Future Concepts for Drug Delivery

Michael R. Jaff, DO

Paul and Phyllis Fireman Endowed Chair in Vascular Medicine

Massachusetts General Hospital

Professor of Medicine

Harvard Medical School

Boston, Massachusetts USA

Michael R. Jaff, D.O.

Conflicts of Interest

2

2

• Consultant

– Abbott Vascular (non-compensated)

– AOPA

– Boston Scientific (non-compensated)

– Cardinal Health

– Cordis Corporation (non-compensated)

– Janacare, Inc

– Medtronic (non-compensated)

– Micell, Inc

– Novella (DSMB)

– Primacea

– Valiant

– Volcano

• Equity

– Access Closure, Inc

– Embolitech

– I.C.Sciences, Inc

– Janacare, Inc

– MC10

– Northwind Medical, Inc.

– PQ Bypass, Inc

– Primacea

– Sano V, Inc.

– Vascular Therapies, Inc

• Board Member

-VIVA Physicians (Not For Profit

501(c) 3 Organization)

• www.vivapvd.com

-Intersocietal Accreditation Commission

-CBSET

January 2016

Attributes of an Ideal DCB Coating

Cross-section view

• Facilitate drug retention on balloon during transit

• Effectively release drug from the balloon to the target lesion site

• Provide adhesion of the drug to the vessel wall

• Drug retention upon restoration blood-flow; formation of depot for long-term release

• Facilitate drug uptake by tissue

Excipients can play a critical role in achieving these attributes

DCB Paclitaxel Content Clinical Efficacy and Safety

Company Device Drug Coating Dose

(μg/mm2)

Aachen-Resonance Elutax PTx (no carrier) 2

B. Braun SeQuent Please PTx – Iopromide

Paccocath Technology 3

Bard-Lutonix MOXY PTx – Polysorbate/Sorbitol 2

Biotronik Passeo-18 Lux PTx – BTHC

Butyryl-tri-hexyl-Citrate 3

Boston Scientific Ranger PTx – Acetyl Tributyl Citrate

Transpax Technology 2

Cook Medical Advance 18 PTx PTx (no carrier) 3

Eurocor Freeway Series PTx – Shellac 3

Medtronic Cotavance PTx – Iopromide

Paccocath Technology 3

Medtronic IN.PACT Series

(Admiral, Pacific) PTx – Urea (FreePac)

3.5

Spectranetics Stellarex PTx - ? 2

Peripheral Drug-Coated Balloons

Clinical Differences in Vessel Patency Effect of Dosing on Safety and Efficacy

67,0% 73,5%

83,7%

89,9%

55% 53,7%

72,4%

LEVANT ILutonix

LEVANT 2Lutonix

Italian RegistryIN.PACT

IN.PACT SFAIN.PACT

12-Month Patency

24-Month Patency

3.5-mcg/mm2

TM* TM* TM* TM*

1 2 3 4

1. Scheinert, D., et al., J Am Coll Cardiol Inv, 2014;7: p. 11-19. 3. Micari, A., et al., J Am Coll Cardiol Inv, 2012;5: p. 331-338. 4. Tepe

G. Presentation, Charing Cross 2014. London 2. US Dept of HHS FDA Executive Summary: Circulatory System Devices Advisory

Panel June 12 ,2014: Bard Lutonix® 035 Drug Coated Balloon PTA Catheter.

2-mcg/mm2

Paclitaxel inhibits restenosis in

peripheral arteries

• SFA, ISR-Model

• High-cholesterol swine

• 28 day follow-up

65 56 48

0

20

40

60

80

100

Uncoated 1 µg/mm2 3 µg/mm2

% Area Stenosis

Milewski K, et al. J Am Coll Cardiol Intv. 2012;5:1081-1088

Impact of Dosing on Neointimal Proliferation and Restenosis

p=0.04

Paclitaxel DCB Content vs. Surface Particle Adhesion and Tissue Uptake

and Distribution

Macro-Crystalline Amorphous Coating Hybrid Coating

Nano-Encapsulation Micro-Crystalline

Paclitaxel Coated Balloon Evolution

Crystalline Aggregate

0

100

200

300

400

500

0 100 200

Cu

mula

tive P

Tx R

ele

ase (

µg)

Time (min)

0,1

1

10

100

1000

0 10 20 30 40

PTx

Co

nce

ntr

atio

n (

ng

/mg)

Time (days)

Effect of DCB Coating Morphology Amorphous vs Crystalline Transpax™

Crystalline Coating Morphology • Lower PTx solubility • Slower dissolution rate • Lower PTx solubility • Slower dissolution rate

