NOBORI

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NOBORITERUMO Clinical Program with
Biolimus A9
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Nobori -the meanings-

• Flag, Sign Something which the team follows.
• Upstream, climb up
• Level up its position higher.
• Koi Nobori
• Children festival in may . To give
  strength and good chance for life . The flag
  fishes fly into the sky and become dragons wich
  are the symbol of strength and long life .

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Plat form
Serpentine Design
Quadrature - link Structure
Corrugated ring Design
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Plat form S-Stent
6-CROWN VERSION 2.5-3.0 mm vessels 2 links -
strut length 1.2 mm
9-CROWN VERSION 3.5-4.0 mm vessels 3 links
strut length 1.0 mm
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S-Stent Asian clinical trial result

• No. of patients(lesions) 120 (137)
• Lesion types 10 A,
  39 B1, 50 B2,1 C
• Lesion length 12.21  3.21
• Mean ref. diameter 2.83 mm
• Diabetics 24
• Procedural success 100
• 6-M f-u MACE(without TLR) 1.6
• TLR 10
• Restenosis rate, 6 mo 16.5
• Late loss 0.86 mm

Catheterization and Cardiovascular Interventions
62439-444 (2004)
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Biolimus A9
BIOLIMUS A9 a new chemical group at 40-O
position of rapamycin ring structure
Most preferred position for stent-based
applications, as it doesnt affect FKBP binding
properties
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Biolimus A9 -Proposed mechanism of Action-
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Lipophilicity
Terumo data
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Phamacokinetics
Safety margins based on AUC at NOAEL have been
proven in animal studies
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PLA Biodegradadable Polymer Coating
Asymetric thin films of PLA Drug occupies gt50 of
the drug/polymer matrix Drug delivery to vessel
wall (high dose)
Vessel wall
Blood stream
Drug is targeting blood vessels and only minimal
amount is released into circulation
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Degradation of Polymer and Release of Drug Over
time
Estimated results available end October
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Tissue distribution (stent pig implant)
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Nobori DES components
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Inhibition of Human T-Cell Proliferation
Pre-Clinical data
Inhibition of Porcine Coronary SMC Proliferation
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Pre-Clinical data -In vivo Animal test-
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Pre-Clinical data -In vivo Animal test-
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Pre-Clinical data -In vivo Animal test-
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Histomorphometric Analysis 28 days
P0,004
P0,003
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Biolimus A9 Stent 28 days Animal Histology Result
Late Loss avg 0.15 mm in pigs
Courtesy S. Kar, CSMC
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Representatice Histopathology 90 days
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Representatice Histopathology 180 days
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Nobori Features

• Biodegradable polymer
• Higly lipophilic Drug specifically designed for
  
• local application
• Fast distribution into the target tissue
• Polymer coating only on abluminal side
• Low drug level in peripheral circulation
• Simultaneous release of drug and degradation
• of polymer, over time

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Clinical Data of Biolimus A9 eluting stent 6 and
Prelominary 12 months Result from the STEALTH 1
Trial

• First In-Man Experience of the Biolimus A9
  Drug-Eluting Stent (BioMatrix-Stent) in Treatment
  of De Novo Coronary Lesions

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Inclusion Exclusion Criteria

• Similar to other FIM studies except higher rate
  of diabetic patients (26.6 in drug arm) and
  longer lesions (15.37mm in drug arm)

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Nobori Features
120 Patients


Control BMS S-Stent n 40
B A9 Eluting Stent n
80
6-Month Follow-up 95 (n114)
12-Month Follow-up 97.5 (n117)
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MACE In Hospital (Hierarchical)
Control BMS Biolimus A9 P value
MACE (Death, MI, or TLR) 2.5 3.8 gt0.99
Death 0.0 0.0 N/A
Q Wave MI 0.0 0.0 N/A
Non-Q Wave MI 2.5 2.5 gt0.99
Emergent CABG 0.0 0.0 N/A
TLR-CABG 0.0 0.0 N/A
TLR-PTCA 0.0 1.3 gt0.99
One patient with spiral dissection during
stent implantation Pt. received 3 non-study
stents One patient with acute stent
thrombosis, clinical driven re-PCI, no MI
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MACE - Out of hospital 6 12 months
MACE Put of hospital 6 12 Months
RESULTS Out of hospital-6 Months Out of hospital-6 Months Out of hosp-12 Months Out of hosp-12 Months
RESULTS S-Stent BioMatrix S-Stent BioMatrix
MACE 0.0 0.0 2.5 2.5
Death 0.0 0.0 2.5 1.3
Q Wave MI 0.0 0.0 0.0 0.0
Non-Q Wave MI 0,0 0.0 0.0 0.0
TLR-CABG 0.0 0.0 0.0 1.3
TLR-PTCA 0.0 0.0 0.0 0.0
Death events were noncardiac 1 traffic accident
(S-Stent) 1 acute leukemia (BioMatrix) RVD
2.25mm (calcified lesion, not expanded at
procedure)
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In-Stent Angiographic Result 6 months
Diameter Stenosis
Late Loss (mm)
Plt0.001
Plt0.001
27.413.9
0.740.45
11.914.6
0.260.43
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Late Loss Edge results
P0.004
P0.73
P0.23
Plt0.001
0.74
0.40
0.26
0.17
0.14
0.10
0.10
0.08
In-segment
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6 months Follow-up IVUS Result
Neointimal Volume Index
Neointimal Volume (NIH volume/Stent Volume)
(mm3/mm)
()
23.5 15.6
1.9 1.3
2.6 3.3 Median (25, 75) 1.4 (0.34, 3.29)
0.2 0.3 Median (25, 75) 0.1 (0.03, 0.28)
BMS
BMS
DES
DES
Out of 81 pts with Follow-up 3D analysis (BMS29,
DES52)
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Summary STEALTH 1 Study

