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Emerging targets in HDL modification: Relevant data from development programs

Emerging targets in HDL modification: Relevant data from development programs. Prof. John Kastelein Academic Medical Centre Amsterdam, The Netherlands. Novel Approaches to Modify Lipids and Lipoproteins. Low Density Lipoprotein High Density Lipoprotein Triglyceride Rich Lipoproteins

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Emerging targets in HDL modification: Relevant data from development programs

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  1. Emerging targets in HDL modification: Relevant data from development programs Prof. John Kastelein Academic Medical Centre Amsterdam, The Netherlands

  2. Novel Approaches to Modify Lipids and Lipoproteins • Low Density Lipoprotein • High Density Lipoprotein • Triglyceride Rich Lipoproteins • Inflammation • Lipoprotein a

  3. New Approaches for Raising HDL What is in development? • Cholesterol Ester Transfer Protein (CETP) inhibitors • ER-Niacin / Laropiprant combination • ApoA1 based strategies • LCAT replacement strategies • ABCA1 agonists

  4. The Verdict is Still Out on CETP Inhibition as a Mechanism

  5. New Approaches for Raising HDL What is in development? • Cholesterol Ester Transfer Protein (CETP) inhibitors • ER-Niacin / Laropiprant combination • ApoA1 based strategies • LCAT replacement strategies • ABCA1 agonists

  6. Nicotinic AcidTreatment of Dyslipidemia and Atherosclerosis • First used as lipid-altering agent in 1955 • Well understood safety profile • Broad spectrum of lipid effects* • ↓LDL-C (15%–25%) • ↑HDL-C (20%–35%) • ↓TG (20%–40%) • ↓Apo B, non-HDL-C, Lp(a) • Cardiovascular (CV) benefits • ↓ CV events (Coronary Drug Project) • ↓ Plaque progression (angiographic and IMT studies) • Niacin added to a statin may address residual CV risk

  7. 100 80 60 Users, % 40 20 0 4 weeks N = 14,386 8 weeksn = 6,349 12 weeks n = 5,277 24 weeks n = 5,402 1 year n = 2,104 Most Patients on ER Niacin TherapyDo Not Reach a 2-g Dose > 1500 mg 1001–1500 mg 751–1000 mg 501–750 mg 500 mg

  8. Effectiveness of 2 g vs 1 gof ER Niacin Mean % change from baseline • Lipid-modifying efficacy generally seen with at least 1 g/day • Use of 2 g versus 1 g provides: • About twice the LDL-C reduction • About twice the HDL-C elevation • Several times the reduction of TG NIASPAN™ US Prescribing information.

  9. Niacin Flushing Pathway: Two Separate Steps and Sites of Action • 1. Epidermal Langerhans Cells • Niacin binds • PGD2 is produced and released • 2. Dermal Blood Vessels • PGD2 binds to DP1 • Vasodilation results Illustrations are artistic renditions. PGD2=prostaglandin D2; PLA2=phospholipase A2; DP1=prostaglandin D2 receptor 1. Benyó Z et al. Mol Pharmacol. 2006;70:1844–1849; Morrow JD et al. J Invest Dermatol. 1992;98:812–815; Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687.

  10. An Overview of the Niacin-Induced Flushing Pathway Epidermal Langerhans Cells Dermal Blood Vessel Niacin Prostaglandin D2 Receptor 1 (DP1) Pathway Arachidonic Acid Pathway Niacin Receptor Phospholipids PGD2 (+) PLA2 DP1 Arachidonic Acid Vasodilationand Flushing PGG2 PGH2 PGD Synthase PGD2 PGF2α PGI2 TXA2 PGE2 PG=prostaglandin; PLA2=phospholipase A2; TXA2=thromboxane A2. Dashed arrows are normal parts of the arachidonic acid pathway that may or may not occur in Langerhans cells. Maciejewski-Lenoir D et al. J Invest Dermatol. 2006;126:2637–2646; Narumiya S et al. Physiol Rev. 1999;79:1193–1226;Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687; Morrow JD et al. Prostaglandins. 1989;38:263–274.

