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  1. 1. Phospholipids Analogs as aPhospholipids Analogs as a New Anti-Inflammatory Anti-New Anti-Inflammatory Anti- Atherosclerosis TherapyAtherosclerosis Therapy Dror HaratsDror Harats The Institute of Lipids and Atherosclerosis Research,The Institute of Lipids and Atherosclerosis Research, ShebaSheba Medical Center, Tel-Hashomer, & Vascular Biogenics LTD,Medical Center, Tel-Hashomer, & Vascular Biogenics LTD, Israel.Israel. Dallas TX, November 2005Dallas TX, November 2005
  2. 2. Confidential – November 2005 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
  3. 3. Confidential – November 2005 Target: Atherosclerosis Meeting the Challenge of a Critical Clinical and Market Need
  4. 4. Confidential – November 2005 TIME Magazine CoverTIME Magazine Cover (March 2004(March 2004((
  5. 5. Confidential – November 2005 Atherosclerosis TimelineAtherosclerosis Timeline FoamFoam CellsCells FattyFatty StreakStreak IntermediateIntermediate LesionLesion AtheromaAtheroma FibrousFibrous PlaquePlaque ComplicatedComplicated Lesion/RuptureLesion/Rupture Endothelial DysfunctionEndothelial Dysfunction Smooth muscle and collagen From first decade From third decade From fourth decade Growth mainly by inflammation and lipid accumulation Thrombosis, inflammation (Adapted from Stary et al. Circulation. 1995;92:1355.)
  6. 6. Confidential – November 2005 * Ross, R. Atherosclerosis, an inflammatory disease. N. Engl. J. Med. 1999, 340: 115 - 126 Atherosclerosis Pathophysiology Current solution Abnormal Cholesterol metabolism Cholesterol build up Statins Only 30% decrease in events Inflammatory response* Increased plaque vulnerability No current solution Etiology Current Treatments: Only Partial Solution VBL’s Solution CI-201 Option: Combination Therapy
  7. 7. Confidential – November 2005 Plaque growth Plaque destabilization / vulnerability Plaque Inflammation Smaller & stable plaque Thrombus Inflammatory Cells Few SMCs Activated Macrophages LesionSizemm2 x100 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
  8. 8. Confidential – November 2005 CI-201 Inhibits Disease ProgressionCI-201 Inhibits Disease Progression Atherosclerotic Plaques )%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
  9. 9. Confidential – November 2005 With No Impact on MetabolismWith No Impact on Metabolism Selected metabolic indices with & withoutSelected 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 IFNIFNγγ ββ actinactin PBSPBS CI-201CI-201 AortaAorta IL-12IL-12
  10. 10. Confidential – November 2005 Oral administrations 9day period 2weeksTime 0 4weeks The effect of CI-201 Administration on Serum SolubleThe 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 collected beforeApoE 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 administration period) and 4 wks lateroral administration began (time 0), 2 wks later (after oral administration period) and 4 wks later.. Blood collection
  11. 11. Confidential – November 2005 %frombaseline IL-10 Serum Levels SAA Levels %frombaseline 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 %frombaseline
  12. 12. CI-201 Anti inflammatory EffectCI-201 Anti inflammatory Effect Atherosclerosis Mice Model Rheumatoid Arthritis Rat Model Link: Inflammatory/immunologic responses Prototype of autoimmune disease CI 201CI 201 Anti inflammatory EffectAnti inflammatory Effect Confidential – September 2005
  13. 13. Similarities Between Atherosclerosis and Rheumatoid Arthritis Atherosclerosis Rheumatoid arthritis Macrophage activation ↑ ↑ T-cell activation ↑ ↑ B-cell activation (oxLDL, HSP Abs) none or ↑ none or ↑ CRP ↑ ↑ Adhesion molecules ↑ ↑ Possible antigens HSP, Ox-LDL, Infectious agents Collagen II, Cartilage antigens, HSP, Infectious agents Confidential – September 2005
  14. 14. Confidential – November 2005 *** * 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 ArthritisScore
  15. 15. CI-201 Treatment Attenuates Inflammatory Cells InfiltrationCI-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 Confidential – September 2005
  16. 16. 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 Confidential – September 2005
  17. 17. Confidential – November 2005 Multiple SclerosisMultiple Sclerosis
  18. 18. Confidential – November 2005 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
  19. 19. Confidential – November 2005 Adapted from Witztum et al. Cell 104;503-516, 2001 AtherosclerosisAtherosclerosis TNF-α Via Immune System Direct Anti- Inflammation (other?)
  20. 20. Confidential – November 2005 CI-201 RadiolabelingCI-201 Radiolabeling O O T OH O T OP O O- O N+
  21. 21. Confidential – November 2005 0 5000 10000 15000 20000 25000 4 8 15 26 Cell Lysate Membrane Cytosol 33 H oxPL Analog Uptake by Human monocytes (U937H oxPL Analog Uptake by Human monocytes (U937)) TotalDPM/Well Time (hr)
  22. 22. Confidential – November 2005 Does oxLDL Compete with oxPL Analog on its Uptake byDoes oxLDL Compete with oxPL Analog on its Uptake by MonocytesMonocytes?? 0 500 1000 1500 2000 2500 3000 O 5ug/ml 25ug/ml 50ug/ml DPM/Well oxLDL concentrations No pre- incubation 2hr pre- incubation (cells+oxLDL) 2hr pre- incubation (oxPL+oxLDL)
  23. 23. Confidential – November 2005 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
  24. 24. Confidential – November 2005 33 H oxPL Analog Uptake by Immune CellsH oxPL Analog Uptake by Immune Cells DPM/Well
  25. 25. Confidential – November 2005 Anti-inflammatory Anti-atherogenic profile within the plaque ArbitraryUnits P=0.005 P<0.05 CI-201, Induces Anti-Inflammatory Response CI-201 Anti-Inflammatory Response in AtherosclerosisCI-201 Anti-Inflammatory Response in Atherosclerosis
  26. 26. Confidential – November 2005 ObservationsObservations • In all animal models tested hence; atherosclerosis, RA and MS, IFN-γ was shown to be involved in disease pathogenesis. • Several lines of evidence that CI-201 reduces the level of IFN-γ.
  27. 27. Confidential – November 2005 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-201 IL-12 IL-27 IL-18
  28. 28. Confidential – November 2005 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-201 T-bet Stat-4 Jak-2 IL-12R IL-12 IL-27 IL-18
  29. 29. Confidential – November 2005 HypothesisHypothesis APC’s TNFα CD40 IL10 INfγ And ??? T cell Atherosclerosis MS RA Other Inflammatory diseases Inflammation Ox-PL analog - CI-201 x
  30. 30. Confidential – November 2005 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
  31. 31. Confidential – November 2005 Thank You!!