In Vitro Dissolution Rate In vivo Coronary PTx Concentration

Crystalline Transpax™

Amorphous Transpax™

Crystalline Transpax™

Amorphous Transpax™

Coating Morphology Determines Particle

Adhesion and Tissue Pharmacokinetics

3 Days 1 Day 15 Minutes 14 Days 7 Days

Anti-paclitaxel Antibody Staining Following TransPax™ DCB-Treatment

Coating crystallinity producing highly

adhesive low-soluble particles may be

key to maintain paclitaxel tissue levels

overtime

Picture courtesy of Boston Scientific

Mix of Crystalline and

Amorphous Structure

Mostly Amorphous

Structure

Larger PTX particles

on vessel surface

Smaller PTX particles

on vessel surface

Pictures courtesy of Spectranetics

Comparative PK Profile of Several Clinically Available DCB

0

10

20

30

40

50

60

70

80

4 hours 1 Day 7 Day 21 Day 30 Day 45 Day 60 Day

Pacl

itax

el L

evel

s (n

g/m

g)

Ranger DCB

In.Pact Admiral DCB

Lutonix DCB

0

5

10

15

20

25

30

35

4 hours 1 Day 7 Day 21 Day 30 Day 45 Day 60 Day

Pacl

itax

el L

evel

s (n

g/m

g)

Ranger DCB

In.Pact Admiral DCB

Lutonix DCB

∆ T

issue L

evels

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

Coating Integrity and Particulate Formation

Coating Integrity and Particulate Implications for DCB Safety

In.Pact Pacific™ 6X40 (3μg/mm²)

Ranger™ 6X40 (2μg/mm²)

Lutonix Moxy™ 6X40 (2μg/mm²)

3 min 10 min T = 0 min

Adherent*

Coating

During

Hydration

Coating

Cracking

During

Hydration

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

SurModics SurVeil™ DCB

Shaft coating Serene™ hydrophilic coating

Proprietary

PhotoLink®

basecoat

Uniform drug topcoat Paclitaxel + proprietary

excipient

2.0 µg/mm² drug load

360°coating coverage

0.035” OTW PTA platform 4–6 mm x 40–100 mm

The SurVeil DCB is a combination product intended to improve luminal diameter for

the treatment of obstructive de novo lesions in femoral and popliteal arteries above

the knee.

SurVeil DCB vs. Competitive DCBs

DCB #1 (From EU Market, dry-expanded)

DCB #2 (From US Market, dry expanded)

SurModics SurVeil DCB (dry-expanded)

SurVeil™ DCB Preclinical Performance (Swine model, through 90 days)

• Safe – Treatment with up to 3x DCBs (100% overlap) is well tolerated – No downstream emboli, ischemia, necrosis, or scarring – No evidence of systemic toxicity

• Efficient – More drug transferred to target tissues than comparators (3-6 fold)

• Desired Biological Effect – Consistent and uniform markers of drug effect

• Smooth muscle cell loss • Proteoglycan deposition • Delayed arterial healing

– Endothelialization nearly complete at 28 days

Robust Biological Drug Effect at 28 days

SurVeil DCB

POBA Control

Competitive DCB

Results in the swine model. All data from SurModics-sponsored studies.

SurModics Delivers More Drug than Leading DCB 2 µg/mm2 3.5 µg/mm2

0

1

10

100

1000

0 day 7 day 14 day 21 day 28 day

Tiss

ue

Co

nce

ntr

atio

n (

µg

/g)

Study UTE038: 40mm Balloons

SurModics SurVeil

In.Pact AdmiralComparator DCB

SurModics DCB Drug Delivery: 5 – 6x higher than DCB #2

5x higher than DCB #3 3 – 4x higher than DCB #1

SurModics Receives FDA IDE Approval for Early Feasibility Study of the SurVeil™ Drug-Coated Balloon (Oct. 2015)

Early Feasibility Study (EFS)

Study Title: A Prospective, Multi-Center, Single-Arm Trial to Assess the Safety and Feasibility of the SurModics Drug Coated Balloon in the Treatment of Subjects with De Novo Lesions of the Femoropopliteal Artery. Study Objective: To assess the safety and functionality of the SurModics drug coated balloon (SurVeil™ DCB) in the treatment of subjects with symptomatic peripheral artery disease (PAD) due to de novo stenoses of the femoral and popliteal arteries.

Study Design

• Prospective, multi-center, single-arm clinical trial

• Trial will enroll up to 15 subjects with symptomatic PAD due to de novo stenoses of the femoral and popliteal arteries.

