The BLAST TrialThe BLAST TrialBBiorest iorest LLiposomal iposomal AAlendronate lendronate

with with SStenting stenting sTTudyudy

Targeted Anti-Inflammatory Targeted Anti-Inflammatory

Systemic Therapy for RestenosisSystemic Therapy for Restenosis

Shmuel Banai, MDShmuel Banai, MD

Tel Aviv medical CenterTel Aviv medical Center

Tel Aviv, ISRAELTel Aviv, ISRAEL

Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest

I, Shmuel Banai, DO NOT have a financial I, Shmuel Banai, DO NOT have a financial interest/arrangement or affiliation with interest/arrangement or affiliation with one or more organizations that could be one or more organizations that could be perceived as a real or apparent conflict of perceived as a real or apparent conflict of interest in the context of the subject of interest in the context of the subject of this presentation.this presentation.

BackgroundBackground

• Inflammation Inflammation is the hallmark of is the hallmark of Atherosclerosis and RestenosisAtherosclerosis and Restenosis

• Monocytes/macrophages Monocytes/macrophages are the key are the key mediators of inflammation mediators of inflammation systemicallysystemically and and locally locally within the within the vessel wallvessel wall

• Patients in a pro-inflammatory state Patients in a pro-inflammatory state are at higher risk for Restenosisare at higher risk for Restenosis

BIOrest LABR-312BIOrest LABR-312

0 2 4 600 11 55 1010 5050 100100

Concentration [uM]Concentration [uM]

Cel

l # [

% o

f ba

selin

e]C

ell #

[%

of

base

line]

Days after InfusionDays after InfusionM

onoc

yte

Mod

ulat

ion

Mon

ocyt

e M

odul

atio

n

MacrophagesMacrophages

ECEC

Danenberg et al, Circulation 2002Danenberg et al, Circulation 2003Danenberg et al, JCP 2003

• A highly selective systemic monocyte inhibitor

• Produces a transient effect lasting several days

BLAST – BLAST – BBIOrest IOrest LLiposomal iposomal AAlendronate with lendronate with SStenting stenting sTTudyudy

BIOrest LABR-312 is a unique, specific and transient BIOrest LABR-312 is a unique, specific and transient means of modulating monocytesmeans of modulating monocytes

HYPOTHESISHYPOTHESIS::

Modulation of systemic and local inflammation will Modulation of systemic and local inflammation will attenuate intimal hyperplasia after BMS implantationattenuate intimal hyperplasia after BMS implantation

OBJECTIVEOBJECTIVE: :

To assess the safety and efficacy of a single IV bolus of To assess the safety and efficacy of a single IV bolus of LABR-312 in the treatment of LABR-312 in the treatment of de novode novo stenotic lesions stenotic lesions in native coronary arteries in a population undergoing in native coronary arteries in a population undergoing PCI with implantation of a BMSPCI with implantation of a BMS

BLAST TrialBLAST Trial

• Phase II dose-finding, randomized, multi-center, Phase II dose-finding, randomized, multi-center, prospective, double blind. prospective, double blind. NN=225 Patients=225 Patients

• Study PI: Prof. Shmuel Banai – Tel Aviv Medical Center Study PI: Prof. Shmuel Banai – Tel Aviv Medical Center

• Participating Medical Centers and PI’s:Participating Medical Centers and PI’s:

BLAST Trial – Parties InvolvedBLAST Trial – Parties Involved

Study Management Study Management Medinol Ltd. Medinol Ltd.

Data Management, Clinical Data Management, Clinical Events Committee and Data Events Committee and Data Safety Monitoring Board Safety Monitoring Board Coordination Coordination

Harvard Clinical Research Institute Harvard Clinical Research Institute (HCRI), Boston, USA(HCRI), Boston, USA

Angiographic Core Angiographic Core LaboratoryLaboratory

Cardiovascular Research Foundation Cardiovascular Research Foundation (CRF), NY, USA (CRF), NY, USA

IVUS Core LaboratoryIVUS Core LaboratoryStanford University Medical Stanford University Medical Center,Center,CA, USACA, USA

Arrhythmia and ECG Core Arrhythmia and ECG Core Laboratory Laboratory

Harvard Clinical Research Institute Harvard Clinical Research Institute (HCRI), Boston, USA(HCRI), Boston, USA

FACS Core Laboratory FACS Core Laboratory BIOrest LTD. , Yavneh, IsraelBIOrest LTD. , Yavneh, Israel

Study MonitoringStudy MonitoringGCP Clinical Monitoring Ltd.GCP Clinical Monitoring Ltd.

