JANUS: the next generation of DESJANUS: the next generation of DES

Daniela Trabattoni, MDDaniela Trabattoni, MD

Centro Cardiologico Monzino, IRCCSCentro Cardiologico Monzino, IRCCSInstitute of Cardiology Institute of Cardiology

University of Milan University of Milan ItalyItaly

Advanced Angioplasty 2004Advanced Angioplasty 2004

Presently available drug eluting stents are characterized by surfacesPresently available drug eluting stents are characterized by surfaces integrally coatedintegrally coated with:with:- - polymer matrices containing the drugpolymer matrices containing the drug- drugs directly linked to the stent surface- drugs directly linked to the stent surface- ceramic coatings embedding the drug- ceramic coatings embedding the drug

Drug Eluting Stent Technologies STATE OF THE ART

They proved to be effective, but also showed potential limitations

Stent strutStent strutcross sectioncross section

Integral coatingIntegral coating

BloodBlood

Vessel wall

DES with integral coating: POTENTIAL LIMITATIONS

1) Relatively low drug loading capability

6) Limitations in Direct Stenting approach

2) Unselected drug release

3) Significant amount of drug lost in the blood stream

4) Potential suboptimal biocompatibility of the surface (at the end of release)

5) Potentially delayed endothelialization

Endothelial cells

Smooth muscle cells

VESSEL WALL

BLOOD

CARBOSTENT JANUS DRUG-RELEASING MECHANISMCARBOSTENT JANUS DRUG-RELEASING MECHANISM

Deep sculpturing on the outer stent surface contains and Deep sculpturing on the outer stent surface contains and releases the drug only toward the vessel wall (no drug is lost releases the drug only toward the vessel wall (no drug is lost

into the blood stream)into the blood stream)

Stable non thrombogenic surface toward the bloodStable non thrombogenic surface toward the blood

STENT STRUTCROSS SECTION

Drug-releasingSculpture

Carbofilm™ CoatedSurface

JANUS Carbostent Distinctive Features

1) Relatively high drug loading capability

2) Targeted drug release

3) No drug lost in the blood stream

4) Carbofilm™ coated surface superior bio- and hemocompatibility

5) Un-hindered endothelialization

6) Suitable for direct stenting approach

Tacrolimus – FK 506

TacrolimusTacrolimus is the active ingredient of two pharmaceutical products is the active ingredient of two pharmaceutical products registered in all the main countries of the world: the registered in all the main countries of the world: the immunosuppressant Prografimmunosuppressant Prograf®®, used in the treatment of patients , used in the treatment of patients after kidney or liver transplantation, and Protopicafter kidney or liver transplantation, and Protopic®®, a drug used in , a drug used in the treatment of atopic dermatitis the treatment of atopic dermatitis

Tacrolimus (FK 506)Tacrolimus (FK 506) Fujisawa Pharmaceutical Co. Fujisawa Pharmaceutical Co.

(Japan)(Japan)

A macrolide antibiotic A macrolide antibiotic produced by Streptomyces produced by Streptomyces

Tsukubaensis Tsukubaensis

Streptomyces Tsukubaensis

• Tacrolimus binds to FK binding protein (FKBP12) Tacrolimus binds to FK binding protein (FKBP12)

• Tacrolimus-FKB12 complex inhibits cytoplasmic phosphatase calcineurin, whichTacrolimus-FKB12 complex inhibits cytoplasmic phosphatase calcineurin, which activates transcription factor NFAT (after dephosphorilation, NAFT translocates activates transcription factor NFAT (after dephosphorilation, NAFT translocates into the nucleus and activates several cytokine genes involved in immune into the nucleus and activates several cytokine genes involved in immune response and inflammation)response and inflammation)

• By inhibition of calcineurin, Tacrolimus By inhibition of calcineurin, Tacrolimus has an inhibitory effect on the expression has an inhibitory effect on the expression of pro-inflammatory cytokynes (IL-2, IL-3, of pro-inflammatory cytokynes (IL-2, IL-3, IL-4, IL-5, IFNIL-4, IL-5, IFN, Gm-CSF and TNF, Gm-CSF and TNF), ), which leads to reduced immune response which leads to reduced immune response and inflammationand inflammation

• Tacrolimus-FKB12 complex has also an Tacrolimus-FKB12 complex has also an antiproliferative effect on vascularantiproliferative effect on vascular SMCs by affecting the expression SMCs by affecting the expression of cell cycle proteinsof cell cycle proteins

Tacrolimus (FK506) Tacrolimus (FK506)

