DrugDrug CoatedCoated BalloonBalloonDrugDrug--Coated Coated Balloon Balloon Technologies I: TechnicalTechnologies I: TechnicalTechnologies I: Technical Technologies I: Technical

Considerations andConsiderations andConsiderations and Considerations and ControversiesControversies

Juan F. Granada, MDJuan F. Granada, MDJuan F. Granada, MDJuan F. Granada, MDExecutive Director and Chief Scientific OfficerExecutive Director and Chief Scientific OfficerSkirball Center for Cardiovascular ResearchSkirball Center for Cardiovascular Research

Cardiovascular Research FoundationCardiovascular Research FoundationColumbia University Medical Center, New YorkColumbia University Medical Center, New York

Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest

Within the past 12 months, I or my spouse/partner have had a Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with thefinancial interest/arrangement or affiliation with thefinancial interest/arrangement or affiliation with the financial interest/arrangement or affiliation with the organization(s) listed below.organization(s) listed below.

Affiliation/Financial RelationshipAffiliation/Financial Relationship CompanyCompany•• Grant/Research SupportGrant/Research Support•• Consulting Fees/HonorariaConsulting Fees/Honoraria•• Major Stock Shareholder/EquityMajor Stock Shareholder/Equity

•• BSCI, Abbott, BSCI, Abbott, MedradMedrad, Caliber, Caliber•• MedradMedrad•• VNTVNT

Affiliation/Financial RelationshipAffiliation/Financial Relationship CompanyCompany

Major Stock Shareholder/EquityMajor Stock Shareholder/Equity•• Royalty IncomeRoyalty Income•• Ownership/FounderOwnership/Founder•• Intellectual Property RightsIntellectual Property Rights

VNTVNT

p y gp y g•• Other Financial BenefitOther Financial Benefit

Mechanism of Mechanism of Drug Delivery and Drug Delivery and Restenosis PreventionRestenosis PreventionRestenosis PreventionRestenosis Prevention

Can a drug delivered locally onlyCan a drug delivered locally onlyCan a drug delivered locally, only Can a drug delivered locally, only one time and without a controlled one time and without a controlled delivery system achieve longdelivery system achieve long--termtermdelivery system achieve longdelivery system achieve long term term

biological efficacy? biological efficacy?

Mechanism of Drug Delivery and Mechanism of Drug Delivery and Restenosis PreventionRestenosis PreventionRestenosis PreventionRestenosis Prevention

DEB 10sBMS

Effect of Carrier on Effect of Carrier on Paclitaxel TransferPaclitaxel Transfer

Cremers B. Thromb Haemost. 2009 Jan;101(1):201-6

TaxusCoated

“Hydrophilic Carriers “Hydrophilic Carriers I P lit lI P lit l

TaxusCoated Balloon

Increase Paclitaxel Increase Paclitaxel Transfer”Transfer”

Cremers B. Cath Cardiov Int. April 2012

Long Term HealingLong Term Healing

PACCOCATH PACCOCATH ISRISR–– F/U F/U 5 Years Follow Up5 Years Follow UpLongLong Term FollowTerm Follow Up AfterUp AfterLongLong--Term FollowTerm Follow--Up After Up After Treatment of Coronary InTreatment of Coronary In--Stent Stent Restenosis With a PaclitaxelRestenosis With a Paclitaxel

ISRRestenosis With a PaclitaxelRestenosis With a Paclitaxel--Coated Balloon CatheterCoated Balloon Catheter

Target Lesion Revascularization

Scheller B, JACC Scheller B, JACC IntvIntv 2012;5:3232012;5:323--3030

4 Years F/u37 37

38.935

40

45

Target Lesion Revascularization

37 37

20

25

30

35

rcen

tage

PCB

69.3

5

10

15

20

Per

Control

4 60

12 Months 2 Years 5 Years

PCB Efficacy in BMSPCB Efficacy in BMS--ISR is ISR is ReproducibleReproducible in FIH Clinical Trialsin FIH Clinical Trials

0.9

ReproducibleReproducible in FIH Clinical Trials in FIH Clinical Trials 86% RRR PEPPER Study (Biotronik)

0.7

0.8

0.9

s (%

) PCB Control0.80±0.79 • 81 patients

• 47% DES-ISR.• LL: 0.07 mm.

