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Does the Elinogrel Data Support a Phase 3 Study? Sunil V. Rao MD The Duke Clinical Research Institute Duke University Medical Center Sunil V. Rao, MD Honoraria: Ikaria My presentation will include off-label discussions: Bivalirudin for ACS, Fondaparinux for ACS and Clopidogrel post-stent Disclosures Research funding Cordis Corporation, Ikaria, sanofi-aventis Consultant Zoll, Terumo Medical, Daiichi Sankyo-Lilly Speakers’ Bureau The Medicines Co, Abbott Vascular, Boehringer Ingelheim Off-label uses of drugs or devices may be discussed during this lecture Elinogrel What is Elinogrel? How does it work? What are the data? Does it justify moving to a larger trial? Background • Antiplatelet therapy is essential to reduce adverse events in patients with ischemic heart disease • Recent clinical trials demonstrate that greater platelet inhibition is associated with improved ischemic outcomes, but increased major bleeding • Reversible platelet inhibition may mitigate these risks and further improve outcomes • Elinogrel is a novel potent platelet inhibitor that competitively and reversibly binds to the P2Y12 receptor and can be administered both intravenously and orally 5 Rao SV. ESC 2010 Properties of Elinogrel • The only reversible and competitive P2Y12 receptor antagonist • Direct-acting: no metabolic activation required • Available for intravenous and oral administration, enabling acute and chronic use • Immediate and near maximal platelet inhibition achieved with IV • Duration of action ‐ Half-life: 12 hours • No major CYP metabolism – low potential for drug-drug interactions (including PPIs) • Balanced clearance: 50% renal; 50% hepatic (10% metabolized to pharmacologically inactive metabolite) 6 Rao SV. ESC 2010 ADP in Platelet Thrombosis Genetic and pharmacological targeting has shown that continued P2Y12 signaling by the < 1 mM ADP generated by platelets during thrombosis at arterial rates of shear is required to maintain stable thrombi ADP P2Y12 Thrombin GP IIb-IIIa Fibrinogen, vWf Collagen 7 Fibrinogen Local change in ADP concentration* local change in elinogrel anti-platelet effect *BJ Folie and LV McIntire, Biophys J.,56, 1121-1141 (1989). G.V. Born and MA Kratzer, J.Physiol., 354, 419-429 (1984) 8 Local change in ADP concentration local change in elinogrel anti-platelet effect Thrombosis (Efficacy) Blood Flow/Shear High Low ADP concentration* Low High Antiplatelet Effect clopidogrel/prasugrel +++ +++ Antiplatelet effect – elinogrel +++ + *BJ Folie and LV McIntire, Biophys J.,56, 1121-1141 (1989). G.V. Born and MA Kratzer, J.Physiol., 354, 419-429 (1984) 9 Hemostasis (Bleeding) Effects of elinogrel vs thienopyridines on thrombosis and bleeding in the mouse Hemostasis clopidogrel elinogrel elinogrel clopidogrel prasugrel (blood loss following tail transection) I H I M H I MH IM Blood Volume Loss (uL) 700 H I MH † † prasugrel IM H M † • 600 500 Thrombosis (FeCl3 injury to 400 mesenteric arteries 300 ‡ 200 ‡ ‡ * * ‡ P<0.0001 vs Prasugrel eq. dose * P<0.005 vs clopidogrel eq. dose . P<0.005vs P2Y 12 KO † P<0.0005 vs P2Y12 KO 100 P R T0 V .C tl 60 12 P 8 R 7. T0 5 60 1 P 28 R T0 20 60 12 8 60 C lo p. 1. 