Study funded by Molecular Insight Pharmaceuticals. All investigators

Phase 2B Study of the Safety and Efficacy of [123I]-BMIPP for Identification of Ischemic

Myocardium Using SPECT in Adults Admitted to the ED for Evaluation of an

Acute Coronary Syndrome

James E. Udelson MD, Timothy Bateman MD, Ethan Spiegler MD, Steven Bergmann MD, Ami Iskandrian MD, John Mahmarian MD,

Gary Heller MD PhD, Michael Kontos MD, Jack Ziffer MD,

Nicholas Borys MD, Norman LaFrance MD,

John Babich PhD, Ernest Garcia PhD

Study funded by Molecular Insight Pharmaceuticals. All investigatorsreceived research support from MIP. JEU and EG are consultants to MIP. JB, NL, NB are employees of MIP.

BackgroundBackground

Data suggest that BMIPP imaging of FA metabolism may have advantages in the dx of ACS compared with existing techniques:

• Better accuracy due to “Ischemic Memory”, identifying ischemia up to 30 hours after symptoms subside

• Reduced radiation exposure

• Possibly eliminating need for pharmacologic / exercise stress

Study ObjectivesStudy Objectives

• To evaluate the performance characteristics (sensitivity, specificity, positive and negative predictive value) of [¹²³I]-BMIPP imaging for detection / exclusion of ACS

• To evaluate the safety of [¹²³I]-BMIPP in patients with suspected ACS

Study DesignStudy Design

• Phase 2B, at 9 US sites• Pts w suspected ACS being initially

evaluated in the ED, to be stratified based on LK of ACS

• BMIPP SPECT imaging within 30 hrs of cessation of sx, after rest injection

• Safety evaluations during admission and up to 30 days post-discharge

Inclusion CriteriaInclusion Criteria

• > 30 years of age, to be admitted via ED for further evaluation of possible ACS

• If female, then not of childbearing potential or negative serum or urine ßHCG pregnancy test within 24 hours prior to receiving test drug

• Able to undergo BMIPP imaging beginning within 30 hrs of symptom cessation

Exclusion CriteriaExclusion Criteria

• History of LVEF < 40%

• Clinical hx of previous MI, Q-waves on ECG consistent with previous MI, or acute STEMI

• Left bundle branch block on ECG

• Known history of significant drug allergy or allergy to contrast media or iodine/iodides

• Formerly or currently on medication that targets fatty acid uptake or metabolism (e.g., etomoxir)

• Serum creatinine level > 2.0 mg per deciliter

Stratifying Likelihood of ACSStratifying Likelihood of ACS

Each pt must ALSO meet criteria for one of 3 LK strata:

Stratum A: HIGH LK FOR ACS

• Sx of ACS, accompanied by at least one of:

• New ST-segment depression

• T-wave inversion

• Elevated initial levels of troponin

Stratum B: INTERMEDIATE LK FOR ACS

• Known hx CAD, by cath or prior revasc, without hx of previous MI

• No stratum A criteria

Stratum C: LOW LK FOR ACS

• Pts who do not meet criteria for Stratum A or B and meet all the following:

• Sx possibly consistent with ACS

• ECG without findings diagnostic for acute ischemia

• Normal initial troponin

[¹²³I]-BMIPP Study Procedures[¹²³I]-BMIPP Study Procedures

Hospitalization Follow-Up

TIME (min) 0 10 20

Inject [¹²³I]-

BMIPP

BMIPP SPECT ~10 Min

IF INDICATED STRESS

MPI

STUDY

ENROLLMENT

IF INDICATED, CORONARY

ANGIOGRAPHY,

REVASCULARIZATION

30 day phone

follow-up for events

and safety

BMIPP SPECT Imaging BMIPP SPECT Imaging

• Dose of 2.5 – 5.4 mCi

• Rest SPECT imaging beginning ~10 mins following injection

• Imaging with double- or triple-headed cameras, LEHR collimators, centered on the 159 keV photopeak of 123I

• No attenuation or scatter correction

BMIPP SPECT Image AnalysisBMIPP SPECT Image Analysis

QA following development of gender-specific QA following development of gender-specific normal DBnormal DB

• 30 women and 30 men with < 5% LK CAD• 20 women and 20 men with known CAD of

varying extent (1-, 2-, and 3VD)• Imaging:

• Normals: rest BMIPP SPECT• CAD pts: rest BMIPP SPECT within 24

hours after inducing ischemia by treadmill exercise

• Subsequent optimization of QA thresholds for abnormality

Folks et al, Folks et al, ASNC 2007ASNC 2007

Mean NormalPatient ProfileMean - SD

0º 90º 180º 270º 360º

% C

ou

nts

Angle

“Risk Stratified” Criteria for BMIPP Defects

LLN

High 2 SD

Int 2.5 SD

Low 3 SD

Criteria for abnormality = 3% LV extent

LK ACSLK ACS

LLN

LLN

Mean NormalPatient Profile

0º 90º 180º 270º 360º

% C

ou

nts

Angle


LLNLowLow 3 SD3 SD


LK ACSLK ACS

Low LK ACSLow LK ACSPatient => Patient =>

NormalNormal

Mean NormalPatient ProfileMean - SD

0º 90º 180º 270º 360º

% C

ou

nts

Angle


LLN

Low 3 SD


High LKHigh LKACS pt =>ACS pt =>

Abnormal by Abnormal by High LK criteriaHigh LK criteria

High 2 SD

LK ACSLK ACS

Study Population SampleStudy Population Sample

Dosed/Complete data for final dx (n) 105 / 97Age (yrs, SD) 56 (13)Women (%) 45Prior MI (%) 0Known CAD / CABG / PCI (%) 36 / 8 / 21Race (%)

Caucasian 52AA 31Hispanic 11

Relation of Sx to BMIPP imagingSx ongoing (% of pts) 32Cessation of sx prior to imaging (%)

0-9 hrs 239-30 hrs 45

Mean time from Sx cessation (hrs) 14 (9)

Final Diagnosis of ACSFinal Diagnosis of ACS

97 pts w complete study data

Low LK ACS

n = 49

Int LK ACS

n = 20

High LK ACS

n = 28

ACS +

n = 3

(prev = 6%)

ACS +

n = 4

(prev = 20%)

ACS +

n = 19

(prev = 68%)

Adjudicated Final Diagnosis

0102030405060708090

100

%

Sens Spec NPV PPV Sens fortrop+ MI

Performance Characteristics of BMIPP Imaging for Detecting ACSPerformance Characteristics of BMIPP Imaging for Detecting ACS

For ACS Dx

85

0102030405060708090

100

%



For ACS Dx

95%% CI: 69,94

85

59

0102030405060708090

100

%



For ACS Dx

95%% CI: 69,94 54,62

85

59

91

0102030405060708090

100

%



For ACS Dx

95%% CI: 69,94 54,62 83,96

85

59

91

43

0102030405060708090

100

%



For ACS Dx

95%% CI: 69,94 54,62 83,96 35,48

85

59

91

43

100

0102030405060708090

100

%



For ACS Dx

95%% CI: 69,94 54,62 83,96 35,48 85,100

BMIPP Imaging in Suspected ACSBMIPP Imaging in Suspected ACS

Pt 310

• 45 yo woman w sx suspicious for ACS (CP x 20 mins)• Initial troponin mildly positive• Peak trop 0.63 ng/mL (ULN 0.2)• BMIPP injected 26 hrs after sx subsided• Cath: LAD 70%, LCx 50%, RCA NL => PCI of LAD

Rest BMIPP SPECTRest BMIPP SPECT

• 48 yo man w sx suspicious for ACS (CP x 30 mins), no prior hx CAD• No ECG changes, initial troponin -• Int LK for ACS• All troponins -• BMIPP injected 8 hrs after sx subsided• Follow-up SPECT: partially reversible lateral wall defect

Pt 403



• 68 yo man w sx suspicious for ACS, prior hx angina, no prior MI• T wave inversions• Initial trop 0.66 ng/mL (ULN 0.1)• Peak trop 1.52 ng/mL• BMIPP injected 20 hrs after sx subsided• Cath: RCA 99%, LAD 95%, LM 75% =>CABG

Pt 508



Quantitative BMIPP DefectsQuantitative BMIPP Defects

16.5

1

20.5

6

0

5

10

15

20

25

Med

ian

BM

IPP

Def

ect

Siz

e (%

LV

Ab

nl

by

QA

)

ACS + ACS - True Pos False Pos

25th, 75th%ile: 6,31 0,5 8,32 4,14

p < 0.0001 p = 0.005

Safety DataSafety Data

• No pt discontinued from study due to adverse event

• 1 SAE – considered by PI as not related to study drug

• No pre- to post-dose changes in lab parameters considered clinically significant

SummarySummary

• In ED pts with suspected ACS, using a novel gender-specific, risk-stratified QA approach, BMIPP imaging demonstrated sensitivity and NPV for ACS similar to that reported for rest MPI

• However, these data were seen even though BMIPP was performed up to 30 hrs after cessation of sx, at mean 14 hrs

• Sensitivity for troponin+ MI is higher in this sample than previously reported for MIBI

• Safe and well-tolerated, consistent with Japanese experience

ConclusionsConclusions

• BMIPP imaging, even many hrs after cessation of symptoms, can detect or rule-out ACS / MI in ED pts with suspected ACS with clinically relevant performance

• The ability to image prolonged post-ischemic abnormalities in FA metabolism (“ischemic memory”), allowing imaging long after symptoms subside, is unique in this setting

• These data support the performance of larger pivotal trials, now ongoing, in this population

Documents

Study funded by Molecular Insight Pharmaceuticals. All investigators