Vasodilator Induced Stress In CONcordance with Adenosine

Binodenoson 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 Pixton

for the VISION 302 and 305 Investigators

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

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

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

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

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

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

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

2-7 Days2-7 Days

Study Design: VISION 302 and 305

Eligible Patients Randomized to Sequence

adenosineadenosine

adenosineadenosine binodenosonbinodenoson

binodenosonbinodenoson

1st Scan1st Scan““MPI #1”MPI #1”

2nd Scan2nd Scan““MPI #2”MPI #2”

2-7 Days

Identical image protocols, camera, isotope, doses, acquisition times and image Identical image protocols, camera, isotope, doses, acquisition times and image time post-dose, time of day, background anti-anginal meds heldtime post-dose, time of day, background anti-anginal meds held

adenosineadenosineadenosineadenosine

adenosineadenosineadenosineadenosine

VISION 305

Double-Blind, Double-Dummy Drug Administration

placeboplacebo0.06 mL/kg0.06 mL/kgin 30 secsin 30 secs

binodenosonbinodenoson1.5 1.5 g/kgg/kgin 30 secsin 30 secs

adenosine, 140 adenosine, 140 g/kg/min x 6 ming/kg/min x 6 min

placebo, 0.047 mL/kg/min x 6 minplacebo, 0.047 mL/kg/min x 6 min

-30 sec 0 1 2 3 4 5 6Time (min)

RPor

RP = radiopharmaceutical

Demographics

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%

VISION 302 VISION 305n=415 n=427

Demographics

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)

n=415 n=427

Reason for referral:Chest Pain 94% 97%Prior MI 4% 7%Prior CABG/PCI 9% 15%

VISION 302 VISION 305

Actual6%

45%24%26%

Target5%

45%25%25%

Low LKIntermed LK

High LKKnown CAD

Actual5%

44%10%41%

Target5%

45%10%40%

Data Analysis and Results

Efficacy: SPECT image concordance

• Methodology

• Results

Side effects

• Methodology

• Results

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

Methods: Segmental Scoring of MPI

Each segment at stress/rest from 0=NL, to 4=severe defectDerived global scores: SSS: sum of stress scores = total abn myocardium at stressSRS: sum of rest scores = extent of infarctSDS = SSS - SRS = extent/severity of ischemia

Circulation 2002

Analysis of SDS

Binodenoson Adenosine SDS = 9 SDS = 8

Stress

Rest

Difference between studies =

SDSbino – SDSadeno = 1 SDS unit

Stress

Rest

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)

Primary Endpoint Analysis of SDS Difference

-3 -2 -1 0 1 2 3

Mean SDS Difference Bino - Adeno

Hypothesis: 95% CI of mean SDS Bino – Adeno difference is within +/- 1.5 SDS units

VISION 302

VISION 305

-1.5 1.5SDS units

Data Analysis and Results

Efficacy: SPECT image concordance

• Methodology

• Results

Side effects

• Methodology

• Results

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

Frequency (%) of Pre-Specified Side Effects

2-3o AVB

Flushing

Chest Pain

Dyspnea

Nausea

Headache

Abdm Discmft

Dizziness

BinoBino

N=402N=402

0*

32*

38*

42*

18

43

25

19

AdenoAdeno

N=404N=404

3%

50

61

51

22

35

28

17

BinoBino

N=419N=419

0*

38*

38*

45*

16*

47

34

19

AdenoAdeno

N=421N=421

1%

58

61

54

22

42

28

19

VISION 305VISION 302

*p<0.05 in sequential testing

Patient-Rated Intensity of Side Effects: 1-10 Visual Analog Scale

Flushing

Chest Pain

Dyspnea

Nausea

Headache

Abdm Discmft

Dizziness

BinoBino

N=402N=402

1.4*

1.7*

2.0*

0.8

1.9

0.9

0.7

AdenoAdeno

N=404N=404

2.8

3.6

2.9

1.1

1.8

1.3

0.8

BinoBino

N=419N=419

1.4*

1.5*

2.0*

0.7*

2.0

1.4

0.7

AdenoAdeno

N=421N=421

2.8

3.3

2.9

1.2

2.0

1.4

0.9

VISION 305VISION 302

*p<0.05 in sequential testing

Blinded Patient Responses to“Which Treatment Did You Prefer?”

71%71%

20%20%

9%9%0

10

20

30

40

50

60

70

80

Bino Adeno No Pref

Per

cen

t

68%68%

21%21%

11%11%

P=0.001P=0.004

VISION 302 VISION 305

Bino Adeno No Pref

Summary

Efficacy In both trials, the extent and

severity of SPECT MPI reversible perfusion defects (ischemia) were similar with binodenoson as with adenosine

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

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