Transcript The Medtronic Advantage

Overview of the Endeavor Resolute
Preclinical and Clinical Programs
Josiah N. Wilcox, Ph.D.
Vice President and Resident Scholar
Science & Technology
Medtronic CardioVascular
Advanced Angioplasty 2008
Hilton London Metropole Hotel
January 25, 2008
Unmet Clinical Needs
in the DES era
• TLR and MACE rates remain high in patients at the highest clinical
risk of TLR
• Diabetics
– 11.3% MACE @ 9 mo—DIABETES Trial, Sabate,
TCT 2004
– 10.9% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005
• Small Vessels
– 9.3% MACE @ 8 mo—SES SMART, Ardissino, JAMA, Dec 8,
2004
– 14.2% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005
• Multi-Vessel Disease
– 14.3% TLR—The Milan DES Experience, Columbo, ACC 2004
Endeavor Resolute™
Design Goals
• Improve clinical outcomes in more
complex lesions
• Maintain current safety profile seen with
Endeavor™ DES
• Extended drug elution to match the
potentially delayed healing times of
complex lesions
• Combat the sustained stimulus to the
proliferative response
Endeavor Resolute
Incorporates the BioLinx™ Polymer System
Retains three components of the Endeavor Sprint™
Coronary Stent System with a new DES polymer
Driver Cobalt Alloy Stent
Stent Delivery System
Drug: zotarolimus
Novel Features of BioLinx Polymer System:
▫
▫
▫
▫
▫
Medtronic proprietary polymer design
Hydrophobic/Hydrophilic polymer blend
Extended release kinetics
Biocompatibility equivalent to PC
Compatible with multiple drug platforms
Hydrophilic vs Hydrophobic Polymers
Polymers can either be hydrophilic or hydrophobic
Hydrophilic = water-loving
Hydrophobic = water-hating
A hydrophilic polymer is
compatiblethat
with water
Evidence
hydrophilic
polymers
A hydrophobic polymer is
not compatible
with water
are
more biocompatibile
Body is approximately 70% water
Hydrophilic vs Hydrophobic
Contact Angles are used to determine if a polymer is hydrophilic or hydrophobic
• Angle formed when water drop applied to polymer surface
• Smaller angle = more hydrophilic
Contact Angle
Hydrophilic
Polymer
θ1
PC (Endeavor)
BioLinx (Endeavor Resolute)
Water-loving
θ2
θ1 < θ2
Hydrophilic
Hydrophobic
Polymer
Hydrophobic
83º
94o
PBMA
115º
SIBS
118º
Fluoro Polymer
129º
Water-hating
The BioLinx Polymer System
Composed of Hydrophilic and Hydrophobic Polymers
•
C10 Polymer (Hydrophobic)
C10
Based primarily on hydrophobic butyl
methacrylate to provide adequate
hydrophobicity for zotarolimus
CH3
CH2
C
CH2
C
•
b
O
O
C19 polymer (Hydrophilic)
O
C
Manufactured from a mixture of
hydrophobic hexyl methacrylate and
hydrophilic vinyl pyrrolidinone and vinyl
acetate monomers to provide enhanced
biocompatibility
C4H9
CH3
CH2
C
Polyvinyl pyrrolidinone (PVP)
Hydrophilic polymer increases initial
drug burst and enhances
biocompatibility
Overall the BioLinx polymer blend
displays a very hydrophilic surface
to the body for biocompatibility
C
O
C19
CH3
CH2
CH
CH2
CH
y
x
•
CH
a
z
N
O
O
O
O
C
C6H13
CH3
PVP
CH2
CH
a
N
O
O
Medtronic Polymer Technologies
PC and BioLinx Polymers Hydrophilic Surface Chemistry
PC Technology
BioLinx
Cell Membrane
Hydrophilic outer surface
Hydrophobic layer
O
N
O
P
[
]
N
O
O
Phosphorylcholine
(PC) Headgroup
Vinyl pyrrolidinone
groups
O
Endeavor Resolute
BioLinx Polymer In Vivo Drug Elution
% Zotarolimus Loading
100
80
60
% Remaining
% Eluted
40
20
<2% (LOQ)
0
0
50
100
Days
150
200
Greater than 85% of zotarolimus is eluted at 60 days
