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