C. Matter - TCT 2002

C. Matter - TCT 2002

RABBIT STUDYRABBIT STUDYRelease KineticRelease Kinetic

Tacrolimus concentration in the iliac artery tissue reached its maximum few days after implantation

This peak corresponds to that of the vessel inflammatory response

A steady tissue concentration was present over the following weeks

Tacrolimus concentration in the vessel tissue

10

100

1000

0 5 10 15 20 25 30

Days

ng/m

g

One month after stent implantation, about 50% of Tacrolimus was One month after stent implantation, about 50% of Tacrolimus was releasedreleased

Tacrolimus concentration in the blood was always below the HPLC Tacrolimus concentration in the blood was always below the HPLC sensitivity threshold, confirming that no drug was released into thesensitivity threshold, confirming that no drug was released into theblood streamblood stream

JANUSJANUS TECNICTECNIC

JANUSJANUS TECNICTECNIC

EEndothelialization at 15 Daysndothelialization at 15 Days(SEM- pig coronary arteries) (SEM- pig coronary arteries)

Prox Mid Dist

CONTROL STENT

JANUS CARBOSTENT

In Vivo Animal Evaluation In Vivo Animal Evaluation Pig Coronary Arteries at 28 DaysPig Coronary Arteries at 28 Days

Non injury model (1.1 : 1)

Animal Study:Animal Study: 2828--day resultsday results

Non Injury modelNon Injury model

Neointimal Area (mmNeointimal Area (mm22)) Neointimal Neointimal Thickness (mm)Thickness (mm)

TecnicTecnic JanusJanus

0,00

0,05

0,10

0,15

0.09

0.06

TecnicTecnic JanusJanus

0,00

0,50

1,00

1,50

1.021.02

0.78

= 32%= 32% = 24%= 24%

Prox Mid Dist

CONTROL STENT

JANUS CARBOSTENT

Injury Model (pig coronary arteries) at 90 days

Overstretch model (1.3:1)

Animal Study: 90-day results

TecnicTecnic JanusJanus

0,00

0,10

0,20

0.13

0.06

TecnicTecnic JanusJanus

0,00

1,00

2,00

1.71

0.49

Neointimal Area (mmNeointimal Area (mm22)) Neointimal Neointimal Thickness (mm)Thickness (mm)

Injury modelInjury model

= 71%= 71% = 58%= 58%

Janus Carbostent Clinical Investigation

JUPITER I Study Design

Phase

Clinical registry 50 patients

Interim analysis at 1 month

“Safety” evaluation

Clinical evaluation randomized 1:1

multicenterdouble blind

Investig. & Core-Lab

Phase

JANUS 100 patients

TECNIC 100 patients

Clinical, angiographic and

IVUS follow-up at 6 months

Clinical follow-up at 12 and 24

months

Follow-up at 1, 6, 12 and 24 months

• 1 month: Clinical

• 6 months: Clinical, angiographic and IVUS

• 12 months: Clinical

• 24 months: Clinical

1.1. Antonio Bartorelli, MDAntonio Bartorelli, MD Centro Cardiologico Monzino (Milano)Centro Cardiologico Monzino (Milano)

2.2. David Antoniucci, MDDavid Antoniucci, MD Ospedale Careggi (Firenze)Ospedale Careggi (Firenze)

3.3. Giancarlo Piovaccari /Andrea Santarelli, MDGiancarlo Piovaccari /Andrea Santarelli, MD Ospedale degli Infermi (Rimini)Ospedale degli Infermi (Rimini)

4.4. Gianbattista Danzi, MDGianbattista Danzi, MD Poliambulanza Hospital (Brescia)Poliambulanza Hospital (Brescia)

5.5. Alberto Benassi, MDAlberto Benassi, MD Hesperia Hospital Modena (Modena)Hesperia Hospital Modena (Modena)

6.6. Roberto Serdoz, MDRoberto Serdoz, MD Ospedale San Pietro FBF (Roma)Ospedale San Pietro FBF (Roma)

JUPITER I Study: JUPITER I Study: Principal InvestigatorsPrincipal Investigators

The JUPITER I studyThe JUPITER I studyInclusion CriteriaInclusion Criteria

Angiographic criteria:Angiographic criteria:• De-novoDe-novo coronary lesions incoronary lesions in native vesselsnative vessels

• Lesion located in target vessel with aLesion located in target vessel with a diameter diameter 3 3 andand 4 4

mmmm

• Target lesionTarget lesion length length 12 mm 12 mm

• The stented target vessel segment must be 3 mm longer than The stented target vessel segment must be 3 mm longer than

the target lesionthe target lesion

• Target lesion with aTarget lesion with a %DS %DS 50% 50% and and <100% (TIMI I) <100% (TIMI I)

