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

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

Feb 14, 2024 140 likes •424 views

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?

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The Role le of In Intravascular Im Imaging

  • f Lip

ipid Core in in Cardiovascular Drug Development

Sean Madden, PhD VP of R&D and Clinical

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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
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NIRS-IVUS

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

Background

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  • 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

NIRS-IVUS

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Intravascular Diffuse Reflectance

Vessel Wall Specular Reflections Diffuse Reflectance Uncollected light NIRS Light

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Laser FORJ Splitter Detector Detector To catheter From catheter Optical Connectors Fiber

Rotates

Slip Ring Wire Ultrasound Umbilical

NIRS-IVUS Console-PBR Layout

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Pharma Pipeline

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The Pharma Objective

Change this plaque… …to this plaque

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

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NIRS-IVUS for Pharma Studies

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

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

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Lipid Core Plaque

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Fibrotic Plaque

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Prior and Ongoing NIRS-IVUS Pharma Studies

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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
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Novel Uses of NIRS-IVUS

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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

Currently unlabeled capability

Phipps, et al. JACC Imag 2015 Van Soest G, et al. JACC Imag 2011

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NIRS Interrogation of Plaque Cap Integrity

  • Cap thickness is a proxy for cap

mechanical strength

  • Collagen content, integrity,

degree of cross linking, presence

  • f 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

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Collagen Integrity Model Algorithm Development

Artery

Chemogram Average spectra from independent samples

1 1 1 1 1 1

PSRed Unpolarized PSRed Polarized

Contour fibroatheroma Apply truth definition

Generate Predictor and Construct ROC

Currently unlabeled capability

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Nicholls, et al JAMA. 2007;297(5):499-508.

Reverse Cholesterol transport by HDL

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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