  11. 2 60 dose advancement dose advancement 50 40 Number of Days per Week % Patients 30 1 20 10 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Weeks on Treatment Weeks on Treatment ER niacin (n = 508) ER niacin/laropiprant (n = 763) OPlacebo (n = 268) Lipid/Flushing Study: Lower Incidence of Moderate or Greater Flushing vs ER Niacin Average number of days per week with moderate or greater flushing symptoms across weeks 1–24 Percentage of patients with moderate or greater flushing symptoms across weeks 1–24

  12. ER Niacin/Laropiprant Lipid Efficacy (Weeks 12-24) 18.8 19.8 * 3.6 Mean % change from Baseline -0.5 -1.2 * p<0.001 vs. Placebo -18.1 -18.9 -21.2 -21.7 * TG (median) * LDL-C HDL-C Maccubbin et al. J Clin Lipidol 2007; 1: 323

  13. 27.5 30 HDL-C 23.4 20 % Change 0 6.0 10 -17.0 -10 -20 0 0 4 8 12 -37.0 % Change -30 Weeks on Treatment -40 -47.9 0 -50 LDL-C -10 -14.7 -60 -20 % Change 0 4 8 12 -21.6 Weeks on Treatment -30 -33.3 TG -40 0 4 8 12 Weeks on Treatment Factorial Study: Lipid Efficacy Primary end point ER niacin/laropiprant (n = 160) Simvastatin (all doses pooled; n = 565) ER niacin/laropiprant + simvastatin (all doses pooled; n = 520)

  14. HPS2-THRIVE (Heart Protection Study 2 – Treating HDL to Reduce Vascular Events) ER niacin/laropiprant 2 g/40mg All patients receive either simvastatin 40mg or ezetimibe/simvastatin 10/40 mg Placebo

  15. New Approaches for Raising HDL What is in development? • Cholesterol Ester Transfer Protein (CETP) inhibitors • ER-Niacin / Laropiprant combination • ApoA1 based strategies • LCAT replacement strategies • ABCA1 agonists

  16. Where to Intervene inHDL-C Metabolism? Hovingh et al. Current Opinion in Lipidology 2005

  17. ApoA1 Based Therapies • ApoA1 Mimetics, such as APL-180 Novartis • Full-length ApoA1, such as ApoA1 Cerenis Therapeutics • Pre-Beta HDL, as generated by delipidation, HDL Therapeutics Inc. • Reconstituted HDL, CSL Ltd. • ApoA1 Milano, The Medicines Company • Trimeric ApoA1, Borean Pharma and now Roche • RVX-208, as developed by Resverlogix

  18. ApoA-I is made in the Liver and Small Intestines. Liver Small Intestines

  19. RVX-208 RVX-208 is an orally active, novel, and synthetic small molecule (<400 kDa) that shares similarities with the Quinazoline family of compounds. IT IS NOT RESVERATROL NOR A DERIVATIVE!

  20. ApoA-I ApoA-I Pool Enhanced R.C.T. pre-b HDL RVX-208 a-HDL3 a-HDL2 RVX-208 increases ApoA-I production, thus triggering HDL synthesis, especially pre-beta HDL known for its potent cholesterol efflux activity.

  21. Cohorts 1- 6 (42 treated and 14 placebo) Single dose of RVX-208 (1-20 mg/kg), fasted A Cohort 7 (12 treated and 4 placebo) B Single dose of RVX-208 (4 mg/kg), fed 80 Subjects Cohorts 8 - 9 (12 treated and 4 placebo) C Multiple doses x 7 days of RVX-208 (4 or 1 mg/kg), b.i.d., fasted D Cohort 10 (6 treated and 2 placebo) Single dose x 7 days of RVX-208 (3 mg/kg), q.d., fasted Schematic of Phase 1a Protocol This color denotes multiple day dosing of RVX-208

  22. Efficacy of RVX-208 in HumansPhase 1b/2a ApoA-I, % Change vs. Placebo * p<0.05, ** p<0.01, *** p<0.001 22

  23. RVX208 α1-HDL Comparison vs. High Dose Statins α1-HDL Strongest Predictor from Framingham Offspring Study ** ** Low HDL Subjects All Subjects ** p<0.008 23 23

  24. Cerenis HDL (CER-001)Homogeneous Drug Product HDL Traditional rHDL complexes HDL Proprietary charged Cerenis rHDL complexes GMP run • Validated, scaleable GMP process for producing proprietary charged lipoprotein complexes