0.5

0.6

Res

teno

si

0.45±0.68

(Taxus)

55% RRR 126 PatientsBMS-ISR= 52% DES-ISR= 48% ISR + SV (< 2 5mm) 54%

0.3

0.4

t Bin

ary

R

0.31±0.22

ISR + SV (< 2.5mm) 54%ISR + Bifurcation 29%

0.1

0.2

-Seg

men

t

0.11±0.44

0 02 0 0

0.20±0.450.16±0.40

N 54 N 54N= 23

-0.1

0PACOCCATH I/II INPACT ISR PEPCAD II PERVIDEO I Spanish Registry

In- -0.02±0.50N=54 N=54 N=66 N=65 N=39 N=34

(Medrad) (Medtronic) (BBraun) (Lutonix) (Eurocor)

Impact of Drug Retention (PK) on Impact of Drug Retention (PK) on Vascular Toxicity and EfficacyVascular Toxicity and EfficacyVascular Toxicity and EfficacyVascular Toxicity and Efficacy

T

Paclitaxel-Eluting Stents in Clinical Trials)

TOXI

C

EFFE

CT

100Typical DEB

clita

xel

n (n

g/m

g)

PEU

TIC

DO

WIMPROVE IMPROVE EFFICACYEFFICACY

ypCurve

rter

ial P

acce

ntra

tion

THER

AP

WIN

DFormulation BDESFormulation A

DES5

Ar

Con

c

ECT

1

NO

EFF

E

25 10050 75

REDUCE REDUCE COMPLICATIONSCOMPLICATIONS

00

Time (Days)25 10050 750

Local Local Tissue Effects (Safety)Tissue Effects (Safety)Vascular Healing According to DosVascular Healing According to Dosee

1= Minimal

Vascular Healing According to DosVascular Healing According to Dosee

Delayed Endothelialization2.17

1.75

1 5

2

2.5

core

Fibrin (Endothelial + Medial)

1.2

1.71.95

1.5

2

2.5

Scor

e

2= Slight3= Moderate4= Marked

1 1

0

0.5

1

1.5M

ean

Sc 11.2

0

0.5

1

Mea

n S5= Massive

UncoatedControl 2x 4x 6x Control 2x 4x 6x

IEL Rupture Presence Amorphous Material

Uncoated

IEL Rupture

2 21.62

2.5

1.52

2.53

n Sc

ore

2.87

1.8722.5

33.5

Scor

e

Cotavance(1x)

00.5

1

Control 2x 4x 6x

Mea

n

0

1

00.5

11.5

Mea

n Cotavance

(6x)

Control 2x 4x 6x Control 2x 4x 6x

Histology picture obtained from CVPath

Mechanism Mechanism of Action of of Action of DCB: Impact DCB: Impact on Drugon Drug Retention and EmbolizationRetention and Embolizationon Drug on Drug Retention and EmbolizationRetention and Embolization

1000

mg

Luminal Surface Vessel Acute Drug Transfer

0

1 H 24 H 7 D 28 D

ng/mMicro-Particles

Macro-Particles

1 Hour 24 Hour 7 Day 28 Day

•• Most of Paclitaxel remains on the vessel Most of Paclitaxel remains on the vessel surfacesurface

Acute Drug Transfer

Distal Circulation*~60 to 70%

surfacesurface•• This “drugThis “drug--reservoir” creates a gradient reservoir” creates a gradient and serves as the source for sustained and serves as the source for sustained drug deliverydrug delivery

Tissue Transfer*~1 to 10%

drug deliverydrug delivery•• Once the drug is transferred to the media Once the drug is transferred to the media of the vessel, tissue clearance depends on of the vessel, tissue clearance depends on well described PK curveswell described PK curveswell described PK curves well described PK curves

Distal Washout of Paclitaxel Coating Distal Washout of Paclitaxel Coating

Distal Tissue Effect Distal Tissue Effect (Embolization)(Embolization)•• Acute Ischemic Events (CLIAcute Ischemic Events (CLI))

Ch i Ti Eff tCh i Ti Eff t•• 120 x 7 mm120 x 7 mm•• Paclitaxel Coated BalloonPaclitaxel Coated Balloon•• ?% of Systemic Concentration?% of Systemic Concentration

•• Chronic Tissue EffectsChronic Tissue Effects•• Other Organs ToxicityOther Organs Toxicity

•• % of Drug Clearance?% of Drug Clearance?•• % Chronic Tissue Retention?% Chronic Tissue Retention?