• << Two target vessels Two target vessels for each patientfor each patient

• One target lesionOne target lesion for each target coronary vesselfor each target coronary vessel

• One Janus stent only (15 mm x 3.0-3.5 mm) One Janus stent only (15 mm x 3.0-3.5 mm) for each target for each target

lesionlesion

(( phasephase))

• Oral anticoagulation Oral anticoagulation unrelated to stent procedureunrelated to stent procedure

• Contraindication / allergy to Contraindication / allergy to aspirin, ticlopidine or aspirin, ticlopidine or clopidogrelclopidogrel

• Depressed LV function Depressed LV function (EF(EF<< 40%) 40%)

• AMIAMI

ClinicalClinical AnatomicAnatomic• Bifurcation lesionsBifurcation lesions• Lesions located in the only Lesions located in the only

remaining vessel or LMremaining vessel or LM• GraftsGrafts• CTOCTO• Massive thrombusMassive thrombus• Heavily calcified lesionsHeavily calcified lesions

Exclusion CriteriaExclusion Criteria(( phasephase))

The JUPITER I studyThe JUPITER I study

Clinical investigation – JUPITER I ( Phase) Status @ November 2003

26

14

63

10

0

5

10

15

20

25

30

Monzino (MI) Careggi (FI) Fatebenefratelli(RM)

Poliambulanza(BS)

Hesperia (MO) Ospedale degliInfermi (RM)

Enrolled patients: 50 - Implanted stents: 58

N°

of

pat

ien

ts

Patient CharacteristicsPatient Characteristics N° patientsN° patients 5050 Male gender 72.9%Male gender 72.9% Age (years) 63.9 Age (years) 63.9 ± 9.0 ± 9.0 Diabetes Diabetes 22.9%22.9%

• IDID 10.4%10.4%• NIDNID 12.5%12.5%

Cholesterol Cholesterol 45.8%45.8% Previous MI 31.2%Previous MI 31.2%

The JUPITER I studyThe JUPITER I study

Antithrombotic TherapyAntithrombotic Therapy

Pretreatment with aspirin (325 mg/day or 500 mg i.v.)Pretreatment with aspirin (325 mg/day or 500 mg i.v.)

Heparin bolus to mantain the ACT > 300 seconds Heparin bolus to mantain the ACT > 300 seconds throughout the procedurethroughout the procedure

Aspirin (325 mg/day) + Clopidogrel loading dose Aspirin (325 mg/day) + Clopidogrel loading dose followed by 75 mg/day forfollowed by 75 mg/day for 2 months2 months

The JUPITER I studyThe JUPITER I study

Acute Angiographic ResultsAcute Angiographic Results

RVD (mm) RVD (mm) 3.16 3.16 ++ 0.42 3.34 0.42 3.34 ++ 0.37 0.37

MLD (mm) MLD (mm) 0.93 0.93 ++ 0.50 3.15 0.50 3.15 ++ 0.36 0.36

DS (%) 71.17 DS (%) 71.17 ++ 17.63 5.40 17.63 5.40 ++ 5.05 5.05

Lesion length (mm)Lesion length (mm) 9.919.91 ++ 1.97 1.97

Acute gain (mm)Acute gain (mm) 2.24 2.24 ++ 0.62 0.62

PrePre Post Post

The JUPITER I studyThe JUPITER I study

Angiographic SuccessAngiographic Success 100%100% -- - -Stent ThrombosisStent Thrombosis 0%0% 0% 0%0% 0%DeathDeath 0% 0% 2.1% (1)* 0%2.1% (1)* 0%Q-wave MIQ-wave MI 0%0% 0% 0%0% 0%non-Q wave MInon-Q wave MI 0% 0% 0% 0% 0% 0% AnginaAngina 0% 0% 2.1% (1)** 0%2.1% (1)** 0%(Urgent) CABG(Urgent) CABG 0%0% 0%0% 0% 0%TL Re-PTCATL Re-PTCA 0% 0% 2.1% (1)** 2.5%2.1% (1)** 2.5%

* Non cardiac death, due to cancer* Non cardiac death, due to cancer** Unscheduled angiography for recurrent angina that revealed distal edge restenosis ( postdilation with a balloon longer ** Unscheduled angiography for recurrent angina that revealed distal edge restenosis ( postdilation with a balloon longer

than the stent)than the stent)

Acute (50 pts)Acute (50 pts) 3-mos (50 pts)3-mos (50 pts)

