Sirolimus Angioplasty Balloon for

In-Stent Restenosis (SABRE) Trial:

3-Year Clinical Follow-Up

Interventional Innovation I: Coronary Interventions and Technologies

Stefan Verheye (SABRE PI), Mathias Vrolix, Indulis Kumsars, Andrejs Erglis, Dace Sondore,

Pierfrancesco Agostoni, Pieter Stella, Kristoff Cornelis, Luc Janssens, Michael Maeng,

Ton Slagboom, Giovanni Amoroso, Lisette Okkels Jensen, Per Thayssen

Juan F. Granada, MDOn Behalf of SABRE Investigators

• I, Juan F. Granada DO NOT have a personal financial

interest/arrangement or affiliation with one or more organizations that

could be perceived as a real or apparent conflict of interest in the context

of the subject of this presentation

• Caliber therapeutics has performed sponsored clinical at the

Cardiovascular Research Foundation within the last 12 months

Disclosure Statement of Financial Interest

Very Late Adverse Events* Following BMS

Implantation: 15-Year Follow-Up (1990-1993)

High restenosis rates at 6 months

Target Lesion Failure (TLF)* continues to accrue at ~2.1% annual rate

Perc

ent

(%)

Cardiac Death / TV-MI

Cardiac Death / TV-MI /TLR

Years after Stent Implantation

50.6%

25.5%

100

80

60

40

20

0

0 5 10 15 20

Yamaji K et al. Circ CV Int. 2010;3:468-475

*DoCE; CD,TVMI, ID-TLR (n= 405)

5-Year TVF Following DES ImplantationLate Events Likely Related to the Permanent Presence of the Metal Stent or Polymers

Target Vessel Failure Through 5 Years by

Randomized Stent Type TWENTE Trial115

10

5

00 360 720 1080 1440 1800

Logrank p=0.18

Logrank p=0.94

8.2%

8.1%

8.6%

10.9%

Incid

ence o

f T

arg

et V

esselF

ailu

re(%

)

n= 697

n= 694ResoluteXience V

1Von Birgelen et al. JAMA Cardiology 2017. 2Kereiakes. JAMA 2017

SPIRIT II2 SPIRIT IV EXAMINATION XV-JAPAN SORT_OUT IV COMPARE RAC TWENTE XV-USA

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Annualized Percentage of Target Lesion Failure (TLF)

Beyond 1 Year by Device and Study2

EES Treatment

ZES Treatment

Study (Reference)

TL

F, A

nn

ualized

(%

)

DES improved short-term (1-year) TLR & clinical outcomes

~2% to 4% annual incidence of TLF at 5 years with the latest generation DES

Re-Intervention is Associated to

Long-Term Increase in MI & DeathPatient Data Pooled Analysis of 21 RCT /32,500 Patients

De

ath

(%)

0 365 730 1095 1460 1825

5

10

1

5

0

Days after revascularization

TLR vs no TVR: HR=1.40, 95% Cl 1.16-1.69; p<0.0005

Non-TLR TVR vs no TVR: HR=1.48, 95% Cl 1.08-2.04; p=0.02

TLR vs non-TLR TVR: HR=0.93, 95% Cl 0.65-1.32; p=0.67

12.2%11.7%

8.9%

No TVR

Non-TLR TVR

TLR

0 365 730 1095 1460 1825

5

10

1

5

0

6.8%

4.2%4.0%

MI(%

)

Days after revascularization

TLR vs no revascularization: HR=2.88,

95% Cl 2.16-3.83; p<0.0001

Non-Emergent, Uncomplicated TLR

Palmerini et al.– JACC Card Inter 2018

An Additional Stent Layer is Associated

to Worse Long-Term Clinical Outcomes

0

8

16

20

4

12

0 6 12 18 24

ISR

(2 stents)

De Novo

(1 stent)

12.8%

Cum

ula

tive I

ncid

ence

of T

LR

(%)

Time after initial procedure (months)

Log rank p<0.0001

4.4%

7.6%

3.1%

Patients with ISR (N=281)

Patients without ISR (N=3194)

Richardt et al. JACC Cardiov Inter 2013

Balloon-Based Sirolimus DeliveryDesign Requirements

• Dose uniformity and reliability is compromised by inefficient drug

transfer from balloon surface; a dedicated delivery mechanism is

required

• Tissue absorption is limited following acute drug transfer:

Sirolimus degradation / diffusion occurs; “drug protection” (i.e.,

encapsulation) is needed

Sirolimus half life is short (~62-hours) and biological effect depends

on maintaining therapeutic levels (sustained and controlled drug

delivery favored)

• Distal embolization must be minimized or eliminated

Virtue® Sirolimus-Eluting Balloon

Particle Delivery Technology

ENHANCED tissue penetration

PROTECTION from rapid elution

CONTROLLED and sustained release

Micro-Porous Angioplasty SystemCompliance of POBA and NO COATING

• Proven clinical data for

treatment of coronary

atherosclerosis

• ALL leading drug-eluting

stents (DES) utilize “limus”

analogs

Sirolimus

• Enables sustained delivery of

sirolimus

• Pharmacokinetics comparable

to proven DES

• Passes critical particulate

testing, a key safety metric

Bioresorbable Particle

Delivery Technology

• Performance equivalent to

standard balloon angioplasty

• Delivers programmed dosage

of drug-loaded particles to

target lesion with minimal

downstream, off-target effects

Micro-Porous

Angioplasty System

Virtue® SEB vs. Limus-Eluting Stent

Bioresorbable particle delivery technology designed to achieve tissue

concentrations of sirolimus compared to clinically proven DES1

1Granada J, et al. EuroIntervention 2016;12:740-747

Arterial Tissue Concentration

Time (days)Mean ± SEM

100

10

1

0 5 10 15 20 25 30

Virtue

Cypher

Xience

Target Therapeutic Concentration: > 1 ng / mg at 4 weeks

Time (days)

120

100

80

60

40

20

0 5 10 15 20 25

Normalized Tissue Kinetics

Virtue

Cypher

Xience

Virtue® SEB: Targeted Drug DeliverySirolimus arterial tissue concentration at target treatment site is

>300-fold higher compared to off-target systemic drug levels

Therapeutic concentration > 1ng/mg

Lung, liver and kidney below level of assay

quantification (0.1 ng/mg) in less than 1 week

Sirolimus Tissue Concentration

CoronaryDistalKidney

LiverLung

1000

100

10

1

0.1

0.01

0.001

0.0001

10 15 20 25 3050

Tis

su

e S

iro

limu

s

Con

ce

ntr

atio

n (

ng/m

g)

Time (Days)

1Granada J, et al. EuroIntervention 2016;12:740-747

SABRE – Coronary ISR StudyStudy Title Sirolimus Eluting Angioplasty Balloon for In-Stent Restenosis, SABRE

Study DesignProspective multi-center study evaluating a Drug Eluting Balloon in patients undergoing percutaneous

revascularization of coronary in-stent restenosis for separate BMS ISR and DES ISR subgroups

Number of Subjects 50

Primary Endpoint

Safety: Target Lesion Failure (TLF)

Composite of cardiac death, target vessel MI and clinically driven target lesion revascularization up to 30

days post index procedure.

Efficacy: In-Segment Late Lumen Loss (LLL) at 6 month Follow Up

Assessed by Quantitative Coronary Angiography (QCA) and adjudicated by an independent

Angiographic Core Lab

Subject Duration Each subject is expected to be enrolled in the study for 36 months

Principal Investigator Dr. Stefan Verheye

Sites 9 sites in Belgium, Netherlands, Denmark and Latvia

Trial Coordinator (CRO) Genae associates nv

Core Lab, CEC & DSMB CRF

Verheye S. JACC Cardiovasc Interv. 2017; 10: 2029-37

SABRE: Baseline Characteristics

Baseline

Characteristics

(ITT Population)

n 50

Age 68 ± 9.5

Male 80%

Diabetes 18%

Hypertension 74%

Hyperlipidemia 74%

Smoking (Previous and Current) 70%

Previous MI 56%

Renal Insufficiency 8%

BMS ISR / DES ISR 32 / 18

Time from Previous PCI (Years) 3.9 ± 4.7

Procedural Characteristics (ITT Population)

Target-Vessel Location

LAD 25 (50%)

Baseline Measurements N = 50

Lesion Length, mm 13.0 ± 4.1

Stent Length, mm 20.9 ± 10.2

Stent diameter, mm 3.14 ± 0.35

RVD*, mm 2.61 ± 0.39

MLD, mm 0.83 ± 0.31

Diameter Stenosis*, % 68.1 ± 11.4

Diffuse Pattern (Mehran Classification) 62% (31)

