Presentation is loading. Please wait.

Presentation is loading. Please wait.

What are the options left?

Published byJázmin Pap Modified over 5 years ago

Similar presentations

Presentation on theme: "What are the options left?"— Presentation transcript:

1 What are the options left?
Targeting HDL-c: What are the options left? Dr. Bryan Brewer Medstar Research Institute Washington DC, USA

2 Current Model of HDL Metabolism
Triglycerides B-100 C-III E Triglycerides B-100 C-III E Triglycerides B-100 C-III LDLR Modification VLDL SR-BI CE CETP TG LDL LRP LPL HL ABCG1 E Triglycerides B-48 C-III LCAT HDL-M, (α3) HDL-L, (α2) HDL-VL, (α1) ABCA1 A-I HDL-VS Preβ-HDL HDL-S, (α4) Chylomicron Macrophage Arterial Wall

3 Targeting HDL-C: What are the Options Left
I. CETP Inhibitors II. ApoA-I Inducers

4 Resverlogix ApoA-I Inducer: RVX 208
ASSERT Clinical Trial (n=299) Modest increases in HDL-C (8.3%) and apoA-I (5.6%) levels. Increase in larger HDL (16.2%, result of successful cholesterol efflux?) ASSURE Clinical Trial (n=310) - Effects of 6 months of RVX 208 on coronary atherosclerosis quantitated by IVUS.

5 Targeting HDL-C: What are the Options Left
I. CETP Inhibitors II. ApoA-I Inducers III. HDL Infusions

6 Concept of HDL Infusion Therapy – Increase Preβ-HDL
Triglycerides B-100 C-III E Triglycerides B-100 C-III E Triglycerides B-100 C-III LDLR Modification VLDL CE CETP TG SR-BI LDL LRP LPL HL ABCG1 E Triglycerides B-48 C-III LCAT HDL-VL, (α1) A-I ABCA1 LCAT HDL-L, (α2) Chylomicron LCAT HDL-M, (α3) A-I Macrophage Arterial Wall A-I Acute HDL Therapy: Key - Infusion of Preβ-HDL A-I HDL-S, (α4) HDL-VS Preβ-HDL

7 Acute HDL Infusion Therapy
2 Step Process for Production of Recombined ApoA-I (rHDL) Phospholipids Synthesized ApoA-I 1 243 aa rHDL A-I Clinical Trials rHDL

8 HDL Infusion Clinical Trial Design: 5 -7 Weekly HDL Infusions With Quantitation of Coronary Atherosclerosis in ACS Patients by Intravascular Ultrasound (IVUS) Treatment Arm Stable Hypolipidemic Drugs Control Arm Day 0 1 2 3 4 5 6 7 8 Week IVUS IVUS Treatment or Control Infusions

9 HDL Infusions in ACS Patients
I. ApoA-I Milano

10 Acute HDL Infusion Therapy
ApoA-I Milano 2 Step Process for Production of Recombined ApoA-I (rHDL) Phospholipids Recombinant Synthesized ApoA-I 1 243 aa rHDL A-I Clinical Trials rHDL

11 Reduction in Atheroma Volume in Acute Coronary Syndrome Patients Following HDL Infusions
46 Acute Coronary Patients: 5 Weekly Infusions ApoA-I Milano Infusion; 11 Saline Infusions 2 4 6 8 10 14 16 - + A-I Milano* -14.10 - - Change in Total Atheroma Volume (mm)3 - 12 -5.34 - *Nissen S et al JAMA 2003;290:

12 HDL Infusions in ACS Patients
I. ApoA-I Milano II. CSL

13 Acute HDL Infusion Therapy
CSL 111 2 Step Process for Production of CSL111 (ApoA-I/PL,rHDL) using Cholate Detergent Phospholipids Isolated ApoA-I from plasma 1 243 aa Cholate Detergent CSL111 (αHDL) A-I Clinical Trials CSL111 Cholate

