The Role le of In Intravascular Im Imaging of Lip ipid Core in - PowerPoint PPT Presentation

The Role le of In Intravascular Im Imaging of Lip ipid Core in in Cardiovascular Drug Development Sean Madden, PhD VP of R&D and Clinical

Outline • What is NIRS-IVUS? • Why and when would a pharma company do an imaging study? • Why might you use NIRS-IVUS in a drug study? • What drug studies have been done so far with NIRS-IVUS? • IBIS-3, YELLOW, YELLOW-II, PACMAN-AMI • What are some new ways in which NIRS-IVUS could be used? • Thin cap • HDL and other non LDL-lowering therapies

NIRS-IVUS

Background • The majority of heart attacks are known to have been caused by lipid core plaque (LCP) • Widely known for decades from autopsy studies

NIRS-IVUS • Infraredx developed the first, and still only, technology to detect LCP in vivo • Approved for use in 2008 • NIRS-IVUS combines a well-known routine method with a new and disruptive technology

Intravascular Diffuse Reflectance NIRS Specular Light Reflections Diffuse Reflectance Vessel Wall Uncollected light

NIRS-IVUS Console-PBR Layout Rotates Slip Ring Detector Umbilical Laser Ultrasound Splitter To catheter From catheter Detector FORJ Fiber Optical Connectors Wire

Pharma Pipeline

The Pharma Objective Change this plaque… …to this plaque

When to do an Imaging Trial • Preclinical? • Questionable value - Histology is available, animal studies very expensive • Phase I/II? • Business surrogate to decide which drugs to move on to PIII • Phase III? • Concurrent mechanistic demonstration, support for submission • Phase IV? • Mechanistic demonstration, label expansion

Gragnano, Felice et al. Atherosclerosis, Volume 269 (2018), 219 - 228

NIRS-IVUS for Pharma Studies

Upper left quadrant shows the problem with IVUS trials 51 hearts 126 coronary segments 2,910 2mm sections Weak correlation R²=0.34

95 hearts 387 coronary segments 3,621 2mm sections Weak correlation R²=0.42 (Similar results in COLOR)

Lipid Core Plaque

Fibrotic Plaque

Prior and Ongoing NIRS-IVUS Pharma Studies

Pharma Trials with NIRS-IVUS • IBIS-3 • Simsek C, et al, Int J Cardiol 2012 Jun 14;157(3):e54-6. • Simsek C, et al, EuroIntervention 2012;8:235 – 241. • YELLOW • Kini AS, et al, J Am Coll Cardiol . 2012;59:E304. • Kini AS, et al, J Am Coll Cardiol . 2013;62:21 – 29. • Dohi T, et al, Eur Heart J – Cardiovasc Imaging . 2015 Jan; 16(1): 81 – 87. • YELLOW II • Kini AS, et al, J Am Coll Cardiol . 2017;69:628 – 640. • WHC • Didier R, et al, JACC Cardiovasc Interv . 2015;8:S20. • PACMAN-AMI • NCT03067844

Novel Uses of NIRS-IVUS

NIRS Interrogation of Plaque Cap Integrity • Potentially advantages over other methods: • Lipid core is first confirmed by NIRS • NIRS remains the only labeled technology for lipid core • Objective and automated • No subjective reader assessment • No border tracings or contours • Immediately available to clinician • Utilizes same underlying NIRS data • Could be used in a pharma research study early Van Soest G, et al. JACC Phipps, et al. JACC Imag Imag 2011 2015 Currently unlabeled capability

NIRS Interrogation of Plaque Cap Integrity • Cap thickness is a proxy for cap mechanical strength • Collagen content, integrity, degree of cross linking, presence of inclusions…etc. are likely as important or more important to mechanical strength than thickness • Diffuse reflectance NIRS is sensitive to all of these properties Currently unlabeled capability

Collagen Integrity Model Algorithm Development Average spectra from Chemogram independent samples Artery PSRed Unpolarized PSRed Polarized 0 1 1 Generate Predictor 1 and 0 Construct ROC 1 0 1 Apply truth definition Contour 0 1 fibroatheroma Currently unlabeled capability

Reverse Cholesterol transport by HDL Nicholls, et al JAMA . 2007;297(5):499-508.

Conclusions • Grayscale IVUS trials have been very effective, but are severely diluted with fibrotic and calcific plaques • Thus their size, length and cost are often prohibitive in lean development programs • Core lab burden is very high • VH-IVUS accuracy and relevance in drug studies has been called into question • NIRS-IVUS has the strongest fundamental basis for lipid core of any available technology, it is highly accurate, and it is highly reproducible • NIRS-IVUS is actually measuring exactly what we want cardiovascular drugs to act upon • NIRS measurements are objective, automated and require very little core lab work • NIRS-IVUS inherently gives the traditional PAV and TAV endpoints • New developments with NIRS-IVUS may be useful to test drugs acting upon reverse cholesterol transport or thickening plaque caps