Virtue™ Sirolimus Eluting Balloon

Length (mm) 17.3 ± 3.5

Diameter (mm) 3.18 ± 0.30

Inflation pressure (Atm) 14.2 ± 2.7

Inflation time (Sec) 39.8 ± 9.7

Post-Index Procedure

RVD (mm) 2.55 ± 0.39

MLD (mm) 2.08 ± 0.32

Diameter Stenosis (%) 17.7 ± 9.2

Bailout Stent 3 (6%)

Verheye S. JACC Cardiovasc Interv. 2017; 10: 2029-37

SABRE: Subject Disposition• 14 Subjects excluded from Per Protocol

Analysis (PP)

The independent Angiographic Core Lab

(CRF) evaluated all major protocol violations

11 subjects excluded from based on core

lab measurements:

• Ostial or major side branch lesions

• Additional lesions in target vessel

• Lesion significantly outside stent edges

• Lesions longer than available balloons

3 subjects with prior DES treated ISR

excluded to eliminate confounding factors

(i.e., multiple stent layers and/or drug

treatments

Intent to Treat Per-Protocol

- 1 screening failure

Enrolled per Informed Consent

N = 51

Included for ITT Analysis

N = 50

30 Day Follow Up

N = 50

30 Day Follow Up

Clinical N = 36

- 3 (No Angio FU)

- 1 (Clinical - Withdrew Consent)

- 1 (Death - unwitnessed)

6 Month - Follow Up

Clinical N = 49

Angiographic N = 47

6 Month - Follow Up

Clinical N = 36

Angiographic N = 36

12 Month Follow up

Clinical N = 49

12 Month Follow up

Clinical N = 36

24 Month Follow up

Clinical N = 48

24 Month Follow up

Clinical N = 35

36 Month Follow up

Clinical N = 48

36 Month Follow up

Clinical N = 35

- 1 (Death - unwitnessed)

Verheye S. JACC Cardiovasc Interv. 2017; 10: 2029-37

SABRE: Angiographic Results at 6 Months Biologic Efficacy Consistent with Therapeutic

Delivery of Sirolimus Despite Complex and Challenging Cases

SABRE Angiographic Results – 6 months

Intent to Treat Per Protocol Number of Patients 50 / 47 36

Reference Vessel Diameter (RVD) mm ** 2.52 ± 0.38 2.52 ± 0.32

Minimum Lumen Diameter (MLD) mm 1.75 ± 0.54 1.96 ± 0.32

% Diameter Stenosis ** 30.3 ± 19.9 22.3 ± 9.4

Change in % Diameter Stenosis ** 12.7 ± 20.6 5.2 ± 11.4

Late Lumen Loss (LLL) mm* 0.31 ± 0.52 0.12 ± 0.33

Binary Restenosis # 19.1% 2.8%

* Trial primary performance endpoint, #Trial secondary performance endpoint, ** RVD reported using Internormal values

Verheye S. JACC Cardiovasc Interv. 2017; 10: 2029-37

SABRE: Clinical Safety Outcomes to 3 YearsIntent to Treat Analysis

(ITT)

Per Protocol Analysis

(PP)

In-Hospital 30 Days 6 Months 1 Year 2 Years 3 Years 6 Months 1 Year 2 Years 3 Years

n 50 50 49 49 49 49 36 36 36 36

Cardiac Death 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.0%)** 1 (2.0%)** 0 (0.0%) 0 (0.0%) 1 (2.8%)** 1 (2.8%)**

TV-MI 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.0%) 1 2.0%) 1 (2.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

TLR 0 (0.0%) 0 (0.0%) 4 (8.2%) 6 (12.2%) 6 (12.2%) 6 (12.2%) 1 (2.8%) 1 (2.8%) 1 (2.8%) 1 (2.8%)

TLF 0 (0.0%) 0 (0.0%)* 4 (8.2%) 6 (12.2%) 7 (14.3%) 7 (14.3%) 1 (2.8%) 1 (2.8%) 2 (5.6%) 2 (5.6%)

*Primary safety endpoint is 30 day TLF. **Cause of death unknown - reported as multiple organ failure non cardiac and non-

neurological. Adjudicated as non-device and non-procedure related.

