Biolimus A9 Drug-Eluting Stents: Technical Aspects and a Comprehensive Review of the EU, Asia-Pacific, and US Clinical Trial Program Eberhard Grube MD FACC, FSCAI HELIOS Heart Center Siegburg, Siegburg, Germany Stanford University, School of Medicine, CA, USA TCT Asia 2006
28
Embed
Biolimus A9 Drug-Eluting Stents: Technical Aspects and … · Biolimus A9 Drug-Eluting Stents: Technical Aspects and a Comprehensive ... AXXESS Plus. Biolimus A9 New ... Key Secondary
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Biolimus A9 Drug-Eluting Stents: Technical Aspects and a Comprehensive Review of the EU, Asia-Pacific, and US
Clinical Trial Program
Eberhard Grube MDFACC, FSCAI
HELIOS Heart Center Siegburg, Siegburg, GermanyStanford University, School of Medicine, CA, USA
TCT Asia 2006
Several New DES are based on Limus-Family drugs
O
HO OO
ON O
O
O HO
O
OO
NNN
N
O
HO OO
ON O
O
O HO
O
OO
NNN
N
NO
O
OO
O
O
HO
O
OH
O
O
O
H3C
OH
CH3
CH3
H3C
CH3
H3C
H3C
CH3
HH
H
H
CH3
H3C
Chiral
NO
O
OO
O
O
HO
O
OH
O
O
O
H3C
OH
CH3
CH3
H3C
CH3
H3C
H3C
CH3
HH
H
H
CH3
H3C
Sirolimus
NO
O
OO
O
O
HO
O
OH
O
O
O
H3C
OH
CH3
CH3
H3C
CH3
H3C
H3C
CH3
HH
H
H
CH3
H3C
Chiral
NO
O
OO
O
O
HO
O
OH
O
O
O
H3C
OH
CH3
CH3
H3C
CH3
H3C
H3C
CH3
HH
H
H
CH3
H3C
Chiral
NO
O
OO
O
O
HO
O
OH
O
O
O
H3C
OH
CH3
CH3
H3C
CH3
H3C
H3C
CH3
HH
H
H
CH3
H3C
Sirolimus
Zotarolimus = ABT 578
N
OO
O
CH3
O
O
O
H3C
O
HO
CH3
CH3
CH3
HOH3C
H
O
OH
H3C
H
CH3
H
OOH
OH3C H3C
Everolimus
N
OO
O
CH3
O
O
O
H3C
O
HO
CH3
CH3
CH3
HOH3C
H
O
OH
H3C
H
CH3
H
OOH
OH3C H3C
Everolimus
Biolimus
Several New DES are based on Biolimus
Biolimus
BioMatrix™
Xtent
AXXESS Plus
Biolimus A9
New Molecular Entity (C55H87NO14)•More lipophilic than sirolimus/everolimus•Immunosuppressant
Mechanism of Action- Anti-proliferative agent- Binds to FKBP-12- Inhibits mTOR activity
Test Method: Lombardo F.; Shalaeva M.; Tupper K.; Gao F.; Abraham M. ELogPoct: A Tool for Lipophilicity Determination in Drug Discovery. J. Med. Chem. 2000, 43, 2922-2928.