Complete drug content exhausted by 180 days
A Robust Durable Coating
• BioLinx is the first polymer
system designed specifically
for DES applications
• The BioLinx Polymer System
provides a durable and robust
coating
• The stent surface is primed to
improve adhesion of the
BioLinx Polymer System
A deployed stent after tracking 3 times in a 5 Fr guide catheter
BioLinx Polymer
System
Primer
Atomic Force Microscopy (AFM) studies
indicate that the interface
between the BioLinx Polymer System and the
primer is very strong
Endeavor Resolute
Inhibition of Neointimal Development at 28 Days
28 day porcine study results
Driver Control
Endeavor Resolute
Endeavor Resolute
Significant inhibition of neointimal development compared to
Driver controls
Endeavor Resolute
Extended Efficacy out to 90 days
60
Stenosis
50
40
Driver (bare)
30
Endeavor Resolute
20
10
0
Day 28
Day 90
Significant inhibition of neointimal development at both 28 and
90 days in porcine coronary arteries
Developing a New Understanding
of the Science of DES Polymer
Biocompatibility
Monocytic Adhesion
Correlates With Polymer Hydrophobicity
Contact
Angle:
Negative
Control
Positive
Control
PC
83°
BioLinx
94°
Hydrophilic
SIBS
118°
PBMA
115°
Fluoro
Polymer
129°
Hydrophobic
Endeavor Resolute with BioLinx
Best in Class biocompatibility equivalent to Endeavor with PC
Comparison of Inflammation Scores
5
4.5
Inflammation Score
4
3.5
Endeavor*
3
Endeavor Resolute*
2.5
Fluro Polymer DES
2
PBMA DES
1.5
1
0.5
0
28 days
90 days
180 days
Time after stenting
Endeavor not tested at 365 days
365 days
*Data on File Medtronic CardioVascular
**Data from Abbott US Physician presentation SE2924433D
Low inflammatory scores seen with Endeavor and Endeavor RESOLUTE stents compared
to DES containing hydrophobic polymers platforms in porcine coronary arteries
The Design of DES Polymers
Hydrophobic vs. Hydrophilic
•
First generation drug eluting stent (DES) coatings have been based on
hydrophobic polymers to hold and elute hydrophobic drugs
–
–
–
SIBS
PBMA
Fluoro Polymer
•
Hydrophobic polymers may stimulate inflammatory reactions
•
Hydrophilic polymers may be more biocompatible in the aqueous body
environment
•
The phosphorylcholine (PC) based polymer used in the second generation
Endeavor DES, is a hydrophilic polymer that shows good biocompatibility
•
The next generation Endeavor Resolute DES coating based on the BioLinx
Polymer System, is a unique blend of hydrophilic and hydrophobic polymers, that
offers both biocompatibility and extended drug elution
•
Hydrophobic polymers may contribute to the problem of Late Stent Thrombosis by
increasing inflammation, endothelial dysfunction and/or expression of
procoagulant proteins in the vessel wall
Endeavor RESOLUTE
Clinical Update
Caution: Endeavor and Endeavor Resolute are investigational devices with an investigational drug, not approved for sale or commercial use.
RESOLUTE
Clinical Trial Design
Single De Novo Native Coronary Artery Lesions
Lesion Length: 14-27mm
Stent Diameters: 2.5, 3.0, 3.5mm
Stent Lengths: 18, 24, 30mm (8/9mm bailout)
Drug Dose: 1.6 g/mm2 stent surface area
Antiplatelet therapy for 6 months
Pre-dilatation required
Endeavor Resolute
Stent
130 Patients (9 additional PK Sub-Study Patients
enrolled after original 130 patients)
12 Sites (New Zealand and Australia)
Clinical/MACE
30d
4mo 6mo
9mo
12mo
2yr
3yr
4 yr
5 yr