Clinical ResultsClinical Results

6-mos (24pts)6-mos (24pts)

The JUPITER I studyThe JUPITER I study

CONCLUSIONS (I)CONCLUSIONS (I)

• Animal studies with Tacrolimus-eluting Janus Carbostent:Animal studies with Tacrolimus-eluting Janus Carbostent:

-- Peak drug concentration in the vascular tissue within the first few Peak drug concentration in the vascular tissue within the first few days, followed by steady concentration over the following monthdays, followed by steady concentration over the following month

-- No drug released into the blood stream No drug released into the blood stream

- - No thrombotic events in spite of a reduced antiplatelet treatmentNo thrombotic events in spite of a reduced antiplatelet treatment (ASA for 7 days only)(ASA for 7 days only)

-- Good endothelialization after 7 days, completed after 15 days Good endothelialization after 7 days, completed after 15 days

- - Reduction of neointimal area and thickness in either non-injury andReduction of neointimal area and thickness in either non-injury and injury porcine model at 28 and 90 days without any sign of toxicityinjury porcine model at 28 and 90 days without any sign of toxicity

CONCLUSIONS (II)CONCLUSIONS (II)

• Clinical study with Tacrolimus-eluting Janus Carbostent:Clinical study with Tacrolimus-eluting Janus Carbostent:

-- In the In the phase of the Jupiter I study, implantation of thephase of the Jupiter I study, implantation of the Tacrolimus-eluting Janus CarbostentTacrolimus-eluting Janus Carbostent™™ was associated with was associated with

100%100% procedural and clinical successprocedural and clinical success -- TLR @ 6 mos was 2.5% in the first 24 pts. Six-mos angio/IVUS TLR @ 6 mos was 2.5% in the first 24 pts. Six-mos angio/IVUS is still ongoing in the remaining is still ongoing in the remaining -phase pts. -phase pts.

-- The randomized The randomized -phase of the Jupiter I study is ongoing to -phase of the Jupiter I study is ongoing to assessassess

the efficacy of Janus Carbostentthe efficacy of Janus Carbostent™™ compared to the no-drug- compared to the no-drug- releasing Tecnic Carbostent releasing Tecnic Carbostent ™™

IN VITRO

PIGSTUDY

CLINICALINVESTIGATION

NEOINTIMAL PROLIFERATION

JANUS PROJECT – EVALUATION PLAN

RABBITSTUDY

LONG-TERM IN VIVO PHARMACOKINETIC

SHORT-TERM IN VIVO PHARMACOKINETIC

I N VITRO PHARMACOKINETIC

HUMAN SMC PROLIFERATION

& MIGRATION

RABBIT SMC PROLIFERATION

& MIGRATION

SCULPTURE FILLED WITH ONE DRUG

(Tacrolimus) AND NO POLYMER

LONGITUDINAL DOSE DISTRIBUTIONLONGITUDINAL DOSE DISTRIBUTION

Variable dose distribution along the longitudinal axis of the stent can be achieved filling the sculptures with different amount of drug

Homogeneous distributionHomogeneous distribution

Two levels distributionTwo levels distribution

Three levels distributionThree levels distribution

(Dose level)

LONGITUDINAL DRUG / DOSE DISTRIBUTIONLONGITUDINAL DRUG / DOSE DISTRIBUTION

Suitable amount of different drugs can be loaded selectively alongthe longitudinal axis of the stent to provide synergic therapeutic effects

Homogeneous distributionof two different drugs

Homogeneous distributionof two different drugs

Two different drugs intwo different areas

Two different drugs intwo different areas

Three levels distributionThree levels distribution

(Dose level)

MECHANICAL IMPACT OF SCULPTURESON THE STENT STRUCTURE

The sculpture impact on stent structural resistance has beencarefully evaluated with the Finite Element Analysis, and thoroughly

verified by means of severe collapse and endurance tests.

No sculpture is locatedin the red/orange areas,

where higher stress is reached

Stress LevelColor Scale

In vitro release kinetics Effect of the drug/polymer ratio

0

50

100

150

200

0 20 40 60 80 100 120Time (h)

Rel

ased

Am

ount

( g

)

TacrolimusTacrolimus/PMMA ratio 2:1Tacrolimus/PMMA ratio 1:2

S 79.15 RCA MID

In Vivo Animal Evaluation In Vivo Animal Evaluation Pig Coronary Arteries at 28 DaysPig Coronary Arteries at 28 Days

Cell colonization filling the stent sculpture (arrow)Cell colonization filling the stent sculpture (arrow)