  25. CER-001-CLIN-001 : 15 mg/kgLCAT Activation

  26. CER-001 Mobilizes Cholesterol in Rabbits: Comparison with ETC-216 CER-001 is at least 10 to 20 time more potent to mobilize cholesterol than ETC-216 * ETC-216 data were extracted from Marchesi M. et al (2004) J Pharmacol Exp Ther, 311(3): p. 1023-31

  27. CHI SQUARE Study Design • 4 Treatment Groups • Placebo • Low dose CER-001 • Mid dose CER-001 • High dose CER-001 • 6 doses per subject • 125 subjects enrolled per group • Estimated 75 - 80% completion rate ==> ~98 subjects w/ follow-up IVUS per group

  28. CHI-SQUARE Study Design 50 Sites Canada, US, France, Netherlands Core IVUS Lab Montreal Heart Up to 1000 Subjects Screened w/ Baseline IVUS following Acute ACS Event 504 Subjects Randomized N = 126 Placebo N = 126 Low dose N = 126 Mid dose N = 126 High dose Screen Period 2 weeks Therapy Period 5 weeks Observation Period 2 to 5 weeks Long Term Follow-up 6 months IVUS Visit Screening Infusion Visits Interim Visit Follow-Up IVUS Visit Follow-Up Visit

  29. CER-001-CLIN-001Overall Conclusions • Administration of a single intravenous infusion of CER-001 at doses up to 45 mg/kg over 1 or 2 hours has been safe and well-tolerated • CER-001 exhibits the desired effect of cholesterol mobilization and is significantly more effective than earlier complexes

  30. IVUS clinical trial using selective delipidated HDL Step 1 Collected~1 litreof plasma Step 2 Plasma enrichedthrough process Step 3 Re-infused preβenriched plasma • Used patients own HDL • Cholesterol removed fromαHDL to yield preβ-HDL • Preβ enriched plasma isre-infused into patient Walksman R, et al. J Am CollCardiol 2010; 55 : 2727-35.

  31. IVUS Clinical Trial Using Selective Delipidated HDL Treatment arm (N=14) 1:1 randomization (N=28) Control arm (N=14) Day 0 1 2 3 4 5 6 7 8 Week IVUS IVUS Treatment or control plasma infusion Walksman R, et al. J Am CollCardiol 2010; 55 : 2727-35.

  32. Results of the IVUS Clinical Trial Using Selective Delipidated HDL 4 2.8 2 0 -2 -1.73 -4 Change in atheroma volume (mm3) -6 -6.24 -8 Preβ-HDL infusion -10 Control infusion -12 -12.18 -14 Change in totalatheroma volume Change in 10mm most diseased segment Waksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.

  33. Conclusion Therapies that raise levels of ApoA-I and pre-beta HDL carry a strong promise for the future of cardiovascular disease prevention

  34. New Approaches for Raising HDL What is in development? • Cholesterol Ester Transfer Protein (CETP) inhibitors • ER-Niacin / Laropiprant combination • ApoA1 based strategies • LCAT replacement strategies • ABCA1 agonists

  35. LCAT Product Gradient Drives Reverse Cholesterol Transport LDL Small HDL Clearance CETP Kidney LDL-R LCAT SR-BI nascent HDL (small, preβ-HDL) Peripheral tissues mature HDL (large, α-HDL) Liver

  36. LCAT Deficiency in Humans • Current Treatments • Dietary fat restriction • ACE inhibitor, ARB’s • Dialysis • Kidney transplantation • Corneal transplantation • >75 gene mutations have been described resulting in two phenotypes • >200 cases reported worldwide • Familial LCAT Deficiency (FLD) • Complete absence of LCAT activity in plasma • Corneal opacities, anemia, proteinuria, renal failure • Glomerulosclerosis a major cause of morbidity and mortality • Fish Eye Disease (FED) • Partial deficiency of LCAT activity in plasma • Corneal opacities

  37. Impaired RCT in Familial LCAT Deficiency Decreased LDL Lp-X Kidney CETP LDL-R Increased LCAT SR-BI nascent HDL (Preβ-HDL) Peripheral tissues mature HDL (α-HDL) Liver

  38. Conclusion In the next five years, we will prove or disprove that additional LDL lowering with other agents than statins is effective and we will show or not show that the HDL hypothesis is true.

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