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V asodilator I nduced S tress I n C ON cordance with Adenosine Binodenoson Pivotal Clinical Trial Program.

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  1. Vasodilator Induced Stress In CONcordance with AdenosineBinodenoson Pivotal Clinical Trial Program James E. Udelson, Bruce Iteld, Fred Weiland, Jack Foster, Robert Bonow, Edward Ficaro, Raymond Gibbons, Gary Heller, Frans Wackers, Richard Barrett, Glenn Pixtonfor the VISION 302 and 305 Investigators

  2. Disclosures • Drs. Udelson, Iteld, Weiland, Foster, Bonow, Ficaro, Gibbons, Heller and Wackers received research grant support and/or consulting honoraria from King Pharmaceuticals R&D • All investigators and/or their institutions received research grant support from King Pharmaceuticals R&D • Drs. Barrett and Pixton are employees of King Pharmaceuticals R&D

  3. Background • Vasodilator stress is widely used in lieu of exercise for SPECT MPI • Mechanism: stimulation of adenosine A2a receptors coronary arteriolar dilation, decreased resistance and increased CBF • Stimulation of other adenosine receptors (A1, A2b, A3) high incidence of side effects (>80%), including 2o/3o AVB, CP, SOB, flushing • More selective A2a receptor stimulation desirable

  4. Background (con’t) • Binodenoson is a highly selective A2a agonist • In Phase 2 cath lab studies, CBFR with I.V. binodenoson was similar to that seen with I.C. adenosine • Phase 2 studies suggested SPECT image concordance with adenosine, and fewer/less severe side effects than adenosine in single-blind studies

  5. VISION Pivotal Trial Program:Primary Objective • To demonstrate that SPECT MPI acquired during binodenoson-stress and adenosine-stress detect similar magnitudes of ischemia in the same patients

  6. Secondary Objectives • To evaluate and compare side effects between binodenoson and adenosine: • Incidence of 2nd or 3rd degree AV block • Incidence, intensity of reported side effects, patient preference

  7. Study Design • Two multi-center trials: VISION 302 (40 sites), VISION 305 (39 sites) • Randomized, active-controlled (adenosine), crossover design • Double-blind, double-dummy drug dosing • Enrolled pts were risk-stratified by ACC pre-test LK for CAD, to ensure broad pt representation

  8. Inclusion/Exclusion Criteria • Inclusion: • Referred for clinical pharm stress MPI • Age ≥ 30 years • Typical or atypical anginal pain • Provide informed consent • Exclusion: • Pregnancy • Very low pre-test LK for CAD • MI within 30 days, PCI or CABG within 3 years, unless new angina • Contraindications for adenosine • LVEF < 0.35, or NYHA HF Class IV

  9. Study Design: VISION 302 and 305 VISION 305 adenosine adenosine Eligible Patients Randomized to Sequence 1st Scan “MPI #1” adenosine binodenoson 2-7 Days 2-7 Days 2nd Scan “MPI #2” binodenoson adenosine Identical image protocols, camera, isotope, doses, acquisition times and image time post-dose, time of day, background anti-anginal meds held

  10. Double-Blind, Double-Dummy Drug Administration adenosine, 140 g/kg/min x 6 min placebo, 0.047 mL/kg/min x 6 min placebo 0.06 mL/kg in 30 secs RP or binodenoson 1.5 g/kg in 30 secs -30 sec 0 1 2 3 4 5 6 Time (min) RP = radiopharmaceutical

  11. Demographics VISION 302 VISION 305 n=415 n=427 Gender (M / F) 37% / 63% 46% / 54% Age (Years, SD) 63.3 (12.0) 62.9 (11.9) BMI (kg/m2, SD) 31.4 (7.0) 31.3 (6.5) Reason for referral: Chest Pain 94% 97% Prior MI 4% 7% Prior CABG/PCI 9% 15%

  12. Demographics VISION 302 VISION 305 n=415 n=427 Gender (M / F) 37% / 63% 46% / 54% Age (Years, SD) 63.3 (12.0) 62.9 (11.9) BMI (kg/m2, SD) 31.4 (7.0) 31.3 (6.5) Reason for referral: Chest Pain 94% 97% Prior MI 4% 7% Prior CABG/PCI 9% 15% Target 5% 45% 25% 25% Actual 6% 45% 24% 26% Target 5% 45% 10% 40% Actual 5% 44% 10% 41% Low LK Intermed LK High LK Known CAD

  13. Data Analysis and Results • Efficacy: SPECT image concordance • Methodology • Results • Side effects • Methodology • Results

  14. Methods: SPECT Image Reviews • Compliant: with FDA Guidelines • Independent Readers: No other involvement with studies or development program, no knowledge of other readers’ interpretations • Blinded: to all treatment data • Separated: Reader reviews of both MPI studies from same patient were separated by 2 weeks or ≥ 50 studies

