phospholipids analogs as a new anti-inflammatory anti- atherosclerosis therapy dror harats the...
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Phospholipids Analogs as a Phospholipids Analogs as a New Anti-Inflammatory Anti-New Anti-Inflammatory Anti-
Atherosclerosis TherapyAtherosclerosis Therapy
Dror HaratsDror HaratsThe Institute of Lipids and Atherosclerosis Research,The Institute of Lipids and Atherosclerosis Research, Sheba Sheba Medical Center, Tel-Hashomer, & Vascular Biogenics LTD, Medical Center, Tel-Hashomer, & Vascular Biogenics LTD,
Israel.Israel.
Dallas TX, November 2005Dallas TX, November 2005
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CI-201 SummaryCI-201 Summary
• Oral Small Molecule
• Anti-Atherosclerotic Anti-Inflammatory
• Reduces Progression Of Disease By Up To 92% In Preclinical Trials
• Additional Proof of Concept In Rheumatoid Arthritis And Multiple Sclerosis
• Phase I Clinical Trials In 2006
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Target: Atherosclerosis
Meeting the Challenge of a Critical Clinical and Market Need
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TIME Magazine CoverTIME Magazine Cover(March 2004)(March 2004)
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Atherosclerosis TimelineAtherosclerosis Timeline
FoamFoamCellsCells
FattyFattyStreakStreak
IntermediateIntermediateLesionLesion AtheromaAtheroma
FibrousFibrousPlaquePlaque
ComplicatedComplicatedLesion/RuptureLesion/Rupture
Endothelial DysfunctionEndothelial Dysfunction
Smooth muscleand collagen
From first decade From third decade From fourth decadeGrowth mainly by inflammation and lipid accumulation Thrombosis,
inflammation(Adapted from Stary et al. Circulation. 1995;92:1355.)
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* Ross, R. Atherosclerosis, an inflammatory disease. N. Engl. J. Med. 1999, 340: 115 - 126
Atherosclerosis
Pathophysiology
Current solution
Abnormal Cholesterol metabolism
Cholesterol build up
StatinsOnly 30% decrease in events
Inflammatoryresponse*
Increasedplaque vulnerability
No current solution
Etiology
Current Treatments: Only Partial Solution
VBL’s Solution
CI-201
Option: Combination Therapy
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Plaque growth
Plaque destabilization/ vulnerability
Plaque Inflammation
Smaller & stable plaque
Thrombus
Thrombus Inflammato
ry Cells
FewSMCs Activated
Macrophages Lesi
on S
ize m
m2
x10
0
0
250
500
750
1000
0 Weeks 3 Weeks
oxLDL
Albumin
Control
P<0.01
CI-201: SM Ox-LDL Derivative to Address InflammationCI-201: SM Ox-LDL Derivative to Address Inflammation
CI-201 is a small molecule rationally designed to mimic OxLDL epitopes
First proof of concept with OxLDL reducing atherosclerosis by ~ 60%
OxLDL
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CI-201 Inhibits Disease ProgressionCI-201 Inhibits Disease Progression
0
10
20
30
40
50
Base Line PBS CI-201 0.1ug/dose
AtheroscleroticPlaques
%(Base Line) -92%
6 month old Apo E KO mice; oral administration with CI-201 or PBS for 3 mos
Reduction in Plaques with CI-201 Treatment
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With No Impact on MetabolismWith No Impact on Metabolism
Selected metabolic indices with & without Selected metabolic indices with & without CI-201 treatmentCI-201 treatment
0
100
200
300
400
500
Body weight Cholesterol Triglycerides
PBS
CI 201 (0.1ug)
IL-10IL-10
IFNIFN
ββ actin actin
PBSPBS CI-201CI-201
AortaAorta
IL-12IL-12
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Oral administrations
9 day period
2 weeksTime 0 4 weeks
The effect of CI-201 Administration on Serum Soluble The effect of CI-201 Administration on Serum Soluble Inflammatory MarkersInflammatory Markers
ApoE mice were orally administered with CI-201 5 times every other day. Blood was ApoE mice were orally administered with CI-201 5 times every other day. Blood was collected before oral administration began (time 0), 2 wks later (after oral collected before oral administration began (time 0), 2 wks later (after oral administration period) and 4 wks lateradministration period) and 4 wks later..