Angio/IVUS
N=30
N=100
Primary Endpoint: Late lumen loss (in-stent) at 9 mths by QCA
Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and
angiographic parameters at 9mths
30 pt Subset: 4mth MACE and angiographic, IVUS parameters*
*Meredith et al: EuroInterv 2007; 3:50-53
RESOLUTE
Patient Flowchart
130 Patients Enrolled
4 Month
Follow-Up
9Month
Follow-Up
12 Month
Follow-Up
Clinical F/U
30/30
Clinical F/U
130/130
Clinical F/U
129/130
100%
100%
Angiographic F/U
30/30
Angiographic F/U
95/100
100%
95%
99.2%
RESOLUTE
Patient Demographics
N=130
Male
Age
Prior MI
Prior PCI
Diabetes Mellitus
Insulin Dependent
Unstable Angina
Hyperlipidemia
Current Smoker – within last 30
days
75.4%
(98/130)
61 +10yrs (130)
45.7%
18.5%
17.7%
2.3%
(59/129)
(24/130)
(23/130)
(3/130)
29.7%
94.6%
22.3%
(38/128)
(123/130)
(29/130)
Meredith et al: EuroInterv 2007; 3:50-53
RESOLUTE
Procedural Characteristics
N=130 patients, 131 lesions
LAD (%)
34.4% (45/131)
B2/C Lesions (%)
81.7% (107/131)
Pre-procedure RVD (mm)
2.81 ± 0.41
Lesion Length (mm)
15.49 ± 6.23
Pre-procedure MLD (mm)
0.82 ± 0.34
Pre-procedure DS (%)
70.50 ± 11.42
Device success
99.2% (130/131)
Procedure success
96.2% (125/130)
Device success
Procedure success
<50% residual in-stent % ds with assigned stent
<50% residual in-stent % ds & without in-hospital MACE
Meredith et al: EuroInterv 2007; 3:50-53
RESOLUTE: 9 Month Follow Up
Angiographic Results
n=96
In-stent
Pre-procedure RVD (mm)
Lesion Length (mm)
MLD (mm)
pre
post
In-segment
2.79 ± 0.40
15.87 ± 6.51
2.74 ± 0.41
0.82 ± 0.35
2.33 ± 0.44
Acute Gain
1.91 ± 0.47
1.51± 0.50
9 mo f/u MLD (mm)
Late Loss (mm)
2.51 ± 0.48
0.22 ± 0.27
2.21 ± 0.45
0.12 ± 0.27
0.12 ± 0.16
10.13 ± 12.63
0.08 ± 0.21
21.08 ± 10.62
1 (1%)
2 (2.1%)
Late Loss Index
9 mo f/u % DS
ABR n (%)
RESOLUTE
Clinical Events to 12 months
9 months
n=130 patients
9-12 months
n=129
12 months
n=129
1.5 (2)
0.8 (1)
2.3 (3)
Cardiac
0.8 (1)
0
0.8 (1)
MI (all) - % (#)
5.4 (7)
0
5.4 (7)
Q Wave
0
0
0
Non Q wave
5.4 (7)
0
5.4 (7)
Death (cardiac) + MI (all) - % (#)
6.2 (8)
0
6.2 (8)
Stent Thrombosis (all) - % ()
0
0
0 (0)
0-30 days
0
0
0 (0)
31-360 days
0
0
0 (0)
TLR - % (#)
0
0.8 (1)
0.8 (1)
TVR (non-TL) - % (#)
0
0
0.0
TVR - % (#)
0
0.8 (1)
0.8 (1)
MACE - % (#/)
6.9 (9)
1.6 (2)
8.5 (11)
TVF - % (#/)
6.2 (8)
0.8 (1)
7.0 (9)
Death (all) - % (#)
RESOLUTE
NQMI to 12 months
Comments
57 year old
67 year old
Prox RCA
Type C Lesion
Acute Marginal side branch of obstructed by
lesion during post dilatation
Mid RCA
No reflow of PDA, prior to stenting
Type B2 Lesion
65 year old
Mid RCA
Type C Lesion
52 year old
Mid LAD
Type C Lesion
51 year old
1st OMA
Type C Lesion
RV Marginal branch has decreased flow
after balloon dilatation prior to stenting
Decreased flow in 1st diagonal side after
post balloon dilatation
Prior MI with MB still 2x baseline at time of
intervention
50 year old
Mid LAD
Wire trauma leading to plaque rupture
during follow- up angiography
75 year old
Mid LAD
Fully patent stent at follow-up. Non Q-wave
MI due to lack of anti-coagulation during
IVUS
RESOLUTE: DAPT
Patients with a Surgical Procedure
History
Index Procedural Info
Time DAPT
Event Description
Outcome up to 12M FU
69 yo male Diabetic
Mid RCA 3.5x30mm stent
1.3 months
Laparoscopy; small bowel resection
No MACE
38 yo female Non-diabetic
Mid RCA 3.5x18 mm stent
3.0 months
Pericardial window for pericarditis
No MACE
1 Obtuse