5 C lo p. 15 C lo p. 50 P ra s. 1 P ra s. 3 P ra s. 1 P 2Y 0 12 K O BLQ<10 0 At each dose level, elinogrel consistently caused less effect on hemostasis. Doses (mg/kg) selected to yield equivalent inhibition of High dose clopidogrel and prasugrel effect hemostasis more than P2Y12-/thrombosis (p<0.001 vs vehicle control) mice 10 Inclusion & Exclusion Criteria INCLUSION • Nonurgent PCI with ≥ 1 coronary lesion amenable to PCI EXCLUSION • Bleeding risk ‐ Anemia/thrombocytopenia, recent trauma or bleeding, CVA or TIA within prior 5 years • Concomitant therapies ‐ Clopidogrel loading dose within 7 days prior to PCI, thrombolytics, oral anticoagulants, fondaparinux • General ‐ Age > 75 yrs, weight < 55 kg, CrCL < 45 cc/min, allergy to study drugs 11 Leonardi S, Rao SV, Harrington RA, et. al. AHJ 2010 Treatment Schema ACUTE PHASE CHRONIC PHASE Peri-PCI ARM 1: clopidogrel Post-PCI 300-600mg Loading Dose PCI 75 mg QD n=200 ARM 2: elinogrel 80 mg IV Bolus+ 50mg PO PCI 50 mg BID n=200 ARM 3: elinogrel 120 mgIVIV 80mg Bolus ++ 100mg 100mg PO PO Bolus PCI 100 mg BID n=200 80mg 120 mgIVIV ARM 4: n=200 150 mg BID PCI Bolus + 150mg PO elinogrel • April 8, 2009 (116 pts enrolled): The DSMC recommended discontinuation of the 50 mg BID dose and increasing IV bolus dose to 120 mg as per protocol • April 16, 2009: Chronic phase extended from 60 days to 120 days of treatment 12 Rao SV. ESC 2010 Endpoints Safety – 24-hr or d/c & 120-day Clinical efficacy • TIMI bleeding: major, minor, • 24-hr or d/c death, MI, stroke, uTVR, GP IIb/IIIa bailout, stent thrombosis bleeding requiring medical attention • Clinically relevant bleeding: major, minor, nuisance • 120-day death, MI, Biological efficacy - periprocedural • 120-day death, MI, stroke, uTVR • Any Troponin* elevation at 24 hrs or d/c • Troponin* elevation > 2 X ULN at 24 hrs or d/c 13 Rao SV. ESC 2010 *Core lab troponin I stroke, uTVR, stent thrombosis INNOVATE-PCI Enrollment US and Canada 424 Europe 228 Canada 132 United States 292 Germany Poland 126 74 Austria 28 14 Rao SV. ESC 2010 Baseline Characteristics Clopidogrel (N=208) Pooled elinogrel 100 mg (N=201) Pooled elinogrel 150 mg (N=207) 61 61 61 Male (%) 77% 77% 78% BMI (kg/m2) 29.0 28.6 29.4 Diabetes mellitus 36% 30% 40% Prior MI 37% 36% 33% ASA 96% 95% 93% On maintenance clopidogrel 46% 46% 45% Femoral access 70.7% 74.0% 75.0% Vascular closure device 33.2% 29.5% 28.9% Median age (yrs) 15 Rao SV. ESC 2010 Pharmacodynamic Effect of Elinogrel vs. Clopidogrel PD Sub-study 5 uM ADP - Peak Peri-PCI 70 Extent of platelet aggregation (%) C (N=17) E100 (N=12) E150 (N=17) 60 50 40 * pre-2nd oral dose * pre-3rd oral dose or discharge * 30 clopidogrel 20 120mg IV + 150mg oral 120mg IV + 100mg oral 10 0 0 0.5 2 6 8 20 TIME AFTER DOSING (hrs) 74% of pts represented above were on maintenance clopidogrel 16 * p<0.025 for both elinogrel vs. clopidogrel comparisons Median, quartiles Pharmacodynamic Effect of Elinogrel vs. Clopidogrel PD Sub-study 5 uM ADP - Peak Day 30 60 Extent of platelet aggregation (%) C (N=17) E100 (N=12) E150 (N=17) 50 40 30 clopidogrel 100mg oral predose 20 150mg oral 10 0 0 2 6 TIME AFTER DOSING (hrs) 17 Rao SV. ESC 2010 Median, quartiles Bleeding at 24 hrs or d/c – TIMI Scale Event Rate (%) Rates and 95% confidence intervals 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Pooled Clopidogrel (n=208) Pooled Elinogrel 80mg IV (n=122) Pooled Elinogrel 120mg IV (n=312) TIMI Major * Mainly at access site 18 TIMI Minor Bleeding Requiring Medical Attention * Rao SV. ESC 2010 Bleeding at 24h-120d – TIMI Scale Rates and 95% confidence intervals 11 Pooled Clopidogrel (n=208) Event Rate (%) 10 9 Pooled Elinogrel 100mg po (n=201) 8 Pooled Elinogrel 150mg po (n=207) 7 6 5 4 3 2 1 0 TIMI Major 19 Rao SV. ESC 2010 TIMI Minor Bleeding Requiring Medical Attention Efficacy at 24 hrs or Discharge Clinical and Biological Endpoints Rates and 95% confidence intervals 35 Event Rate (%) 30 Pooled Clopidogrel (n=208) Pooled Elinogrel 80mg IV (n=118) 25 Pooled Elinogrel 120mg IV (n=312) 20 15 10 5 0 D/MI/S/uTVR/2b3a/ST 20 Rao SV. ESC 2010 Any Tn Elevation Any Tn > 2 X ULN Efficacy at 24h-120 Days Event Rate (%) Rates and 95% confidence intervals 8 Pooled Clopidogrel (n=208) 7 Pooled Elinogrel 100mg (n=200) Pooled Elinogrel 150mg (n=204) 6 5 4 3 2 1 0 Death/MI/Stroke/uTVR 21 Rao SV. ESC 2010 Death/MI/Stroke/uTVR/ST Adverse Events Clopidogrel N=208 Pooled elinogrel 100 mg N=201 Pooled elinogrel 150 mg N=207 Any SAE 11.1% 14.9% 12.6% Drug d/c due to AE or SAE 7.2% 7.5% 10.1% Dyspnea* 4.3% 15.4% 12.1% Bradycardia 0.5% 1.0% 0.5% Syncope 0.5% 1.5% 0.5% ALT/AST > 3x^ 1.0% 4.0% 4.8% ALT/AST > 5x 0.5% 2.0% 3.4% * Dyspnea was generally mild, transient, and infrequently led to discontinuation ^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when treatment was continued; No Hy’s Law cases. 22 Conclusions • IV and oral elinogrel result in greater and more rapid antiplatelet effect than clopidogrel during both the acute and chronic phase of therapy • No excess TIMI major or minor bleeding at both the 24-hr and 120-day timepoints • Dose-dependent trend of increase in less severe bleeds (Bleeding Requiring Medical Attention), mostly occurring at the vascular access site in the peri-procedural period • No significant differences in efficacy at 24 hrs or 120 days (trial not powered for efficacy) 23 Conclusions (2) • Adverse events similar between elinogrel and clopidogrel ‐ Dyspnea more frequent in the elinogrel arms • Mild, transient, infrequently led to discontinuation ‐ Excess in transaminase elevation cases in the elinogrel arms • Occurred early and were generally asymptomatic • All resolved even when treatment was continued • No Hy’s Law cases 24 What is a phase 2 trial? PHASE II TRIALS: Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. A unicorn? Phase 2 trials are NOT phase 3 trials Not usually powered for clinical endpoints Unusual to see statistically significant differences in clinical outcomes An overwhelmingly positive Phase 2 trial is a unicorn… We all wish they existed, but they don’t! So…is a phase 3 trial justified? Yes! Attractive IV to oral transition The drug inhibits platelets PK/PD data Bleeding Only way to determine efficacy, safety, and liver outcomes is with an adequately powered pahse 3 trial www.scripintelligence.com