BLAST Trial - Study EndpointsBLAST Trial - Study Endpoints

• Primary Endpoint: In-Stent angiographic Late Primary Endpoint: In-Stent angiographic Late Loss @ 6mLoss @ 6m

• Secondary endpoints: IVUS measurements, Secondary endpoints: IVUS measurements, clinical outcomes, monocyte count and clinical outcomes, monocyte count and function by FACS function by FACS ((Fluorescence Activated Cell Sorter)Fluorescence Activated Cell Sorter)

• Pre-Specified subgroup analyses including:Pre-Specified subgroup analyses including: DiabetesDiabetes Baseline monocyte countBaseline monocyte count Unstable AnginaUnstable Angina

Total Patients RecruitedTotal Patients RecruitedN=225N=225

Placebo (saline)Placebo (saline)N=74N=74

Low Dose (1µg LABR-312)Low Dose (1µg LABR-312)N=77N=77

High Dose (10µg LABR-312)High Dose (10µg LABR-312)N=74N=74

PlaceboPlaceboN=57N=57

Low DoseLow DoseN=56N=56

PlaceboPlaceboN=26N=26

Low DoseLow DoseN=31N=31

High DoseHigh DoseN=26N=26

BMS Stenting+Drug AdministrationBMS Stenting+Drug AdministrationQCA, IVUS, Blood sampling for monocytes @ Screening, 0, 8, 16, 24 hQCA, IVUS, Blood sampling for monocytes @ Screening, 0, 8, 16, 24 h

6m Clinical+Angiographic f/u Per-Protocol Analysis6m Clinical+Angiographic f/u Per-Protocol Analysis

6m IVUS f/u subset6m IVUS f/u subset

Randomization 1:1:1Randomization 1:1:1

High DoseHigh DoseN=59N=59

30d Clinical f/u30d Clinical f/u

1º1ºEndptEndpt

Main Inclusion/Exclusion CriteriaMain Inclusion/Exclusion Criteria

• De-novo lesions in native coronary arteriesDe-novo lesions in native coronary arteries

• LL<30mm, 2.5mm<RVD<3.5mm, 1 or 2 VDLL<30mm, 2.5mm<RVD<3.5mm, 1 or 2 VD

• No bifurcations, LM, OstialNo bifurcations, LM, Ostial

• Up to 3XULN cTnUp to 3XULN cTn

DMDM

NSTEMINSTEMI

Unstable AnginaUnstable Angina

Pro-Inflammatory PatientsPro-Inflammatory Patients

Clinical and demographic characteristicsClinical and demographic characteristics

PlaceboPlaceboLow DoseLow DoseHigh High DoseDoseP valueP value

Age (yrs)Age (yrs)58.1±8.258.1±8.262.3±10.262.3±10.260.1±9.460.1±9.4NSNS

Male (%)Male (%)87.787.791.191.186.486.4NSNS

Prev MI (%)Prev MI (%)30.430.419.619.623.723.7NSNS

DM(%)DM(%)38.638.633.933.928.828.8NSNS

HTN (%)HTN (%)66.766.776.876.869.569.5NSNS

Hchol (%)Hchol (%)75.475.489.189.186.286.2NSNS

Curr. Smoker (%)Curr. Smoker (%)42.642.625.525.536.236.2NSNS

Unstable Angina (%)Unstable Angina (%)66.766.769.669.653.453.4NSNS

BLAST Trial Main Safety ResultsBLAST Trial Main Safety Results

Placebo Placebo N=71N=71

Low Dose Low Dose N=74N=74

High Dose High Dose N=73N=73P valueP value

MACEMACE26.5%26.5%25.4%25.4%20.8%20.8%NSNS

DeathDeath2.8%2.8%0%0%0%0%NSNS

MI*MI*22.1%22.1%11.3%11.3%12.5%12.5%NSNS

Clinically Driven Clinically Driven TLRTLR5.9%5.9%15.5%15.5%12.5%12.5%NSNS

SAE Probably SAE Probably Related to DrugRelated to Drug1.4% (1)1.4% (1)2.7% (2)2.7% (2)1.4% (1)1.4% (1)NSNS