Marginal 2.5x18 mm stentdiscontinued
3.0 months
Anterior bowel
for cancer
No MACE had
15
Patients
APresection
Therapy
and
77 yo female Non-diabetic
Mid RCA 3.0x24 mm stent
3.2 months
Total hip replacement
No MACE
surgical procedures
Laminectomy
71 yo male Non-diabetic
Prox5
Circumflex
2.5x18 mm stent
4.9 months
Thoracentesis for right pleural effusion
Yes : Death, non-cardiac, mesothelioma
females
75 yo male Non-diabetic
Prox10
LAD 3.5x18males
mm stent
4.9 months
Elective resection of the prostate
No MACE
76 yo male Non-diabetic
Mid RCA 3.5x18 mm stent
Catarct surgery
No MACE
1 diabetic 5.6 months
61 yo female Non-diabetic
2.5x18 mm stent
5.7 months
Eye surgery to remove malignant nerve
No MACE
2Dist Circumflex
MACE
Events
by 12 months
sheath tumor
54 yo male Non-diabetic
Prox Circumflex 2.5x24 mm stent
Right knee medial menisectomy
No MACE
Both deaths5.8 months
due to Cancer
59 yo male Non-diabetic
1 Obtuse Marginal 3.0x30 mm stent
5.8 months
Total laryngectomy and neck dissection
No MACE
Melanoma
58 yo, male Non-diabetic
PDA 3.0x18mm stent
6.0 months
Surgical repair of retinal detachment
No MACE
Mesothelioma
68 yo female Non-diabetic
Mid LAD 2.5x18 mm stent
6.0 months
Arthroscopic surgery of shoulder
No MACE
66 yo male Non-diabetic
st
st
65 yo male Non-diabetic
Mid RCA 3.5x30 mm stent
6.1 months
Elective cholecystectomy
No MACE
64 yo male Non-diabetic
1st Obtuse Marginal 3.0x18 mm stent
6.3 months
Elective Cardioversion for atrial flutter
No MACE
75 yo male Non-diabetic
Mid LAD 2.5x18 mm stent
6.5 months
Patient died
Yes: Death, non-cardiac, melanoma with
metastisis
RESOLUTE Clinical Program
Current Outline
US Studies
Angiographic/IVUS Studies
Randomized to Taxus
n = ~430
RESOLUTE II
2.25 mm n=~150
RESOLUTE Small
38 mm n=~100
RESOLUTE Long
4.0 mm n=~100
RESOLUTE Large
Pivotal Study
Randomized to Taxus
n = ~1500
RESOLUTE IV
OUS Study
All Comers
(CE Mark)
Randomized to Xience
n = 2300
RESOLUTE III
RESOLUTE III
International RCT vs Xience: PI: Patrick Serruys
All Comer
Dual APT ≥ 6 months
Endeavor Resolute
N=1150
N = 2300
15-20 International Sites
Randomization 1:1
Xience
N=1150
Clinical Follow-up
30d
6mo
1yr
Angiographic Follow-up
2yr
3yr
4 yr
5 yr
13 mo
Primary Endpoint: Non-inferiority TLF (Cardiac Death, TLR, MI) at 12 months
Secondary Clinical Endpoints:
Cardiac death/MI or TLR
Secondary Angiographic Endpoints: (n=460)
In-stent and In-segment DS%, In-stent and In-segment LL at 13 months
Secondary OCT Endpoints: (n=~50)
Stent Strut Tissue Coverage, Stent Apposition at 13 months
Thank You
Mauri et al. N Engl J Med 2007;356:1020-9.
Endeavor: Mauri et al. TCT. 2007
Xience: FDA Panel Meeting Nov. 29, 2007
DES In Perspective
ARC Definite and Probable to 3 years
3.0%
2.5%
No. at Risk
Pooled Data
1 Year
2 Years
3 Years
ARC ST %
2.0%
Endeavor
Cypher
Taxus
*Xience
1.5%
1301
1287
675
863
848
823
1351
1300
1117
397
377
n/a
1.0%
0.5%
0.0%
0
360
*Represents “SPIRIT II and III 2-year Complete Analysis” from Panel
720
Days
1080
1440
Mauri et al. N Engl J Med 2007;356:1020-9.
Endeavor: Mauri et al. TCT. 2007
Xience: FDA Panel Meeting Nov. 29, 2007
DES In Perspective
Cardiac Death and MI to 3 years
Pooled Data
Endeavor
Cypher
Taxus
*Xience
Cardiac Death and MI %
9%
1 Year
2 Years
3 Years
1301
1287
675
863
848
823
1351
1300
1117
397
377
n/a
6%
3%
0%
0
360
*Represents “SPIRIT II and III 2-year Complete Analysis” from Panel
720
Days
1080
1440