Blood collection
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% f
rom
bas
elin
e
base line 2wks 4wks base line 2wks 4wks
0
2000
4000
6000
8000
10000
12000
14000
IL-10 Serum Levels SAA Levels
base line 2wks 4wks base line 2wks 4wks
0
200
400
600
800
1000
1200
% fr
om b
asel
ine
Control CI-201 Control CI-201
P<0.05(84%-3053%)(100%-22,850%)
(100%-132%)
(30%-144%)
Baseline 14 days 28 days Baseline 14 days 28 days
Baseline 14 days 28 days Baseline 14 days 28 days
Anti-inflammatory effects of CI-201Anti-inflammatory effects of CI-201%
from
bas
elin
e
CI-201 Anti inflammatory EffectCI-201 Anti inflammatory Effect
AtherosclerosisMice Model
Rheumatoid ArthritisRat Model
Link: Inflammatory/immunologic responses
Prototype of autoimmune disease
CI 201 CI 201 Anti inflammatory EffectAnti inflammatory Effect
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Similarities Between Atherosclerosis and Rheumatoid Arthritis
AtherosclerosisRheumatoid arthritis
Macrophage activation↑↑
T-cell activation↑↑
B-cell activation )oxLDL, HSP Abs(none or ↑none or ↑
CRP↑↑
Adhesion molecules↑↑
Possible antigensHSP, Ox-LDL, Infectious agents
Collagen II, Cartilage antigens, HSP, Infectious agents
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Days from arthritis induction8 10 12 14 16 18 20 22
0
2
4
6
8
10
CI-201 4mg/kgControl***
* P<0.05
** P<0.01
*** P=0.005
**** P<0.005
**** * **** **** * *
*
Effect of CI-201 on Arthritic Score Adjuvant-induced RA Model
Treatment effected 65% reduction in paw swelling
Art
hri
tis
Sc
ore
CI-201 Treatment Attenuates Inflammatory Cells Infiltration CI-201 Treatment Attenuates Inflammatory Cells Infiltration Within The JointWithin The Joint
Lewis Male rats were orally treated with CI-201 before and after adjuvant induced arthritis. Joints were collected on day 24 )arthritis peak( decalcified and stained with H&E.
Severe bone destruction )red arrows(, new bone formation and destruction of the synovial lining
)n=6(.
No evidence of disease or mild lymphocytic infiltrate )n=6(
CI-201Control
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CI-201 (1,10µg/mouse) Treatment Decreased Clinical Signs of ArthritisCI-201 (1,10µg/mouse) Treatment Decreased Clinical Signs of Arthritis
Set of 5 oral administrations every day
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Multiple SclerosisMultiple Sclerosis
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CI-201: Results SummaryCI-201: Results Summary
CI-201
Atherosclerosis Rheumatoid Arthritis
Multiple Sclerosis
IL-10
SAA
Atherosclerotic Progression
92%
Cytokine Marker (Test in Progress)
Clinical Improvement
Paw Swelling (65%)
Reduction of Inflammatory Markers Correlative to Reduction in Inflammatory Conditions
Cytokine Marker (Test in Progress)
Preliminary very encouraging results
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Adapted from Witztum et al. Cell 104;503-516, 2001
AtherosclerosisAtherosclerosis
TNF-
Via Immune System
Direct Anti-Inflammation
(other?)
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CI-201 RadiolabelingCI-201 Radiolabeling
O
O
T
OH
O
T
OP
O
O-
O
N+
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0
5000
10000
15000
20000
25000
4 8 15 26
Cell LysateMembraneCytosol
33H oxPL Analog Uptake by Human monocytes (U937)H oxPL Analog Uptake by Human monocytes (U937)To
tal D
PM /
Wel
l
Time (hr)
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Does oxLDL Compete with oxPL Analog on its Uptake by Does oxLDL Compete with oxPL Analog on its Uptake by MonocytesMonocytes??
0
500
1000
1500
2000
2500
3000
O5ug/ ml25ug/ ml50ug/ ml
DP
M /
Wel
l
oxLDL concentrations
No pre-incubation
2hr pre-incubation
(cells+oxLDL)
2hr pre-incubation
(oxPL+oxLDL)
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Cells Involved in the “GameCells Involved in the “Game””
Antigen presenting cells (APC)
B cells
Dendritic cells
Macrophages
Activated T-cells
Primary stimulation-Signal I
Secondary costimulation-Signal II
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33H oxPL Analog Uptake by Immune CellsH oxPL Analog Uptake by Immune CellsD
PM /
Wel
l
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0
0.1
0.2
0.3
0.4
0.5
0.6
PBS, control CI-201
IL-10
0
0.04
0.08
0.12
PBS, control CI-201
IFN-gamma
Anti- inflammatory Anti- atherogenic profile within the plaque
Arb
itrar
y U
nits
P=0.005
P<0.05
CI-201, InducesAnti-Inflammatory Response
CI-201 Anti-Inflammatory Response in AtherosclerosisCI-201 Anti-Inflammatory Response in Atherosclerosis
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ObservationsObservations
• In all animal models tested hence; atherosclerosis, RA and MS, IFN-was shown to be involved in disease pathogenesis.
• Several lines of evidence that CI-201 reduces the level of IFN-
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CI-201: Proposed Mechanism of Action ICI-201: Proposed Mechanism of Action I
APC
Thp
IFN-γ
Th1Th2
IL-4
IL-4
IL-10
CI-201IL-12
IL-27
IL-18
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CI-201: Proposed Mechanism of Action IICI-201: Proposed Mechanism of Action II
APC
Thp
IFN-γ
Th1Th2
IL-4
IL-4
IL-10
CI-201T-bet
Stat-4 Jak-2
IL-12R
IL-12
IL-27
IL-18
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HypothesisHypothesis
APC’s TNF
CD40
IL10
INf
And ???
T cell
Atherosclerosis
MS
RA
Other Inflammatory diseases
Inflammation
Ox-PL analog - CI-201
x
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Summary of ResultsSummary of Results
• First-in-class anti-atherosclerotic / anti inflammatory drug
• Proof of concept in additional inflammatory diseases )RA, MS(
• Oral administration
• Effective at low doses
• Potentially synergistic application with Statins
• Safe – as shown by preliminary safety data
• Phase I Clinical Trials to begin Q2 2006
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Thank You!!