/IIIa*

clopidogrel*

ASA

GP IIb/IIIa*

clopidogrel*

* 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

rNAPc2

10 mcg/kg

rNAPc2

10 mcg/kg

½ Std† UFH (n=26)½ Std† UFH (n=26)

No UFH (n=26)No UFH (n=26)

2 Sequential Panels

Unblinded

PK, PD, Cont ECG, 6 mth clinicalAngiograms reviewed by Core LabThrombosis monitored by Investigators

Endpoints

Major/Minor Bleed

Thrombotic Bailout‡

F1+2, PT, PK

Holter Ischemia

1

2

Entry Criteria and Study Schema

rNAPc2/placebo

(rNAPc2/placebo)

Angio +/- PCIAngio +/- PCI

IV GP IIb/IIIa (encouraged)

144h144h00 48h48h 96h96h

R in hospital

192h192h(8d)(8d)

Enox q 12h or UFHAspirin 75-325 mg daily x 6 mths

Inclusion: Age 18-75, rest sx > 5min w/i 48h c/w ACS+ markers or ST deviation or TIMI Risk Score > 3Planned early invasive strategy

Exclusions: STEMI, creatinine > 4, bleed risk, planned CABG <7d

(rNAPc2/placebo)

Clopidogrel 300/75 (encouraged)

Up to 3 doses administered as determined by clinical circumstances and length of hospitalization

Baseline Characteristics

rNAPc2 PlaceboNo. of patients 215 40Age (median) 58 yrs 56 yrsAge > 65 yrs 28 18Women 34 20nSTE-MI 53 50ST dev > 0.5mm 47 45Diabetes 34 33Mean TIMI Risk Score (0-7) 3.5 3.7

Data shown are % of patients All p = NS

Concomitant Treatments

rNAPc2 Placebo(n=215) (n=40)

# Study drug doses: 1 85 832 14 183 1 0

*Enoxaparin / UFH 71 / 33 75 / 33Clopidogrel 81 85GP IIb/IIIa inhibitor 53 53Treatment Strategy: PCI 45 58

CABG 11 3Medical 44 40

Data shown are % of patients* Excludes 52 patients in the heparin de-escalation phase All p =

NS

# patients: 40 21 21 20 21 20 20 40 26 26 215† 3/4 major bleeds were CABG-related 2-3 days post dose

0

5

10

15

20

placebo 1.5 2 3 4 5 7.5 10 10 10 AllrNAPc2

% P

ati

en

ts

TIMI Minor: >3 to 5 g/dL Hgb loss

TIMI Major: >5 g/dL Hgb loss or ICH

1° Study Endpoint: Adjudicated TIMI Major or Minor Bleeding

2.5

4.8

0 0

4.8 5.0 5.0

7.5

3.7*

Dose of rNAPc2 (mcg/kg)

# bleeds ->1 1 1 1 1 3† 4†

4

p-value for trend = 0.23

p = NS for each pairwise comparisons with placebo

*p = 0.50 for comparison with placebo (1° endpoint)

0 1

3.8

Dose- Ranging Phase HDE AllrNAPc2

Other Safety EndpointsrNAPc2 Placebo

(n = 215) (n = 40) P-value

Minimal Bleeding 9.8 10.0 NSProvoked by procedure 8.4 5.0 NSSpontaneous 1.4 5.0 NS

RBC Transfusion 5.6 2.5 NSFresh Frozen Plasma 1.4 2.5 NSPlatelet Transfusion 0.5 2.5 NSRecombinant FVIIa (antidote) 0 0 --Serious Adverse Events 30 33 NSrNAPc2 Antibody @ 42d 13* 0 0.01 Data shown are % of patients* No allergic symptoms, anaphylaxis, or clinical manifestations were reported

Plasma Concentration of rNAPc2 (Dose Ranging Phase)

0

25

50

75

100

125

150

175

200

Baseline 2-6h 48h 7d post

10 mcg/kg

7.5 mcg/kg

5.0 mcg/kg

4.0 mcg/kg

3.0 mcg/kg2.0 mcg/kg

1.5 mcg/kg

Placebo

rNAPc2 (ng/mL) rNAPc2 dose

Trend p <0.0001 at 2-6h and 48h

Median International Normalized Ratio (INR) – Dose Ranging

1

1.25

1.5

1.75

2

2.25

2.5

Baseline 2-6h 48h 7d post

10 mcg/kg7.5 mcg/kg5.0 mcg/kg4.0 mcg/kg3.0 mcg/kg2.0 mcg/kg1.5 mcg/kgPlacebo

INR rNAPc2 dose

Trend p <0.0001

Trend p = 0.02

Correlation of Log Conc and INR

Adjusted r2 = 0.26 correlation coefficient = 0.51 p < 0.0001

log(rNAPc2 concentration µg/kg)

INR

3 4 5 6

12

34

5

2-6 hours post dose

F1+2 Concentration: A Measure of New Thrombin Generation (All Pts)

-20

-15

-10

-5

0

5

10

15

20

25

30

Placebo 1.5-5 mcg/kg7.5 mcg/kg10 mcg/kg

%in Median F1+2 from Randomization

rNAPc2 dose

Randomization 2-6h 48h

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

*

**†

***

Incidence of Ischemia by Dose

21

33

21

26

119.0

17

37

0

5

10

15

20

25

30

35

40

placebo 1.5 2 3 4 5 7.5 10

7/34

% pts

6/18 4/19 5/19 7/19 3/18 2/18 7/79

Dose of rNAPc2 in mcg/kg

Trend p = 0.013

• Median duration of recording was 6.7 days

• Continuous ECGs were interpreted by a blinded central core laboratory

20.6

9.3

26.9

0

5

10

15

20

25

30

placebo rNAPc2 1.5-5 mcg/kg rNAPc2 7.5-10 mcg/kg

Incidence of Ischemia

% pts

p = 0.64

p = 0.12

p = 0.002

3-way p = 0.007

7/34 25/93 9/97

Heparin De-Escalation Results

Unblinded HDE Double-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

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 identified in patients receiving 10 mcg/kg rNAPc2 + standard heparin

Clinical Endpoints at 42 DaysrNAPc2 placebo (n=215) (n = 40)

All-cause Mortality 0 0New Myocardial Infarct* 2 3Clinical Rec Ischemia* 8 8D / MI* / RI* 10 10 Holter ischemia* 0-7 days 18 21Revasc post discharge 10 13Stroke 0.5 0Any of the above 30 38

Data shown are % of patients* Central blinded adjudicated All p = NS

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

Summary and Conclusions