DESIGN GOALS AND PRE-

CLINICAL EVIDENCE OF

NEXT GENERATION DCB

Juan F. Granada, MDExecutive Director and Chief Scientific Officer

CRF-Skirball Center for Innovation

Columbia University Medical Center, New York

DISCLOSURE STATEMENT OF FINANCIAL INTEREST

Within the past 12 months, I or my spouse/partner have had a financial

interest/arrangement or affiliation with the organization(s) listed below:

Grant/Research Support: Abbott Vascular, Amaranth Medical, Angiometrix,

AstraZeneca, Bioventrix, Boston Scientific, Caliber Therapeutics, Cardia, Cardiac

Implants, Cagent, Cardiovascular Systems Inc., Cardiosolutions, Celladon,

Cephea, Circulite/Heartware, ControlRad, Corindus Vascular Robotics, CR

Bard/Lutonix, DC Devices, Direct Flow Medical, Draper, Edwards LifeSciences,

Fulgur Medical, Guided Delivery Systems, Intact Vascular, Lutonix, Marvel

Medical, Medtronic, Mercator, MedAlliance, Meril Life Sciences, Microvention,

MicroInterventional Systems, Mitralign, Neovasc, Nitiloop, Nitinotes, Orbus Neich

Medical, REVA Medical, Siemens, Sonivie, Spectranetics, Svelte, Stentys,

Surmodics, Thoratec, UniQure, Volcano, WL Gore, Zenvalve

SUSTAINABILITY OF BIOLOGICAL EFFICACY

OVER TIME: A NEED FOR HEAD TO HEAD RCT

DCBDose

(µg/mm2) Excipient RCT Data

Lutonix 035 (Bard) 2.0 Polysorbate & Sorbitol 1- and 2-year

IN.PACT (Medtronic) 3.5 Urea 1-, 2-, and 3-year

Blinded Core Lab-

adjudicated

primary patency

LEVANT II Trial1-2 IN.PACT SFA Trial3-5

1-Year

2-Year

3-Year

Not available

Δ31.7%P<0.001

Δ28.8%P<0.001

Δ16.7%P<0.001

Δ5.6%P=0.05

Δ24.4%P<0.001

Primary patency definitions: LEVANT II defined primary patency as PSVR ≤ 2.5 and freedom from TLR1-2;

IN.PACT SFA defined primary patency as PSVR ≤ 2.4 and freedom from CD-TLR3-5.

1. Rosenfield K, et al. NEJM:373:145-53 (2015).

2. Presented by Laurich C, SVS Chicago 2015.

3. Tepe G, et al. Circ 131:495-502 (2015).

4. Laird J, et al. JACC 66:2329-38 (2015).

5. Krishnan P, presented at VIVA, Las Vegas 2016.

DCB: PROPOSED MECHANISM OF ACTION

3 Days1 Day15 Min 14 Days7 Days

Picture courtesy of BSCI

(1) Paclitaxel Particle Adhesion (2) Paclitaxel Particle Surface Retention

0 8 1 6 2 4

0

2 5

5 0

7 5

1 0 0

H o u r s

% D

ru

g D

iss

olu

tio

n*

I N . P A C T

L u t o n i x

* D e r i v e d p e r c e n t a g e v a lu e s c o n s t r a in e d b y 0 a n d 1 0 0

(3) Paclitaxel Particle Solubility (4) Paclitaxel Tissue PK

Picture courtesy of Medtronic Picture courtesy of Spectranetics

Granada JF. TCT2009

IMPACT OF PACLITAXEL COATING TYPE ON

DOWNSTREAM PARTICLE EMBOLIZATION

Kolodgie FD, J Vasc Interv Radiol 2016;27:1676-85

EXPERIMENTAL EVALUATION OF DCB USE IN THE

SFA TERRITORY IN PRESENCE OF DISTAL WOUNDS

Wound Creation; Bilateral Treatment

PTA or DCB x1 vs. DCB x3 (5-6 mm x 80 mm)

Hollander Scoring-Margin Separation

Pictures courtesy of Bob Melder, Medtronic

PTA

DC

Bx

1D

CB

x3

ARROWS INDICATE WOUND MARGINDAY 0 DAY 14 DAY 28

PACLITAXEL PARTICLE SOLUBILITY

DETERMINES LONG TERM

PACLITAXEL TISSUE LEVELS

0 8 1 6 2 4

0

2 5

5 0

7 5

1 0 0

H o u r s

% D

ru

g D

iss

olu

tio

n*

I N . P A C T

L u t o n i x

* D e r i v e d p e r c e n t a g e v a lu e s c o n s t r a in e d b y 0 a n d 1 0 0

Granada JF. Interventional Cardiology (2E). Chapter 32

Gongora CA. JACC Cardiovasc Interv. 2015;8:1115-23Figure courtesy of Medtronic

NEXT GENERATION DCB FEATURES

• Controlled crystallinity

• Reproducible drug content

• Predictable tissue levels

• Long residency time

• Low particulate content

Acute Drug Transfer

Acute Drug Transfer

Particulate

FormationCoating

Stability

Gongora CA. JACC Cardiovasc Interv. 2015 Jul;8(8):1115-23

IN VITRO PARTICULATE FORMATION

COATING TYPE IMPACTS PARTICULATE FORMATION,

ACUTE DRUG TRANSFER AND TISSUE RESIDENCY

Highly Crystalline

Drug Content Variability

Inconsistent Tissue Levels

High Residency Time

High Particulate Content

1ST GENERATION

DCB COATINGNEWER GENERATION DCB COATINGS

REDUCTION IN BALLOON PACLITAXEL CONTENT

Decreased Paclitaxel

Particle Solubility

Controlling Paclitaxel

Particle Crystallinity

Encapsulating

Paclitaxel Particles

IMPACT OF PACLITAXEL BALLOON DOSE IN NEOINTIMAL PROLIFERATION (RESTENOSIS)

Granada JF. JACC Cardiovasc Interv, Oct 2012

Cotavance DCBReduction in %AS

• SFA, ISR-Model

• High-cholesterol swine

• 1-µg/mm2: 13.2%

(p=0.5) VS. PTA

• 3-µg/mm2: 26%

(p<0.04) VS. PTA

Data on File, Skirball Center for Innovation

QVA % DIAMETER STENOSIS

AT 42 DAYS IN THE FAMILIAL

HYPERCHOLESTEROLEMIA

MODEL OF SFA RESTENOSIS

IMPACT OF LOWER

DOSE PACLITAXEL

CONCENTRATION ON

NEOINTIMAL

PROLIFERATION

Histology

Termination42 Days

2-mcg/mm2 3.5-mcg/mm2

• A strong clinical foundation support the use of DCB technologies in the SFA territory (when clinically indicated)

• The mechanism of action of DCB appears to be clearer; particle coating solubility clearly impact clinical outcomes

• One-year efficacy data is promising for all DCB; however, sustainability of the clinical effect will drive clinical adoption

• In the SFA territory, the safety profile of DCB has been proven; then, new generation DCB technologies must focus in matching or exceeding current clinical DCB performance

• Lower-dose DCBs have the potential to reduce downstream particle embolization without compromising biological efficacy allowing the potential use in other vascular applications

CONCLUSIONS

DESIGN GOALS AND PRE-

CLINICAL EVIDENCE OF

NEXT GENERATION DCB

Juan F. Granada, MDExecutive Director and Chief Scientific Officer

CRF-Skirball Center for Innovation

Columbia University Medical Center, New York