14 Gel Electrophoresis of CSL111 (rHDL)
Patel, S. et al. J Am Coll Cardiol 2009;53:

15 Reduction in Atheroma Volume in Acute Coronary Syndrome Patients Following HDL Infusions
183 Acute Coronary Patients: 4 Weekly Infusions, 123 Patients Received CSL111 rHDL Infusion; 60 Patients Control Infusions 2 4 6 8 10 14 16 - + A-I Milano* -14.10 -5.34 ERASE** **Tardif JC et al. JAMA 2007;297: - - Change in Total Atheroma Volume (mm)3 - 12 -5.34 - *Nissen S et al JAMA 2003;290:

16 CSL has reformulated CSL111 and are currently developing CSL112

17 Phase I CSL112 (αHDL3) Infusions in Humans
4 8 12 16 20 24 Hours Cholesterol (mg/dl) Free Cholesterol Cholesteryl esters Diditchenko S et al Presented at ISA 2012 Australia

18 HDL Infusions in the ACS Patient
I. ApoA-I Milano II. CSL III. Cerenis

19 Acute HDL Infusion Therapy:CER-001
2 Step Process for Production of CER-001 (ApoA-I,PL/Sphingomyelin) (αHDL) Synthesized ApoA-I 1 243 aa Phospholipids + Sphingomyelin ApoA-I/PL/ Sphingomyelin A-I Clinical Trials Cerenis-001 (αHDL)

20 Acute HDL Infusion Therapy
Effect of Cerenis CER-001 Infusion on Plasma Lipoproteins 4 8 12 16 20 24 Hours Cholesterol (mg/dl) Free Cholesterol Cholesteryl esters

21 CHI SQUARE Clinical Trail
IVUS Analysis of the Effect of Cerenis CER-001 on Coronary Atherosclerosis Control Arm 6 Infusions ? mg/kg n =500+ 21

22 HDL Infusions in ACS Patients
I. ApoA-I Milano II. CSL III. Cerenis IV. HDL Therapeutics

23 Synthesis of Ligands for the ABCA1 Transporter
2 Step Process for Production of rHDL 1 Step Process for Synthesis of Preβ-HDL αHDL 1 Challenges of 2 Step Procedure 1. Low Yield 2. Safety 4. Cost 3. αHDL vs preβ-HDL- specificity for ABCA Transporter 5. Regulatory Hurdles 243 aa Synthesized ApoA-I Phospholipids Selective HDL Delipidation A-I Preβ-HDL A-I Clinical Trials Selective HDL Delipidation Clinical Trials rHDL rHDL

24 HDL Selective Delipidation
Increase Preβ Levels by Converting αHDL to Preβ-HDL A-I A-I A-I αHDL Preβ-HDL ”Loaded Dump Truck” “Unloaded Dump Truck” 24 24

25 Preβ Enriched Plasma Obtained by HDL Selective Delipidation
Plasma Bag 1 Plasma Collected Preβ Enriched Plasma Obtained By Selective HDL Delipidation A-I αHDL Preβ-HDL 20% % Plasma Bag 2 Preβ Enriched Plasma A-I A-I αHDL Preβ-HDL 95% % Preβ-HDL

26 2-D Gel Electrophoresis of Control Plasma, Sham Treated Plasma and Selective HDL Delipidated Plasma Demonstrating a Shift from aHDL to preb-HDL with Selective HDL Delipidation a HDL a HDL a HDL Preb-1 Preb-1 Preb-1 Sham Treated Plasma Selective HDL Delipidation Control Plasma Analysis performed by Dr. B. Asztalos, Tufts University Boston, MA

27 2-D Gel Electrophoresis of Control Plasma, Sham Treated Plasma and Selective HDL Delipidated Plasma Demonstrating a Shift from aHDL to preb-HDL with Selective HDL Delipidation a HDL a HDL a HDL Preb-1 Preb-1 Preb-1 Sham Treated Plasma Selective HDL Delipidation Control Plasma Analysis performed by Dr. B. Asztalos, Tufts University Boston, MA

28 Step 1 Collected ~1 Liter of Patients Plasma
HDL Therapeutics Human Trial: Conducted Using Autologous Preβ-HDL Enriched Plasma Step Collected ~1 Liter of Patients Plasma Step 2 Cholesterol removed from αHDL to yield preβ-HDL Step 3 Re-infused Preβ Enriched Plasma 28

