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Study funded by Molecular Insight Pharmaceuticals. All investigators

Phase 2B Study of the Safety and Efficacy of [ 123 I]-BMIPP for Identification of Ischemic Myocardium Using SPECT in Adults Admitted to the ED for Evaluation of an Acute Coronary Syndrome.

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Study funded by Molecular Insight Pharmaceuticals. All investigators

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  1. 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 investigators received research support from MIP.JEU and EG are consultants to MIP. JB, NL, NB are employees of MIP.

  2. Background 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

  3. Study 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

  4. Study 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

  5. Inclusion 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

  6. Exclusion 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

  7. Stratifying Likelihood of ACS • 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 Each pt must ALSO meet criteria for one of 3 LK strata: • 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

  8. [¹²³I]-BMIPP Study Procedures IF INDICATED STRESS MPI Inject [¹²³I]-BMIPP BMIPP SPECT ~10 Min TIME (min)0 10 20 Hospitalization Follow-Up IF INDICATED, CORONARY ANGIOGRAPHY, REVASCULARIZATION 30 day phone follow-up for events and safety STUDY ENROLLMENT

  9. 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

  10. BMIPP SPECT Image Analysis QA following development of gender-specific normal 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, ASNC 2007

  11. “Risk Stratified” Criteria for BMIPP Defects LK ACS High 2 SD LLN % Counts Int 2.5 SD LLN Low3 SD LLN 0º 90º 180º 270º 360º Angle Criteria for abnormality = 3% LV extent

  12. “Risk Stratified” Criteria for BMIPP Defects LK ACS % Counts Low LK ACS Patient => Normal Low3 SD LLN 0º 90º 180º 270º 360º Angle Criteria for abnormality = 3% LV extent

  13. “Risk Stratified” Criteria for BMIPP Defects LK ACS % Counts High 2 SD LLN High LK ACS pt => Abnormal by High LK criteria Low3 SD 0º 90º 180º 270º 360º Angle Criteria for abnormality = 3% LV extent

  14. Study Population Sample Dosed/Complete data for final dx (n) 105 / 97 Age (yrs, SD) 56 (13) Women (%) 45 Prior MI (%) 0 Known CAD / CABG / PCI (%) 36 / 8 / 21 Race (%) Caucasian 52 AA 31 Hispanic 11 Relation of Sx to BMIPP imaging Sx ongoing (% of pts) 32 Cessation of sx prior to imaging (%) 0-9 hrs 23 9-30 hrs 45 Mean time from Sx cessation (hrs) 14 (9)

  15. Final 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 = 4 (prev = 20%) ACS + n = 19 (prev = 68%) ACS + n = 3 (prev = 6%) Adjudicated Final Diagnosis

  16. Performance Characteristics of BMIPP Imaging for Detecting ACS For ACS Dx

  17. Performance Characteristics of BMIPP Imaging for Detecting ACS 95%% CI: 69,94 For ACS Dx

  18. Performance Characteristics of BMIPP Imaging for Detecting ACS 95%% CI: 69,94 54,62 For ACS Dx

  19. Performance Characteristics of BMIPP Imaging for Detecting ACS 95%% CI: 69,94 54,62 83,96 For ACS Dx

  20. Performance Characteristics of BMIPP Imaging for Detecting ACS 95%% CI: 69,94 54,62 83,96 35,48 For ACS Dx

  21. Performance Characteristics of BMIPP Imaging for Detecting ACS 95%% CI: 69,94 54,62 83,96 35,48 85,100 For ACS Dx

  22. BMIPP Imaging in Suspected ACS • 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 SPECT Pt 310

  23. BMIPP Imaging in Suspected ACS • 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 Rest BMIPP SPECT Pt 403

  24. BMIPP Imaging in Suspected ACS • 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 Rest BMIPP SPECT Pt 508

  25. Quantitative BMIPP Defects p < 0.0001 p = 0.005 25th, 75th%ile: 6,31 0,5 8,32 4,14

  26. Safety 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

  27. Summary • 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

  28. Conclusions • 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

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