Lipophilicity of Biolimus A9 and Other Limus Drugs
Biolimus A9 Pharmacokinetics
With a 10X higher lipophilicity, BA9 partitions with higher affinity into fatty tissues and is less available in blood compared to SirolimusAnimal studies suggest comparable potency and safetyReadily attaches to and enters smooth muscle cell membranesBinds to immunophillins inside the cell, causing cell cycle arrest at G0Powerful immunosuppressant
Asymetric thin films of PLA degrade by surface erosionDrug occupies >50% of the drug/polymer matrixPhysical contact and drug delivery to vessel wall only, not bloodstream
Vessel wall
Bloodstream
Drug targets blood vessel walls and only a minimal amount is released into circulation
Single De Novo Native Coronary Artery Lesions (Type A-B2)Vessel Diameters: 2.75 - 4.0 mm
Stent Diameters: 2.5 - 4.0 mmLesion Length: ≤24 mm
Stent Lengths: 12 - 28 mmPre-Dilatation Required/Post-Dilatation at physician discretion
Anti-Platelet Therapy for 3 months
30d 3mo 6mo 12 moClinical Follow-Up
Angiographic / IVUS Follow-UpPrimary Endpoint: In-Segment Late Loss at 6 months (QCA)
Key Secondary Endpoints: MACE (death, MI, or TLR) at 30 days, 6 and 12 monthsDevice and Procedure (Clinical) SuccessClinically driven TLR and TVF at 6 and 12 monthsPharmacokinetics of Biolimus ABR, LL and % volume obstruction at 6 and 12 months
S-Stent Control
n=40
BioMatrix™n=80 Sites: Germany (2) and Brazil (1)
STEALTH I FIM Randomized (2:1), Double-Blind, Multi-Center Clinical Trial
(Single Center Subset)
STEALTH I Clinical Trial
6-Month Follow-up:97.5% (n=118)
12-Month Follow-up:97.5% (n=118)
120 Patients
Control BMS S-Stentn = 40
BioMatrixn = 80
Cumulative Hierarchical MACE
0.0%0.0%0.0%0.0%TLR-CABG
1.3%0.0%1.3%0.0%TLR-PTCA
12 Months6 MonthsRESULTS
2.5%
0.0%
2.5%
5.0%
S-Stent
1.3%1.3%2.5%Non-Q Wave MI
5.1%3.8%2.5%MACE
1.3%0.0%0.0%Death*
1.3%1.3%0.0%Q Wave MI
BioMatrixBioMatrixS-Stent
*Death events were noncardiac: 1 diabetic foot syndrome (S-Stent) and 1 acute leukemia (BioMatrix)
pre
BioMatrix Case Example
6-month Follow-up
post
STEALTH-1 12 mths follow-up
BioMatrix Case Example
STEALTH I: Late Loss—Edge Results
In-segment
0.140,00
0,20
0,40
0,60
0,80
Late
Los
s
Proximal In-Stent Distal In-Segment
Control BMSBiolimus A9
P=0.004P=0.73P=0.23 P<0.001
50%65%
20%69%
0.170.10
0.08
0.74
0.26 0.100.40
0.14
0
2
4
6
8
10
Serial Volume Index Changesin-stent
Lumen Volume Index
8.9±0.1
5.9±0.1
(mm3/mm)
5.7±0.9
7.2±1.4 7.4±1.3 6.9±1.3
Uncoated S-stent BioMATRIXBioMATRIX
6-monthBaseline 12-month 6-monthBaseline 12-month
p<0.01p<0.01
*Complete 14 Serial Volumetric Analysis cases (BMS 3, DES 11)*Nonparametric Wilcoxon Signed Rank Test
p=0.61p=0.02
STEALTH I: Subgroup analysisDiabetics(oral or insulin dep)
STEALTH I FIM CompletedBEACON Web-based Registry OngoingLEADERS OUS- Efficacy Study 1Q 2006STEALTH II US - Efficacy Study 1H 2006
Ongoing TrialsAsia
Aim: The BEACON Registry has been designed to evaluate continued safety and efficacy of the BioMatrix Biolimus A9-eluting stent in a broader patient population
Key Secondary Endpoints: MACE (death, MI, or TLR) at 30 days, 6, and 9 monthsDevice, Lesion and Procedure SuccessClinically driven TLR, TVR at 6 and 9 monthsMLD, Binary Restenosis and Late Loss at 9 monthsVolumetric Obstruction at 9 months
TAXUS Control n= ~720
Evaluable
BioMatrix™ IIn= ~720
Evaluable ~70 Sites: US and Canada
STEALTH II US Pivotal Randomized (1:1), Double-Blind, Multi-Center Study
STEALTH II: US PIVOTAL
Trial:– Prospective, multi-center,
1:1 randomized comparison of BioMatrix™stent with Taxus™ stent
Enrollment:– 1,584 patients from ~70
sites. Data collection at 1, 6, 9, and 12 months, and annually thereafter for 5 years
Patients with Ischemic Heart Disease due to stenotic lesions of native coronary arteries with reference vessel diameter ≥ 2.5mm and ≤ 3.5mm.
30 d 6 mo 9 mo 12 mo 2-5 yrs
Clinical Follow-Up
Angiographic / IVUS Follow-Up
Primary Endpoint: MACE free survival at 12 months
IVUS Follow-up in subgroups of 50 pts each
Nobori Stentn= ~ 1200
~70 Sites: EU and Asia
NOBORI II EU/AsiaRegistry
Pat# 1-150Pat# 151-300
Pat# 301-450
Summary
Extensive preclinical studies confirm safety and efficacy of Biolimus A9™ and the BioMatrix™StentThe STEALTH I trial demonstrated that Biolimus A9™ is an effective drug for use in DESLarger clinical trials are now underway, to test the durability of these results in larger populations and a wider range of more complex lesions