29 HDL Selective Delipidation***
Reduction in Atheroma Volume in Acute Coronary Syndrome Patients Following HDL Infusions 28 Acute Coronary Patients: 7 Weekly Infusions, 14 Received Delipidated HDL and 14 Control Plasma Infusions 2 4 6 8 10 14 16 - + HDL Selective Delipidation*** ***Waksman R et al J. Am. Coll Card 2010;55: C -12.10 A-I Milano* -14.10 -5.34 ERASE** **Tardif JC et al. JAMA 2007;297: - - Change in Total Atheroma Volume (mm)3 - 12 -5.34 - *Nissen S et al JAMA 2003;290:

30 HDL Selective Delipidation*
Comparison of Change in Total Atheroma Volume in the HDL Therapeutics HDL Infusion and Saturn Trials 2 4 6 8 10 14 16 - + HDL Infusion SATURN Statin Therapy -12.10 HDL Selective Delipidation* - 6.4 - 4.4 Atorvastatin SATURN Trial** Rosuvastatin - - Change in Total Atheroma Volume (mm)3 - 12 -5.34 7 Weeks 2.2 Years - *Waksman R et al J. Am. Coll Card 2010;55: C *Nicholls SJ et al, N Eng J Med 2011;365:

31 Targeting HDL-C: What are the Options Left
I. CETP Inhibitors II. ApoA-I Inducers III. HDL Infusions IV. LCAT Inducers

32 LCAT Targeted Therapy ACP-501 (rhLCAT) Clinical Summary
ACP-501 safe and tolerable at all doses evaluated No SAE’s Rapid and substantial increase in HDL-C (43% increase from baseline) and cholesterol esterification Evidence that RCT pathway is being activated

33 LCAT Targeted Therapy ACP-501 (rhLCAT) I. Familial LCAT Deficiency Orphan Drug Opportunity

34 Lipid Filled Macrophage in the Heart
LCAT Therapy: Infusion of rLCAT For Treatment of Familial LCAT Deficiency Liver Intestine LDLr LCAT CETP A-I αHDL ABCG1 LDL CD36 SR-A SR-BI Lp-X Kidney (FC/PL) αHDL LCAT ABCA1 A-I αHDL Preβ-HDL Lipid Filled Macrophage in the Heart

35 LCAT Targeted Therapy ACP-501 (rhLCAT) I. Familial LCAT Deficiency Orphan Drug Opportunity II. Infusions of rLCAT to Reduce Coronary Plaques

36 LCAT Therapy: Infusion of rLCAT For Treatment of Coronary Plaques
Liver Intestine LDLr CETP LDL CD36 SR-A SR-BI ABCG1 A-I A-I ABCA1 LCAT A-I αHDL Preβ-HDL Lipid Filled Macrophage in the Heart αHDL Acute rLCAT Infusions

37 LCAT Overexpression Increased Plasma HDL and Decreased Atherosclerosis in LCAT Transgenic Rabbits
Hoeg et al. Proc Natl Acad Sci USA.1996;93:

38 Take Home Messages √ √ √ √
Epidemiological and clinical trial evidence established that low HDL is an independent risk factor for CVD. √ Novel HDL therapies are under development including CETP Inhibitors, ApoA-I inducers, HDL infusions and LCAT inducers. √ HDL infusions in ACS patients were associated with marked regression of atherosclerosis and have a high probability of decreasing clinical events. √ Clinical trials will be required to definitively establish if increasing HDL will decrease clinical cardiovascular events.

Download ppt "What are the options left?"

Similar presentations

Residual risk: Is LDL target enough?

Residual risk: Is LDL target enough?
The future of HDL raising

The future of HDL raising
Lipoprotein Structure, Function, and Metabolism

Lipoprotein Structure, Function, and Metabolism
Friend or Foe? High HDL Cholesterol. High Density Lipoprotein Origin: liver Content: 18-25% TC content 45-55% Protein 2-7% TG 20-30% Phospholipids Density:

Friend or Foe? High HDL Cholesterol. High Density Lipoprotein Origin: liver Content: 18-25% TC content 45-55% Protein 2-7% TG 20-30% Phospholipids Density:
De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood pressure Prof. John Deanfield University.