No MI during procedure – safe delivery of sirolimus formulation

No 30 day Major Adverse Cardiac Events (MACE) – primary endpoint

6 month, 1 year, 2 year and 3 year TLF rates comparable to clinically available technologies

No new revascularization events between 1 year and 3 years

SABRE ITT Results Demonstrate SafetyNo events in first 90 days and No TLR events beyond angiographic follow up

1 TV-MI in first year and 1 unknown cause death between year 1 and year 3

#

Events from 1st Year to 3rd YearEvents in 1st Year

180 360 540 720 900 1080

1098

6

4

7

5

32

10

0

0 – 12 Months

12 – 36 Months

Nu

mb

er

of T

LR

eve

nts

SABRE ITT - TLR

N = 50

# 5 TLR events occurred at time of 6 month angiographic follow up

Days from Index PCI

** Cause of death unknown - reported as multiple organ failure non

cardiac and non-neurological. Adjudicated as non-device and non-

procedure related.

**

Events in 1st Year Events from 1st Year to 3rd Year

Num

be

r o

f M

I /

Dea

th / S

ten

t T

hro

mb

osis

SABRE ITT – MI / Death / Stent Thrombosis

N = 50109

8

6

4

7

5

3

21

0

180 360 540 720 900 10800

0 – 12 Months

12 – 36 Months

Days from Index PCI

Virtue® SEB Compare Favorably to

PCB’s in Key Safety Measures

Sirolimus Eluting Balloon Paclitaxel Coated Balloon

Virtue1

B Braun

SeQuent2B Braun

SeQuent3

Biotronic

Pantera

Lux4

BSC

Agent5

Medtronic

In.Pact6

RegistryITT PP

N 49 36 154 137 148 65 / 59 428

Cardiac Death 0.0% 0.0% 1.3% 2.2% 2.0% 3.1% 1.3%

MI 2.0% 0.0% 3.2% 2.1% 5.5% 3.1% 4.3%

Thrombosis 0.0% 0.0% NR 0.7% 0.0% 0.0% NR

Coronary ISR PCB Trials: 12 Month Clinical Follow Up

1Verheye et al. Virtue SABRE Trial JACC: Cardiovascular Interventions 2017. 2Alfonso et al: RIVS IV JACC 2015. 3Byrne et

al: ISAR-DESIRE 3 Lancet 2013. 4Jensen et al BIOLUX RCT Eurointervention 2018. 5Nef et al. AGENT Trial PCR 2018

Widder et al. 6FALCON-Registry Eurointervention 2018.

Annualized Risk: Virtue® SEB

Data Favorable to Paclitaxel DCBVirtue® SEB Compares Favorably to DES AND Paclitaxel DCB

1.0%

3.9%

2.3%

1.4%

3.1%2.9%

0%

1%

2%

3%

4%

5%

PCB PES PCB EESVirtue

SEB

ITT

Virtue

SEB

PPA

nn

ualiz

ed

Ris

k o

f T

LF

Fo

llow

ing 1

stye

ar

1Virtue SABRE Trial: Verheye et al JACC: Cardiov Intervent 2017; 2Unverdorben et al,

PEPCAD II ISR Eurointervention 2014; 3 Alfonso et al: RIVS IV JACC 2015

Target Lesion Failure Rate

PEPCAD II-ISR RIBS IV

Coronary In-Stent-Restenosis (ISR)

SABRE1Virtue® SEB ITT

Sirolimus - Eluting Balloon

Virtue® SEB PP

PEPCAD II – ISR2SeQuent PCB Paclitaxel - Coated Balloon

PES Paclitaxel - Eluting Stent

RIBS IV3SeQuent PCB Paclitaxel - Coated Balloon

EES Everolimus - Eluting Stent

• The Virtue® SEB has demonstrated:

A sirolimus elution and safety profile similar to metallic DES

A clinical SAFETY and EFFICACY despite a challenging DES-ISR population

• The SABRE Trial showed:

Angiographic Late Loss: ITT 0.31-mm and PP: 0.12-mm

Clinical Outcomes:

• ITT: 0.0% MACE in hospital and 14.3% TLF at 3 years

• PP: 0.0% MACE in hospital and 5.6% TLF at 3 years

• No TLR events (ITT) following 6 month angiographic assessment

• 1 MACE between year 1 and year 3 (unwitnessed death)

• An IDE study in coronary ISR (SABRE PP population) is under development

SABRE Feasibility Study Summary