Optics in CardiologyApril 21, 2018

I did it for the patients>>: My journey from academia to industry and back to academia

Dr. James MüllerBrigham and Womens’ Hospital

Boston, MA

Conflict of Interest

CEO, SpectraWAVE, Inc, which is building a combination OCT-Spectroscopy Catheter

Zurich University Heritage and Optics In Cardiology

Photoelectric effect1921 Nobel Prize in Physics PTCA

Dr. Paul Müller1915- 2015

The Problem -- Vulnerable Plaques and Patients

Lipid-core Plaques

+1.2 MillionHeart AttacksPer Year in US

and Complicate Stenting

5

Muller, Tofler, StoneCirculation, 1989

Introduction of the“Vulnerable Plaque”concept

A “Vulnerable” Nuclear Weapon

0

200

400

600

800

1000

1200

1400

1600

1800

1985 1990 1995 2000 2005 2010 2012

"Vulnerable Plaque" and"Case-Crossover" Citations per year

(Google Scholar)

Vulnerable Plaque

Case Cross-over

= 14,221

= 6,259

Case-crossover ,Maclure, Mittleman, 1990

VP, 1989

Other Applications of the Case-Crossover Method

Exposure Outcome ResultOdds Ratio

Air Pollution Mortality fromCOPD inBarcelona

1.1

Anger MI in Stockholm 9.0

Air Pollution Mortality in Seoul 1.02

Air Pollution Mortality inPhiladelphia

1.05

Benzodiazepine Auto accident 1.6 (not for SSRI)

Family Quarrel Childhoodaccident

2.6

1100 1200 1300 1400 1500 1600 1700 1800 1900

Cholesterol

Cholesteryl Linoleate

Cholesteryl Oleate

Collagen

Cholesterol

Cholesteryl Linoleate

Cholesteryl Oleate

Collagen

1.0

0.8

0.6

0.4

0.2

wavelength

abso

rban

ce

Diffuse Reflectance NIR Spectroscopy to Identify Chemical Composition of Unknown Substances

Absorbance

Spectroscopy in 1998

40 mm 36 mm 26 mm 20

mm

Chemogram Findings in a Coronary Autopsy Specimen:

Comparision with Histology

14

NIRS to differentiate patients with two different types of plaques

15

Fibrotic / Calcified PlaqueLipid-Rich Plaque

LumenLumen

NIRS and IVUS Combined Catheter

Sheath

IVUSTransducer

Catheter Core Tip

FiberOptics

NIRS Mirrors

NIRS Image(Chemogram)

IVUS Image

Structure

Composition

Confidential 16

Intravascular Coronary Diagnostics Using Light and Sound to Image Coronary Arteries

1999Founded by

Dr. James Muller

17

2008FDA Approval

Spectroscopy used to

image coronary arteries

2010FDA Approval

Dual modality

Spectroscopy/IVUS

Catheter

TVC Imaging System

• Laser

• Computer with

algorithms

• Pull-back and Rotation

(PBR) Device

TVC Insight Catheter• Single Use

• Dual Modality

• Spectroscopy – lipid core plaque

• IVUS – plaque structure

2012

Commercial

Launch

Courtesy Dr. Ryan Madder, TCT 2012

19

Investor Update 2014

The Myth of the “Vulnerable Plaque”Transitioning From a Focus on Individual Lesions toAtherosclerotic Disease Burden for Coronary Artery Disease Risk AssessmentArmin Arbab-Zadeh, MD, PHD,* Valentin Fuster, MD, PHD: JACC 2015

Requiem for the ‘vulnerable plaque’Peter Libby and Gerard Pasterkamp, EHJ, March 2015

The Vulnerable Plaque Hype-pothesisSteve Nissen, MD, CRT Meeting

Soon, the Data will Speak

Identification of Vulnerable Patients by NIRS

Schuurman, Oemrawsingh et alEHJ, 2018

25

1500 PCI patientswith ACS or SAwith NIRS-IVUSimaging of 2 or morevessels

Max 4 mm LCBI >250 for 100% FU

Max 4 mm LCBI ≤ 250 for 50% FU

2 year MACE from a new lesion at patient and coronary segment level

The Lipid-rich Plaque (LRP) StudyDr. Ron Waksman, PI

PI, Europe, Dr. Carlo Di MarioResults TCT Sept, 2018

PROSPECT 2 Study

PROSPECT / ABSORB RCT

Dr. David Erlinge, Dr. Gregg Stone

“PROSPECT 2”

600 Patients“ABSORB”

180 pts > 70% Plaque Burden,Non-Flow -Limiting

900 ACS Patients Undergoing PCI

GDMT Only90 Patients

BVS Scaffold +

GDMT 90 Patients

Assess Treatment Effect in Sub-set with LCP

No LCPLCP No LCPLCPNIRS/IVUS

Predicts MACE

BVS Scaffold

0 100 200 300 400 500 600 700 800 900 10000

5

10

15

20

25

30

35

Max 4mm LCBI

3-Y

ea

r E

ve

nt R

ate

(%

)