• A low restenosis (3.9 vs 7.7, P0.4) and
  decreased late
• loss (0.26 vs 0.74mm, Plt0.001) was found in
  Biolimus A9
• DES arm
• Neointimal volume (2.6 vs 23.5, Plt0.001) was
• significantly lower in Biolimus A9 DES compared
  to
• uncoated S-stent
• No restenosis occurred at the edges in either
  cohort
• Late stent incomplete apposition was comparable
  (3 vs 3)
• Preliminary results at 12 months confirm good
  safety
• profile
• No late stent thrombosis up to 12 months follow-up

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NOBORI I
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Study Objective

• Demonstrate safety and efficacy of new rapamycin
  derivative, Biolimus A9, eluted from
  bioabsorbable PLA-coated stent, compared to the
  Taxus stent, in de novo coronary lesions

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Study Design
Prospective, randomized, controlled,
non-inferiority, Multicenter, 2 arms Trial, 21
randomization
n 360
Nobori Stent n 240
Taxus Stent n 120
Primary Endpoint In-Stent Late Loss at 9 Months
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Secondary Endpoints (1)

• Angiographic in-stent and in-segment binary
  restenosis rate (gt50 diameter stenosis) at 9
  month post-procedure.
• In-stent, in-segment, proximal, and distal MLD at
  9 month post-procedure.
• TLR at 9 month post-procedure.
• TVR at 9 month post-procedure.
• MACE (death, Q wave non-Q wave MI), emergent
  CABG or TVR) at 30d and 4,9 12 months
  annually up to 5 years.
• Stent Thrombosis at 30d and 9 months.

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Secondary Endpoints (2)

• Neointimal hyperplasia volume at 9 month
  post-procedure as measured by intravascular
  ultrasound (IVUS)
• Device Success defined as achievement of a final
  diameter stenosis of lt30 by vissual assessment
  and lt50 by QCA, using the assigned device only
• Procedural success defined as achievement of a
  final diameter stenosis of lt30 by visual
  assessment and lt50 by QCA, using any
  percutaneous method, without the occurrence of
  death, Q wave or non-Q wave MI, or repeat
  revascularization of the target lesion during the
  hospital stay

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Follow-up
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Inclusion Criteria (1)

• Age gt 18 years
• Subject eligible for PCI
• Acceptable candidate for CABG
• Clinical evidence of Ischemic Heart Disease
  and/or positive functional study
• Documented stable angina pectoris or unstable
  angina pectoris or with documented silent
  ischemia.
• Single de novo coronary artery lesion with ?
  50 and ?100 stenosis in 1 or 2 vessels (if both
  lesions and vessels meet inclusion/exclusion
  criteria)

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Inclusion Criteria (2)

• Lesion length ? 5mm and 25 mm,
• covered by 1 study stent (normal to normal)
• Target reference diameter vessel
• ? 2,5 mm and 3,5 mm (visual assessment)
• Compliance with all Follow-up evaluations
• No direct stenting

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Exclusion Criteria (1)

• Female of childbearing potential
• Documented left ventricular ejection fraction
  (LVEF) ?30
• Evidence of an acute myocardial infarction within
  48 hours of
• the intended treatment
• Known allergies to the following aspirin,
  Clopidogrel bisulfate
• (Plavix.) or Ticlopidine (Ticlid.), heparin,
  stainless steel,
• contrast agent (that cannot be adequately
  premedicated) or
• drugs similar to Biolimus A9 (i.e. tacrolimus,
  sirolimus,
• everolimus, ABT 578).
• A platelet count ?100,000 cells/mm3 or ?700,000
  cells/mm3 or
• a WBC ?3,000 cells/mm3.
• Acute or chronic renal dysfunction (creatinine
  ?2.0mg/dl or
• ?150µmol/L).