Paclitaxel Formulation TypesPaclitaxel Formulation TypesImpact on Biological PerformanceImpact on Biological PerformanceImpact on Biological PerformanceImpact on Biological Performance

Coating “B” AmorphousCoating “B” AmorphousCoating “A” CrystallineCoating “A” CrystallineCrystalline Amorphous

Particles Released +++ ++Uniform Coating ++ +++Drug Transfer to Vessel +++ ++Drug Transfer to Vessel +++ ++Drug Retention vs. Time +++ +Biological Effectiveness +++ ?g

Tissue Transfer and RetentionTissue Transfer and RetentionCrystalline versus Amorphous CoatingsCrystalline versus Amorphous CoatingsCrystalline versus Amorphous CoatingsCrystalline versus Amorphous Coatings

Tissue Drug Concentration (%)Tissue Drug Concentration (%)

100.00EFFECTIVE

50.00

25.00

12.50

Crystalline Coating 1: higher uptake, higher retention

Crystalline Coating 2: lower uptake, higher retention

6.25

3.13

3.06

1h 24h 7d 28d

3.06

1.53

0.77

0 38

Amorphous Coating 3: higher uptake, lower retention

1h 24h 7d 28d

Time

0.38

0.19

0.10

SAFE

Second Generations CoatingsSecond Generations CoatingsPaclitaxel Coated Balloon TechnologiesPaclitaxel Coated Balloon TechnologiesPaclitaxel Coated Balloon TechnologiesPaclitaxel Coated Balloon Technologies

First generation DCBFirst generation DCBFirst generation DCB First generation DCB technologies have already technologies have already migrated into their secondmigrated into their second•• Manual dipping processManual dipping process migrated into their second migrated into their second generation providing more generation providing more precise coatings, tissue drug precise coatings, tissue drug

•• Automated and controlled Automated and controlled drug coatingdrug coating

delivery and lower delivery and lower particulate count… particulate count…

•• Inconsistent D:E mixtureInconsistent D:E mixture•• Improved coating mixture Improved coating mixture and uniformityand uniformityand uniformityand uniformity

••Limited scale productionLimited scale production••Large scale reproducibilityLarge scale reproducibility••Large scale reproducibilityLarge scale reproducibility

Fact#1:Fact#1: Limited Evidence Based Limited Evidence Based Medicine Leading to Clinical PracticeMedicine Leading to Clinical Practice

RCT of PCB for the Treatment of De Novo SFA Disease (ITT= PTA Only)RCT of PCB for the Treatment of De Novo SFA Disease (ITT= PTA Only)

Medicine Leading to Clinical PracticeMedicine Leading to Clinical Practice

0.61-0.05

PACIFIER(Medtronic)(Medtronic)

N=45“Still less than “Still less than

0.461.09LEVANT I

POBAN=35N=39(Lutonix)(Lutonix)

( )( )several several hundred hundred

0.30.8Fem-PAC PCBN=34

N=31(Medrad)(Medrad)patients having patients having 6 month 6 month

0.41.7Thunder N=48

N=41(Medrad)(Medrad)angiographic angiographic data and long data and long

-0.5 0 0.5 1 1.5 2

Angiographic Late Loss (mm)

term follow up” term follow up”

Fact #2:Fact #2: PCB May Have Limited PCB May Have Limited Efficacy in DESEfficacy in DES ISRISR

BMS ISR 157 P ti t

Efficacy in DESEfficacy in DES--ISR ISR

• DIOR II PCB Technology (3 µg/mm2)

BMS-ISR: 157 Patients.DES-ISR: 83 Patients.Frequency of Stent Implantation 4.9%DIOR II PCB Technology (3 µg/mm )

• 40.6% Diffuse ISR• Length Covered by PCB 24±9.1 mm• Follow Up: 228 ± 44 days (97.6% of Patients)

1214 13,4

12,2

q y p %• In.Pact Falcon (Medtronic)• 75 patients, 122 lesions

ISR 62 7%

4681012

9,8

5,97,2

9,8

BMS

• ISR 62.7%• Diffuse disease 34.7%

• Death/MI/TVR: 13.3%Angiographic Follow Up (63 9%):

024 2

1,32,6

01,2 1,2 1,2 1,2

BMS

DES• Angiographic Follow Up (63.9%):

• Restenosis 30.8%• DES-ISR: 47.5%• BMS ISR: 0%• BMS-ISR: 0%• De Novo: 16.1%

J Shannon, TCT-14, TCT2011

Fact #3:Fact #3: A PTA Balloon is Not An Ideal A PTA Balloon is Not An Ideal Platform (A Stent May Be Needed!)Platform (A Stent May Be Needed!)