CEC Adjudicated @ 180dCEC Adjudicated @ 180d

* MI excluding peri-procedural = 1.8%, 1.8%, 1.7% Placebo, Low Dose, High Dose respectively

BLAST Trial Main Efficacy ResultsBLAST Trial Main Efficacy Results

PlaceboPlacebo Low DoseLow DoseHigh DoseHigh DoseP valueP value

In-Stent LL (mm)In-Stent LL (mm)0.86±0.600.86±0.600.83±0.570.83±0.570.81±0.680.81±0.68NSNS

In-Stent MLD In-Stent MLD (mm)(mm)1.77±0.801.77±0.801.75±0.811.75±0.811.87±0.711.87±0.71NSNS

% DS% DS36.64±24.8836.64±24.8834.86±27.1634.86±27.1633.29±23.8033.29±23.80NSNS

IVUS % Volume IVUS % Volume ObstructionObstruction24.2±14.524.2±14.524.4±11.624.4±11.626.3±15.526.3±15.5NSNS

But are they truly the same?But are they truly the same?

Gaussian p>0.25

Non-Gaussian p<0.005

Cumulative DistributionsCumulative Distributions

Hypothesized Differential ResponseHypothesized Differential Response

Protocol mandated sub-group analysis

• Diabetes

• Baseline monocyte count

Based on inflammatory stateBased on inflammatory state

Diabetic SubgroupDiabetic Subgroup

In-Stent LL In-Stent LL (mm)(mm)PlaceboPlacebo Low Low

DoseDose

P (low P (low dose vs. dose vs. Placebo)Placebo)

High High DoseDose

P (high P (high dose vs. dose vs. Placebo)Placebo)

Non-DiabeticsNon-Diabetics0.74±0.580.74±0.580.82±0.580.82±0.580.570.570.82±0.710.82±0.710.600.60

DiabeticsDiabetics1.05±0.601.05±0.600.86±0.560.86±0.560.300.300.77±0.620.77±0.620.160.16

Pre-Specified Inflammatory SubgroupPre-Specified Inflammatory Subgroup

In-Stent LL In-Stent LL (mm)(mm)PlaceboPlacebo Low Low

DoseDose

P (low P (low dose vs. dose vs. Placebo)Placebo)

High High DoseDose

P (high P (high dose vs. dose vs. Placebo)Placebo)

Low Low Monocytes*Monocytes*0.67±0.500.67±0.500.86±0.570.86±0.570.240.240.86±0.700.86±0.700.290.29

High High Monocytes**Monocytes**1.00±0.621.00±0.620.78±0.600.78±0.600.180.180.67±0.500.67±0.500.030.03

50-50 Split based on baseline monocyte count

* Low Monocytes = Less than median value pre-injection* Low Monocytes = Less than median value pre-injection* High Monocytes = More than median value pre-injection* High Monocytes = More than median value pre-injection

ConclusionsConclusions

• In the overall study cohort, LABR-312 had no In the overall study cohort, LABR-312 had no averageaverage effect on in-stent Late Loss effect on in-stent Late Loss

• In the pro-inflammatory patients (mandated In the pro-inflammatory patients (mandated subgroup analysis including >50% of the cohort), subgroup analysis including >50% of the cohort), there was a pronounced, statistically significant there was a pronounced, statistically significant reduction in Late Loss with LABR-312reduction in Late Loss with LABR-312

• This differential response could be identified and This differential response could be identified and predicted predicted a-prioria-priori provides the potential  provides the potential for personalized medicinefor personalized medicine

• Future clinical trials will likely focus on the Future clinical trials will likely focus on the dichotomization and extension of treatment effectdichotomization and extension of treatment effect