De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood pressure Prof. John Deanfield University.
Lipoprotein Structures, Function and Metabolism (1)

Lipoprotein Structures, Function and Metabolism (1)
Lipoprotein Structure and Function

Lipoprotein Structure and Function
Clinical Trial Results. org The ERASE Trial: Effect of rHDL on Atherosclerosis-Safety and Efficacy Presented at American College of Cardiology Annual Scientific.

Clinical Trial Results. org The ERASE Trial: Effect of rHDL on Atherosclerosis-Safety and Efficacy Presented at American College of Cardiology Annual Scientific.
Emerging targets in HDL modification: Relevant data from development programs Prof. John Kastelein Academic Medical Centre Amsterdam, The Netherlands.

Emerging targets in HDL modification: Relevant data from development programs Prof. John Kastelein Academic Medical Centre Amsterdam, The Netherlands.
Heartbeat – Dec 2003 AHA 2003 AHA 2003: Tackling LDL and HDL for atheroma regression Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai.

Heartbeat – Dec 2003 AHA 2003 AHA 2003: Tackling LDL and HDL for atheroma regression Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai.
Comparison of the Progression of Coronary Atherosclerosis for Two High Efficacy Statin Regimens with Different HDL Effects: SATURN Study Results SJ Nicholls,

Comparison of the Progression of Coronary Atherosclerosis for Two High Efficacy Statin Regimens with Different HDL Effects: SATURN Study Results SJ Nicholls,
SATURN: Objective To compare the effects of rosuvastatin 40 mg versus atorvastatin 80 mg on progression of coronary atherosclerosis assessed by intravascular.

SATURN: Objective To compare the effects of rosuvastatin 40 mg versus atorvastatin 80 mg on progression of coronary atherosclerosis assessed by intravascular.
Low HDL remains a predictor of cardio- vascular risk in statin-treated patients Barter P et al., N Engl J Med 2007; 357: 1301-10.

Low HDL remains a predictor of cardio- vascular risk in statin-treated patients Barter P et al., N Engl J Med 2007; 357:
Effect of on Oral Agent Inducing ApoA-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study SJ Nicholls, CM Ballantyne, PJ.

Effect of on Oral Agent Inducing ApoA-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study SJ Nicholls, CM Ballantyne, PJ.
Results of the First Major Clinical Trial of An Oral Agent Inducing ApoA-I Synthesis: A New Approach to Raising HDL and CV Risk Modification SJ Nicholls,

Results of the First Major Clinical Trial of An Oral Agent Inducing ApoA-I Synthesis: A New Approach to Raising HDL and CV Risk Modification SJ Nicholls,
Clinical Trial Results. org METEOR Trial Presented at the American College of Cardiology Annual Scientific Session March, 2007 Presented by Dr. John R.

Clinical Trial Results. org METEOR Trial Presented at the American College of Cardiology Annual Scientific Session March, 2007 Presented by Dr. John R.
Clinical Trial Results. org ILLUSTRATE Presented at the American College of Cardiology Annual Scientific Session March, 2007 Presented by Dr. Steven E.

Clinical Trial Results. org ILLUSTRATE Presented at the American College of Cardiology Annual Scientific Session March, 2007 Presented by Dr. Steven E.
Date of download: 7/8/2016 Copyright © The American College of Cardiology. All rights reserved. From: Impact of Dual Lipid-Lowering Strategy With Ezetimibe.

Date of download: 7/8/2016 Copyright © The American College of Cardiology. All rights reserved. From: Impact of Dual Lipid-Lowering Strategy With Ezetimibe.
Yale Mitchel, MD Cardiovascular Disease Department

Yale Mitchel, MD Cardiovascular Disease Department
Lipids in the diet are hydrolyzed in the small intestine, and the resultant fatty acids and monoglycerides are repackaged with apoB-48 into TG-enriched.

Lipids in the diet are hydrolyzed in the small intestine, and the resultant fatty acids and monoglycerides are repackaged with apoB-48 into TG-enriched.

Similar presentations

Ads by Google