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Exclusion Criteria (2)

• Previous or planned bachytherapy in the target
  vessel.
• Target vessel has evidence of thrombus or is
  excessively
• tortuous that makes it unsuitable for proper
  stent delivery and
• deployment
• Previous bare metal stenting ( less than 1 year)
  anywhere
• within the target vessel
• Previous drug-eluting stenting anywhere within
  the target
• vessel.
• The target lesion requires treatment with a
  device other than
• PTCA prior to stent placement (e.g. but not
  limited to
• directional coronary atherectomy, excimer
  laser, rotational
• atherectomy, etc.)
• Significant (?50) stenosis proximal or distal
  to the target
• lesion that might require revascularization or
  impede run off

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Exclusion Criteria (3)

• Heavily calcified lesion and/or calcified lesion
  which cannot be
• successfully predilated
• Target lesion is located in an arterial or
  venous bypass graft.
• Ostial target lesion
• Target lesion involves a side branch ?2.0mm in
  diameter
• Subject is currently participating in an
  investigational drug or
• device study that has not completed the primary
  endpoint or
• that clinically interferes with the current
  study endpoints.
• (Note Trials requiring extended follow-up for
  products that were
• investigational, but have since become
  commercially available,
• are not considered investigational trials)

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Exclution Criteria (4)

• Prior participation in this study.
• Within 30 days prior procedure subject has
  underwent a
• previous coronary interventional procedure of
  any kind
• Within 60 days post-procedure subject requires
  planned
• interventional treatment of any non-target
  vessel. Planned
• intervention of the target vessel after the
  index procedure is
• not allowed.
• Within 60 days prior or post procedure subject
  has been/will
• require implantation with a non-Biolimus A9
  drug eluting
• stent in a non-target vessel.
• Stroke or transient ischemic attack within the
  prior 3 months.

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Exclusion Criteria (5)

• Active peptic ulcer or upper GI bleeding within
  the prior 6
• months.
• Unprotected Left main coronary artery disease
  (stenosis gt50)
• In the investigators opinion subject has a
  co-morbid
• condition (s) that could limit the patients
  ability to participate
• in the study, compliance with follow-up
  requirements or impact
• the scientific integrity of the study
• Planned surgery within 6 months after index
  procedure
• Life expectancy less than 1 year

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NOBORI 1 Organization
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Study Organization (1)

• Principal Investigator Dr. Bernard CHEVALIER
• Steering Comittee Dr. Eulogio GARCIA
• Pr. Patrick SERRUYS
• Pr. Sigmund SILBER
• Dr. Harry SURYAPRANATA
• Data management analysis Cardialysis
  /Rotterdam
• Site monitoring compliance Cardialysis
  /Rotterdam
• Core lab Angiographic Laboratory Cardialysis
  /Rotterdam
• Core IVUS laboratory Cardialysis /Rotterdam
• Sponsor TERUMO

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NOBORI 1 Study Organization (2)

• Clinical Event Comittee Dr Gian Batista DANZI
• Dr Philip URBAN
• Dr Bernard REIMERS
• Data Safety Monitoring Board .
• 1 - Prof. Tijssen, Academic Medical Center
  Amsterdam
• (statistician, andhead of the DSMB)
• 2. Prof. Verheugt, Academic Medical Center
  Nijmegen
• (Professor in cardiology)
• 3. Dr. Vranckx, interventional cardiologist,
  Virgajesse
• Hospital in Hasselt, Belgium.

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NOBORI 1 Sites Investigators

• Belgium Liege / CHU Legrand
• Aalst / OLV Wijns
• Brussels / St Jan Erard
• Netherlands Rotterdam / Thoraxcenter Serruys
  (S.C)
• Zwolle / Diagram
  Suryapranata (S.C)
• Eindhoven / Catharina Bonnier/Koolen
• UK London / Kings Thomas
• Manchester / Royal infirmary Ordoubadi
• Brighton / Royal Sussex
  Hildick-Smith

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NOBORI 1 Sites Investigators

• Denmark Aarhus / Stelby Thuesen
• Spain Madrid / Maranon Garcia (S.C)
• Barcelona / Del mar Serra
• France St Denis / CCN Glatt
• Toulouse / Pasteur Fajadet
• Paris / CHU Mondor Teiger
• Massy / J.Cartier Morice
• Quincy / C.Galien Garot
• Tours / St Gatien Blanchard
• Caen / CHU Hamon
• Toulouse / CHU Carrie

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NOBORI 1 Sites Investigators

• Germany Bad soden / Praxis Reifart
• Munich / Gemeinschafts Silber
  (SC)
• Bad Nauhein / Kerckhoff Hamm
• Munich / Innenstadt Schiele
• Leipzig / Universitatsklinik. Sick / Schuler
• Trier / Krankenhaus Hauptmann
• Frankfurt / Bethanien Nowack
• Korea Seoul / Asan medical center Park
• Australia Adelaïde / Royal Adelaide Worthley
• Melbourne / Monash Meredith

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Planed Schedule

• Protocol Feb 2005
• EC/CA submissions March 2005
• First patient enrolled May 2005
• Full start of the study Sept 2005
• Last patient enrolled Dec 2005
• Last patient last visit Dec 2010

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Nobori Clinical Program

• Status Type of
  study
• STEALTH Finished
  Randomized (BMS)
• NOBORI 1 Enrollment ongoing
  Randomized (Taxus)
• NOBORI PK October 05
  Registry
• NOBORI SV/LL November 05 Registry
• NOBORI Israel December 05
  Registry
• NOBORI 2 July 06
  Registry
• NOBORI Japan 2006
  Randomized
• Total Number of Patients to be Treated with
  Nobori Stent 2.500

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Terumo DES Program