NearIR Spectroscopic NIRS Technology Update James Muller MD

` Near-IR Spectroscopic (NIRS) Technology Update James Muller MD CEO, Infra. Re. Dx, Inc.

DISCLOSURES James E. Muller, MD Salary – Infra. Re. Dx, Inc.

Spectroscopy to Identify Chemical Composition of Unknown Substances absorbance 1. 0 0. 8 0. 6 Cholesteryl Oleate Cholesterol Collagen 0. 4 Cholesteryl Linoleate 0. 2 1100 1200 1300 1400 1500 1600 1700 1800 1900 Wavelength nm Pure substances studied on benchtop without blood interference 3

Selection of Electromagnetic Wavelength Region for Spectroscopic Lipid-core Plaque Identification in Vivo Infrared region -- valuable for identification of complex molecules but difficult in vivo Near-infrared spectroscopy is feasible for in vivo use – chemical information from overtones of vibrations X-Ray Gamma Ray Inner Electron Nuclear Visible Ultraviolet Bonding Electrons Microwave Infrared Molecular Rotations Molecular Vibrations Radio Nuclear Spin in Magnetic Field 10 -11 10 -9 10 -7 10 -5 10 -3 10 -1 103 l, cm 1011 109 107 105 103 101 10 -3 n, cm-1 1021 1019 1017 1015 1013 1011 109 107 n, Hz Tissue damage Water absorption w

Spectroscopy Instrumentation Tunable Source and Detector Sample Fiber delivery and collection

From Spectrum to Chemogram Multiple components Complex mixture spectra Sl p m x ÷ √ Algorithms extract the relevant portions of the mixture signal and create a probability map of lipid rich plaque l High scatter ms Medium scatter ms ms Low scatter l l Variable scattering properties

Mountain View and “Lipid Core Burden Index” LCBI = Fraction of Chemogram image pixels above probability of 0. 6 Scaled from 0 to 1000

Validation NIR vs. Histology in Human Coronary Autopsy Specimens Arteries studied in blood-perfused system with histologic registration via a slotted fixture Over 2, 000 spectra acquired in over 550 NIR pullbacks of 51 validation hearts

Definition of lipid-core plaque of interest Lipid rich plaque of interest • 2 mm Histologic Sectio Lipid-core plaque of interest definition: • Fibroatheroma • Necrotic core > 0. 2 mm thick and > 60 degrees in angular extent • Cap thickness < 0. 45 mm (average minimum thickness = 0. 17 mm) Negative • 115 LRP(+) blocks found by histology (4. 3% prevalence)

Comparison of Chemogram with Histology Truth 45 yo female Cause of Death: anoxia high low

Chemogram and Histology of LCP Narrowing 11

NIR accuracy versus histology in autopsy specimens – AUC = 0. 80 (95%CI: 0. 76 -0. 84) in vivo Sl pm x÷√ ex vivo

Clinical Validation of NIR SPECTACL Clinical Study In Vivo Clinical Spectra ≈ Ex Vivo Autopsy Spectra ≈ Histology Ex Vivo Autopsy Study Autopsy study Gardner, et al, Ø In-Vivo Study, Waxman et al, JACCi 2009 JACC Imaging, § Study of 100+ patients in 6 hospitals 2008. § Endpoint -- spectral similarity between patient scans and autopsy scans

FDA Statement re Intracoronary NIR Spectroscopy “This is the first device that can help assess the chemical make-up of coronary artery plaques and help physicians identify those plaques with lipid cores, which may be of particular concern. ” Daniel Schultz, M. D. , Director of the Center for Devices and Radiological Health, April, 2008

Multimodality Imaging IVUS NIR-IVUS-Histo