The BLAST TrialBiorest Liposomal Alendronate

with Stenting sTudy

Targeted Anti-Inflammatory

Systemic Therapy for Restenosis

Shmuel Banai, MDTel Aviv medical Center

Tel Aviv, ISRAEL

Disclosure Statement of Financial Interest

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

Background

• Inflammation is the hallmark of Atherosclerosis and Restenosis

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

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

(2 )Unique Liposomes as Trojan horses; Encapsulated BP are phagocytosed exclusively by monocytes

Targeting Monocytes

(3 )Liposome degradationin lysosome releases BP

(4 )Intracellular BPs inhibit the cell

(1 )Free Bisphosphonates (BPs) can not cross cell membranes

BIOrest LABR-312

0 2 4 60 1 5 10 50 100

Concentration [uM]

Cel

l # [

% o

f ba

selin

e]

Days after InfusionM

onoc

yte

Mod

ulat

ion

Macrophages

EC

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 – BIOrest Liposomal Alendronate with Stenting sTudy

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

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

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

BLAST Trial

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

• Study PI: Prof. Shmuel Banai – Tel Aviv Medical Center • Participating Medical Centers and PI’s:

Tel Aviv Sourasky – S. Banai Shaare Zedek – Y. Almagor Baruch Padeh – Y. Hasin Bnei Zion – U. Rosenschein Rabin – R. Kornowski Sheba – V. Guetta

Lady Davis – B. Lewis Meir – M. Mosseri Kaplan – O. Ayzenberg Hillel Yaffe – A. Frimerman Western Galilee – S. Atar

BLAST Trial – Parties Involved

Study Management Medinol Ltd.

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

Harvard Clinical Research Institute (HCRI), Boston, USA

Angiographic Core Laboratory

Cardiovascular Research Foundation (CRF), NY, USA

IVUS Core Laboratory Stanford University Medical Center,CA, USA

Arrhythmia and ECG Core Laboratory

Harvard Clinical Research Institute (HCRI), Boston, USA

FACS Core Laboratory BIOrest LTD. , Yavneh, Israel

Study Monitoring GCP Clinical Monitoring Ltd.

BLAST Trial - Study Endpoints

• Primary Endpoint: In-Stent angiographic Late Loss @ 6m (High / Low Dose vs. Placebo)

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

• Pre-Specified subgroup analyses including: Diabetes Baseline monocyte count Unstable Angina

Total Patients RecruitedN=225

Placebo (saline)N=74

Low Dose (1µg LABR-312)N=77

High Dose (10µg LABR-312)N=74

PlaceboN=57 (77% f/u)

Low DoseN=56 (73% f/u)

PlaceboN=26

Low DoseN=31

High DoseN=26

BMS Stenting (Pressilion)+Drug AdministrationQCA, IVUS, Blood sampling for monocytes @ Screening, 0, 8, 16, 24 h

6m Clinical+Angiographic f/u Per-Protocol Analysis on a per-patient basis

6m IVUS f/u subset

Randomization 1:1:1

High DoseN=59 (80% f/u)

30d Clinical f/u

1ºEndpt

Main Inclusion/Exclusion Criteria

• De-novo lesions in native coronary arteries• LL<30mm, 2.5mm<RVD<3.5mm, 1 or 2 VD• No bifurcations, LM, Ostial• Up to 3XULN cTn

• DM• NSTEMI• Unstable Angina

Pro-Inflammatory Patients

Baseline Patient Characteristics

Placebo Low Dose High Dose

P value

Age (yrs) 58.1±8.2 62.3±10.2 60.1±9.4 NS

Male (%) 87.7 91.1 86.4 NS

Prev MI (%) 30.4 19.6 23.7 NS

DM (%) 38.6 33.9 28.8 NS

HTN (%) 66.7 76.8 69.5 NS

Hchol (%) 75.4 89.1 86.2 NS

Curr. Smoker (%) 42.6 25.5 36.2 NS

Unstable Angina (%) 66.7 69.6 53.4 NS

Baseline Lesion Characteristics

Placebo Low Dose High Dose P value

RVD (mm) 2.75±0.46 2.67±0.47 2.84±0.41 NS

MLD (mm) 0.77±0.28 0.76±0.31 0.85±0.33 NS

Lesion Length (mm) 12.14±4.58 12.12±4.62 13.14±5.47 NS

LAD (%) 36.9 45.2 36.8 NS

Diffuse (>20mm) (%) 7.7 4.8 8.8 NS

Lesions treated per patient 1.16±0.37 1.11±0.31 1.20±0.45 NS

BLAST Trial Main Safety Results

Placebo N=71

Low Dose N=74

High Dose N=73 P value

MACE 26.5% 25.4% 20.8% NS

Death 2.8% 0% 0% NS

MI* 22.1% 11.3% 12.5% NS

Clinically Driven TLR 5.9% 15.5% 12.5% NS

SAE Probably Related to Drug 1.4% (1) 2.7% (2) 1.4% (1) NS

CEC Adjudicated @ 180d

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

BLAST Trial Main Efficacy Results

Placebo Low Dose High Dose P value

In-Stent LL (mm) 0.86±0.60 0.83±0.57 0.81±0.68 NS

In-Stent MLD (mm) 1.77±0.80 1.75±0.81 1.87±0.71 NS

% DS 36.64±24.88 34.86±27.16 33.29±23.80 NS

IVUS % Volume Obstruction 24.2±14.5 24.4±11.6 26.3±15.5 NS

0

2

4

6

8

10

12

Placebo

High Dose

Late Loss (mm)

Freq

uenc

y

But are they truly the same?

Gaussian p>0.25

Non-Gaussian p<0.005

Cumulative Distributions

0 0.5 1 1.5 2 2.5 3 3.50.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

Placebo f/uHigh Dose f/u

In Stent MLD [mm]

% O

f Pati

ents

-20 0 20 40 60 80 1000.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

Placebo f/uHigh Dose f/u

%Diameter Stenosis

% O

f Pati

ents

At 6 month follow up

Hypothesized Differential Response

-0.25 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 30

2

4

6

8

10

12

14

Placebo

Low Dose

Late Loss (mm)

Freq

uenc

y

:Gaussian Single peak

:Non-Gaussian Left-skewed/double peak

Protocol mandated sub-group analysis

• Diabetes• Baseline monocyte count

Pre-hoc analysis based on inflammatory state

Diabetic Subgroup

In-Stent LL (mm) Placebo

Low Dose

P (low dose vs. Placebo)

High Dose

P (high dose vs. Placebo)

Non-Diabetics 0.74±0.58 0.82±0.58 0.57 0.82±0.71 0.60

Diabetics 1.05±0.60 0.86±0.56 0.30 0.77±0.62 0.16

Pre-Specified Inflammatory Subgroup

In-Stent LL (mm) Placebo

Low Dose

P (low dose vs. Placebo)

High Dose

P (high dose vs. Placebo)

Low Monocytes* 0.67±0.50 0.86±0.57 0.24 0.86±0.70 0.29

High Monocytes** 1.00±0.62 0.78±0.60 0.18 0.67±0.50 0.03

50-50 Split based on baseline monocyte count

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

Conclusions

• There were no safety concerns associated with BIOrest LABR-312

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

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

• This differential response could be identified and predicted a-priori, providing the potential for personalized medicine

• Future clinical trials will focus on the documented clinical effect in pro-inflammatory patients