PTA study (2002)PTA study (2002)

Platform (A Stent May Be Needed!)Platform (A Stent May Be Needed!)PTA study (2002)PTA study (2002)

74 patients74 patients43% major dissections43% major dissections32% residual stenosis >30%32% residual stenosis >30%

ABSOLUTE: Stent vs. PTA (2006)ABSOLUTE: Stent vs. PTA (2006)104 patients, 1:1 randomization104 patients, 1:1 randomization32%32% insufficient PTA result led to insufficient PTA result led to cross cross over to stentover to stentover to stentover to stent

RESILIENT: Stent vs. PTA (2008)RESILIENT: Stent vs. PTA (2008)206 patients 2:1 randomization 206 patients 2:1 randomization 40% PTA 40% PTA cross over to stentcross over to stent due to flow limiting due to flow limiting

Expansion in path of least resistanceExpansion in path of least resistanceSignificant shear stress and traumaSignificant shear stress and trauma

Expansion mechanism leads to:Expansion mechanism leads to:

ggdissections and residual stenosisdissections and residual stenosis

Pacifier: DEB vs. PTA (2011)Pacifier: DEB vs. PTA (2011)91 patients, 1:1 randomization91 patients, 1:1 randomization

Significant shear stress and traumaSignificant shear stress and traumaHigh dissection rateHigh dissection rateElastic recoilElastic recoilAbrupt closureAbrupt closure

21% and 35%21% and 35% bail out stenting due to bail out stenting due to flow limiting dissections and residual flow limiting dissections and residual stenosisstenosis

Abrupt closureAbrupt closure

Acute failure reported in ~30 - 40% of PTA case requiring additional treatment

Slide (modified) courtesy of Eitan KonstantinoSlide (modified) courtesy of Eitan Konstantino

Vascular Healing of BMSVascular Healing of BMS--PCB Combination PCB Combination Compared to Taxus Stent in Coronaries of FHSCompared to Taxus Stent in Coronaries of FHSpp

AS 21.5%* AS 29.6%*# AS 55.1%#

PESPES 22ndnd Gen PCB + BMSGen PCB + BMS BMSBMS **PESPES 22ndnd Gen PCB + BMSGen PCB + BMS BMSBMS

p=nsp=0.01

p=0.01p=0.01

p=0.02

p=0.01

p=0.01p=0.01

p=0.01

4.00

*p=ns*p=ns

#p<0.05#p<0.05

p=0.01p=0.01

p

p=ns

p=nsp=0.11

2.00

2.50

3.00

3.50

PES

PCB+BMSp=ns

p=0.02 p=ns

0.00

0.50

1.00

1.50 BMS

P.P.BuszmanP.P.Buszman et alet al., TCT2011, SCCR. ., TCT2011, SCCR.

Endothelialization Fibrin Deposition Neointima Maturity Media Hypocellularity Peri-Strut Inflammation

Primary Effectiveness Outcomes Provisional BMS versus DESy

“It is possible that in selected cases and due to the scaffolding effect, peripheral DES may be more effective g , p p y

than PCB…then if we are obliged to migrate into a combined approach (PCB + BMS), PCB use will be

restricted to longer lesions and smaller vascular territories”

Dake M D et al. Circ Cardiovasc Interv 2011;4:495Dake M D et al. Circ Cardiovasc Interv 2011;4:495--504504

Fact #4: Fact #4: SirolimusSirolimus AnaloguesAnalogues• Rapalogs provide well-established therapeutic benefit• Rapalogs provide high level of safety – DES “drug of choice”• PTX chosen for DEB because tissue transfer/absorption is far simpler• So why we do not use them?

