the blast trial biorest liposomal alendronate with stenting study targeted anti-inflammatory...
Post on 01-Jan-2016
218 Views
Preview:
TRANSCRIPT
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
top related