(21.3%) (15%) (16.2%) (16.3%) (13%) (7.6%) (5%) (3.1%) (1.3%) (1.3%)Distribution of LCBI from COLOR:

No. of Evaluable Patients (1000): 213 150 162 163 130 76 50 31 13 13

Estimate of Evaluable Events (116): 4 5 8 18 27 21 15 10 4 4

Event Rate

Prospect 1

(17%)

(34%)

LCBI 974

LCBI 68

Possible Outcome of LRP Study: Risk that a 30 mm coronary segment with a given 4 mm Max LCBI will produce a MACE event in 3 years. Estimate only. Dr. Jim Muller, Infraredx, Inc., March, 2015

MedicalFailure

Medical Success

Early FinancialSuccess

Ardian

Connor Medical

ThePromised Land

Early Financial Failure

Infraredx?(Definite early financial failure,medicaloutcome

pending)

Return to Academic Medical Center

SpectraWAVE, Inc.

SpectraWAVE -- Combined OCT-Spectroscopy system

Uemura et al, Acta Cardiologia Sinica, 2014; Fard A, and Tearney GJ; Opt Express, 2013

OCT Provides: • Accurate measurements• Fibrous cap thickness• Stent apposition• Thrombus• Dissection• Vasa vasorum

Lipid

LUMEN

SuspectedVulnerable plaque

+ = OCT-S

Spectroscopy Automated identificationof cholesterol plaque

The Search for Vulnerable Plaque and Patient –A Long and Winding Road

33

Circadian Rhythmof MI, 1985Triggers of

CV Events1987

Vulnerable PlaqueConcept, 1989

NIRS2008

NIRS-IVUS2010

Prediction Trials Start 2014

Gill Heart, KY,1998 Infraredx, IncFounded

Treatment Trials2018 & Patient Care

SpectraWAVE, IncOCT-NIRS 2017

Industry AcademiaAcademia

Features of Academia and Industry

Academia

Positive

Patient care encourages research

Teaching and research focus

Negative

Difficult to stay funded

Pressure to see patients quickly

Industry

Positive

Focused drive to commercialization and wide use of a product

Funding less difficult than in academia

Negative

For start-up, constant need to raise funds

Assumed to be pitching for commercial reason

Prevention of Nuclear War –A Long and Winding Road

35

Exchange StudentTo Moscow 1967

US USSRHealth Cooperation1972 Summit Mtg

International Physicians for Prevention of Nuclear War Wins Nobel Peace Prize1985

Co-FounderIPPNW,1980

Co-FounderNKaUSPhysicians forPrevention of Nuclear War2018

Dr. JeromeFrank bookOn Nukes

ICAN Wins Nobel Peace Prize2017

Nuclear ActivismCardiology OnlyNuclear Activism

Ambassador Ri of the United Nations –Responsible for DPRK Relations with the United States 14 April 2018

The International Campaign to Abolish Nuclear Weapons (ICAN) is a coalition of non-governmental organizations in one hundred countries promoting adherence to and implementation of the United Nations nuclear weapon ban treaty. This landmark global agreement was adopted in New York on 7 July 2017.

Awarded the 2017 Nobel Peace Prize

Annual Meeting, 22 April, 2018 Geneva, Switzerland

Harvard Medical School

Eugene Braunwald, MDCalum MacRae, MD, Ph.DJim Kirshenbaum, MDJohn Parrish, MDFarouc Jaffer, MDSam Goldhaber, MD Gary Tearney, MD, Ph.DBrett Bouma, Ph. DPeter Stone, MDGeoffrey Tofler, MDStephan Willich, MDMurray Mittleman, MDMalcom MacLure, Ph.DKevin Croce, MDRon Blankstein, MDTom Brady, MDAhmed Tawakol, MD

Clinical Trial Colleagues

David Erlinge, MDGregg Stone, MDJohn Ambrose, MDRob Wilensky MDJim Goldstein MDRon Waksman, MDSergio Waxman, MDTakashi Akasaka, MDYasunori Ueda, MDCarlo DiMario,MDFrancesco Prati, MDAntonio Columbo, MDGary Mintz MDAkiko Maehara, MDLorenz Rabe, MDWolfgang Koenig, MDRenu Virmani, MDRyan Madder, MDJames Ware, Ph.D

InfraReDx/Nipro IncSean Madden, Ph.DSteve Sum, Ph.DMichael Hendricks, MSPriti ShahJay CaplanCraig Gardner, Ph.DEd Hull, Ph.D

Erasmus Medical Center

Ton van der Steen, Ph.DPatrick Serruys, MDEvelyn Regar, MDGijs van Soest, Ph.DRohit Oemrawsingh, MDYoshinobu Onuma, MDJurgen LigthartEric BoersmaPh.D

Bob McNeil Ph.DBill PriestBill HollandBill MarquardKen Jones Jack Gill, PhDSano SanUjihara San