19

Paclitaxel Irreversibly Inhibits Arterial SMC

Tissue Distribution and Retention of Paclitaxel Make

Proliferation and Migration Using a Single Dose

it an Ideal Agent for Local Drug Delivery

Control (hSMC)(+) anti–ß-tubulin

Sirolimus

P lit l (hSMC)

Sirolimus

PaclitaxelPaclitaxel (hSMC)

(+) anti–ß-tubulin Dextran

A L i t l P N tl A d S i USA 2004 101

Axel DI. Circulation. 1997;96:636-645

A. Levin et al., Proc Natl Acad Sci USA, 2004, 101, 9463-9467.

Drug Eluting Balloon Nanoparticle Based Drug Eluting Balloon Nanoparticle Based ((Si liSi li ) B ll Dil t ti S t) B ll Dil t ti S t((SirolimusSirolimus) Balloon Dilatation System) Balloon Dilatation System

Nanoparticle delivery technology• Enhanced tissue penetration• Protection from rapid degradation

Angioplasty balloon dilation systemAngioplasty balloon dilation system•• Fully integrated combination deviceFully integrated combination device•• SemiSemi--compliant ballooncompliant balloonp g

• Controlled and sustained release• Complete degradation

pp•• Full range of sizes and diametersFull range of sizes and diameters

Regular dilatation pressures plus Sirolimus

nanoparticle delivery

21 Slide courtesy (modified) of Caliber TherapeuticsSlide courtesy (modified) of Caliber Therapeutics

Elution Control and Dose FeasibilityElution Control and Dose FeasibilitySirolimusSirolimus Delivery Using a Porous BalloonDelivery Using a Porous BalloonSirolimusSirolimus Delivery Using a Porous BalloonDelivery Using a Porous Balloon

Tissue PK at 28 Days Following Sirolimus Delivery

Slide courtesy (modified) of Caliber TherapeuticsSlide courtesy (modified) of Caliber Therapeutics

Opportunities for ImprovementOpportunities for ImprovementB ll S f M difi tiB ll S f M difi tiSIROLIMUSSIROLIMUS

DEB Nanoparticle Based DEB Nanoparticle Based Balloon Dilatation System Balloon Dilatation System

(CALIBER)(CALIBER)

Balloon Surface ModificationBalloon Surface ModificationTechnologiesTechnologies

(AVIDAL)(AVIDAL)(CALIBER)(CALIBER)

DCB Microcrystalline Coating DCB Microcrystalline Coating (MICELL)(MICELL)

Dedicated DCB Platforms Dedicated DCB Platforms (QUATRO)(QUATRO)(MICELL)(MICELL) (QUATRO)(QUATRO)

Illustrative spot analysis by TOF‐SIMS

DCB Nanocrystalline Coating DCB Nanocrystalline Coating (CMI)(CMI)

Niche DCB Platforms Niche DCB Platforms (CONIC)(CONIC)( )( )

DCB ConclusionsDCB Conclusions•• PCB are technological suited to become the ideal interventional PCB are technological suited to become the ideal interventional

tool for the treatment of ISR and SFA diseasetool for the treatment of ISR and SFA disease•• Although efficacious for the treatment of BMSAlthough efficacious for the treatment of BMS ISR its overallISR its overall•• Although efficacious for the treatment of BMSAlthough efficacious for the treatment of BMS--ISR, its overall ISR, its overall

efficacy to treat DESefficacy to treat DES--ISRISR needs to be further studied needs to be further studied •• The DCB+BMS combination may lead to similar DESThe DCB+BMS combination may lead to similar DES--like clinical like clinical

outcomes (i eoutcomes (i e stent thrombosisstent thrombosis)) Then the synergistic use ofThen the synergistic use ofoutcomes (i.e., outcomes (i.e., stent thrombosisstent thrombosis)). Then, the synergistic use of . Then, the synergistic use of these devices deserves further investigation in a prospective these devices deserves further investigation in a prospective manner manner

•• Second generation PCBs appear to offer impro ed coatingSecond generation PCBs appear to offer impro ed coating•• Second generation PCBs appear to offer improved coating Second generation PCBs appear to offer improved coating platforms providing more precise drug transfer to the tissueplatforms providing more precise drug transfer to the tissue

•• However, there is still a lot of room for improvement in regards However, there is still a lot of room for improvement in regards p gp gto dosing, method of transfer and PK behaviorto dosing, method of transfer and PK behavior

•• Emerging data involving competitive devices (i.e., DES) will Emerging data involving competitive devices (i.e., DES) will determine the clinical applicability of DCB in thedetermine the clinical applicability of DCB in the cathcath--lablabdetermine the clinical applicability of DCB in the determine the clinical applicability of DCB in the cathcath lablab

•• However, the DCB field has reached a feasibility phase, is However, the DCB field has reached a feasibility phase, is rapidly evolving and is here to stay for the long runrapidly evolving and is here to stay for the long run