  15. Methods: Segmental Scoring of MPI Each segment at stress/rest from 0=NL, to 4=severe defect Derived global scores: SSS: sum of stress scores = total abn myocardium at stress SRS: sum of rest scores = extent of infarct SDS = SSS - SRS = extent/severity of ischemia Circulation 2002

  16. Analysis of SDS Stress Stress Rest Rest Binodenoson Adenosine SDS = 9 SDS = 8 Difference between studies = SDSbino – SDSadeno = 1 SDS unit

  17. Primary Efficacy Endpoint Hypothesis • Mean paired difference between SDS (extent/severity of ischemia) of binodenoson images and adenosine images is within 1.5 SDS units in either direction, and • Fewer than 10% pts with highly discordant results (severe ischemia on one, no ischemia on alternate image)

  18. Paired Difference VISION 302Binodenoson-Adenosine SDS Mean SDS difference = -0.09 140 N=374 120 100 80 Number of patients 60 40 20 0 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 SDS Difference Bino - Adeno

  19. Paired Difference VISION 305Binodenoson-Adenosine SDS 160 140 120 100 80 60 40 20 Mean SDS difference = -0.68 N=391 Number of patients 0 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 SDS Difference Bino - Adeno

  20. Primary Endpoint Analysis of SDS Difference VISION 302 VISION 305 -1.5 1.5 Hypothesis: 95% CI of mean SDS Bino – Adeno difference is within +/- 1.5 SDS units Mean SDS Difference Bino - Adeno -3 -2 -1 0 1 2 3 SDS units

  21. 197 38 14 6 38 13 7 2 9 8 9 5 5 7 6 10 Binodenoson vs. Adenosine AgreementPer-Patient Basis, Reader-Defined SDS VISION 302 Adenosine Binodenoson Normal(SDS: 0-1) Mild(SDS: 2-4) Moderate(SDS: 5-8) Severe(SDS: >8) Normal (SDS: 0-1) Mild(SDS: 2-4) Moderate(SDS: 5-8) Severe(SDS: >8) Patients in Extreme Off-Diagonal Cells: 11/374 (3%) Exact categoricalagreement: 229/374 (61%)

  22. Data Analysis and Results • Efficacy: SPECT image concordance • Methodology • Results • Side effects • Methodology • Results

  23. Assessment of Side Effects: Methodology • When side effects occurred, pts were asked to rate severity on a 1 – 10 point VAS scale • At follow-up, while still blinded, pts were asked which study they preferred • Order of analysis of individual side effects was pre-specified for sequential testing, to account for multiplicity

  24. Frequency (%) of Pre-Specified Side Effects VISION 302 VISION 305 Bino N=402 0* 32* 38* 42* 18 43 25 19 Adeno N=404 3% 50 61 51 22 35 28 17 Bino N=419 0* 38* 38* 45* 16* 47 34 19 Adeno N=421 1% 58 61 54 22 42 28 19 2-3o AVB Flushing Chest Pain Dyspnea Nausea Headache Abdm Discmft Dizziness *p<0.05 in sequential testing

  25. Patient-Rated Intensity of Side Effects: 1-10 Visual Analog Scale VISION 302 VISION 305 Bino N=402 1.4* 1.7* 2.0* 0.8 1.9 0.9 0.7 Adeno N=404 2.8 3.6 2.9 1.1 1.8 1.3 0.8 Bino N=419 1.4* 1.5* 2.0* 0.7* 2.0 1.4 0.7 Adeno N=421 2.8 3.3 2.9 1.2 2.0 1.4 0.9 Flushing Chest Pain Dyspnea Nausea Headache Abdm Discmft Dizziness *p<0.05 in sequential testing

  26. Blinded Patient Responses to“Which Treatment Did You Prefer?” VISION 302 VISION 305 80 71% 70 68% 60 P=0.004 P=0.001 50 Percent 40 30 20 21% 20% 10 11% 9% 0 Adeno No Pref Bino Adeno No Pref Bino

  27. Summary Efficacy • In both trials, the extent and severity of SPECT MPI reversible perfusion defects (ischemia) were similar with binodenoson as with adenosine

  28. Summary Side effects • The incidence and intensity of flushing, chest pain and dyspnea were significantly reduced with binodenoson • Patients preferred binodenoson in a blinded analysis • AV block was not observed with binodenoson

  29. Conclusions • Selective adenosine A2a receptor stimulation with binodenoson for pharmacologic stress MPI: • Can be performed safely with 30 sec bolus dosing • Provides similar clinical information on the extent/severity of ischemia as adenosine • Is associated with a significant reduction in the incidence and intensity of many side effects

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