• All enrolled subjects will be treated with the SurVeil™ DCB

• Up to 3 clinical sites in the United States (US)

Use in Complex Lesions Dissection Potential and Crossover

to the Use of Stents

Vessel Dissection in the DCB Era Location Study Dissection

Rates

SFA PACIFIER 73.5%

SFA-pop THUNDER 56%

SFA LEVANT 2 63.7%

Femoro-Popliteal Dissections

THUNDER Trial Reported Rates

Dissection Type Percentage

A/B 64%

C/D/E 36%

Comparison of 6 Month THUNDER Study Angiographic Data

PTA

w/o

Dissections

Dissection

Grade A/B

Dissection

Grade C/D/E

All

Dissection

Binary Restenosis 43% 50% 62% 55%

Patency (Extrapolated) 71%-91% 50% 38% 45%

TLR Rates 10.5% 33% 44% 37%

24 Month Clinical Results of THUNDER Study

Dissection

Grade A/B

Dissection

Grade C/D/E

All

Dissection

TLR Rates 43% 78% 56%

Sealing Dissections But Decreasing Metal Burden (Tack-It)

84,5

22,3

175,9

38,7

276,5

52,4

0

50

100

150

200

250

300

'60-80Stents: ≤40mm (n= 40) Stents: ≥100mm (n = 24) Stents: 60 - 80mm (n = 31)

Me

tal S

urf

ace

Are

a (m

m2)

Tacks in TOBA Stents

74% Less

78% Less

Metal

81% Less

Metal

130 Patients, 12 Month Patency = 76.4%

DCB Use and Adjunctive Therapy Other PTA Technologies – Compliant – Non-Compliant

Scoring Balloons Cutting Balloon

AngioSculpt

Chocolate Balloon

Rotational Atherectomy Rotablator

CSI Orbital Atherectomy

Other Atherectomy Devices Silverhawk/Rockhawk JetStream

Excimer Laser

Pre-Procedure Post LB/ Final Lithoplasty Balloon Calcification

DS=100%

Lesion Length=76.5 mm Total Length of Calcium

74.8 mm

Prox. RVD=5.50 mm

Dist. RVD=6.05 mm

MLD=4.59 MM

DS %=21.94%

27.5mm OL

Lithoplasty (Shockwave)

Alternative Drugs and Delivery Mechanisms

Sirolimus DCB (SELUTION™) Cell Adherent Technology (CAT)

Arterial Tissue Drug Concentration Sirolimus (RAP) versus Paclitaxel (PAX)

Therapeutic Effect ≥ 1 µg/g

En Face Scanning Electron Microscope at 24 hours

262

44

21 19

59

1 0,3 0

35

11 3 0 0

50

100

150

200

250

300

1 hour 7 days 28 days 60 days

Tis

su

e D

rug

Co

nc

en

tra

tio

n [

ug

/g]

Med Alliance SELUTION - RAP

Bard LUTONIX - PAX

Medtronic IN.PACT - PAX

Med Alliance – PK Study (2014-004), Medtronic – Presentation R.J. Melder (LINC 2012), Bard – Catheterization and Cardiovascular Interventions 83:132–140 (2014)

28-Day Yucatan Swine High Injury Model

2,6 2,8

1,5

1,9

0,3 0,4 0

0,5

1

1,5

2

2,5

3

Medial Injury Medial SMC Loss Medial Fibrin

Histological Comparison – Scoring

SELUTION DCB

CONTROL POBAP=0.05

P=0.001

P=0.002

Baseline RCA DES-ISR Post Virtue (3.0 x15) 6 Month Follow-up

LLL: 0.11 mm

Virtue (Caliber): Microporus Balloon Angioplasty System

SABRE Study: 47 ISR Patients LLL: 0.31 ± 0.52

Granada JF, TCT2015

Conclusions • Drug-eluting technologies are expected to play an expanding role

in endovascular treatment of PAD

• DCBs show promising results in the SFA territory in a selected patient population

• New generation DCB technologies have achieved:

– Optimal transfer rates and tissue retention at low loading doses

– Lower particulate formation and drug loss in transit

• DCB use may yield relative cost savings in certain clinical situations

• Adjunctive technologies (ie, atherectomy) may be needed to expand the clinical use of DCBs

Future Concepts for Drug Delivery

Michael R. Jaff, DO

Paul and Phyllis Fireman Endowed Chair in Vascular Medicine

Massachusetts General Hospital

Professor of Medicine

Harvard Medical School

Boston, Massachusetts USA