2016 Archived Content

Targeting Cardio-Metabolic Diseases Header

Much of new drug development for cardiometabolic diseases such as type 2 diabetes, hyperlipidemia and atherosclerosis is centered around compounds that target the liver. For example, the recently launched lipid-lowering alternative to statins are inhibitors of PCSK9, a protein in the liver that effects cholesterol metabolism. This day-and-a-half conference focuses on new cardiometabolic drug targets, mostly PCSK9 and the connections between cardiometabolic disease and liver metabolism, especially as manifested in a disease of the fatty liver, NASH (Non-Alcoholic SteatoHepatitis). 

Final Agenda


• September 19 Symposium: Autoimmunity – Small Molecule Approaches

• September 20-21 Conference: Targeting Cardio-Metabolic Diseases

• September 21-22 Conference: Metabolomics in Drug Discovery

Day 1 | Day 2 | Download Brochure

Tuesday, September 20

7:00 am Registration Open and Morning Coffee


8:05 Chairperson’s Opening Remarks

H. James Harwood, Ph.D., Delphi BioMedical Consultants, LLC

8:20 FEATURED PRESENTATION: PCSK9 (Proprotein Convertase Subtilisin Kexin): From Gene to Therapy

Jay D. Horton, M.D., Professor, Internal Medicine and Molecular Genetics; Chair, Obesity and Diabetes; Chief of Division of Digestive and Liver Diseases, UT Southwestern Medical Center

Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a serine protease that is secreted into the blood and controls levels of LDL cholesterol. Here data will be presented that defines the mechanism of PCSK9’s action, explores the relationship between PCSK9 levels and plasma LDL cholesterol concentrations, and that describes new therapeutic strategies to block the activity of PCSK9.

8:50 New CETP Inhibitor K-312 Suppresses PCSK9 Production and Atherosclerosis

Masanori Aikawa, M.D., Ph.D., Director, Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital and Associate Professor of Medicine, Harvard Medical School

The novel CETP inhibitor K-312 raises HDL- and lowers LDL-cholesterol levels in animals. K-312 also decreases PCSK9 expression in cultured hepatocytes, seemingly via CETP-independent mechanisms. K-312 administration to cholesterol-fed rabbits raises HDL, decreases LDL, and attenuates atherosclerosis. In addition, K-312 reduces PCSK9 in the circulating blood of rabbits (high-sensitivity mass spectrometry). K-312 represents novel strategies to reduce residual global burden of cardiovascular disease.

9:20 Peptide Inhibitors of PCSK9 Derived from Phage Display

Yingnan Zhang, Ph.D., Scientific Manager, Department of Early Discovery Biochemistry, Genentech

PCSK9 is a negative regulator of hepatic LDL receptor. We developed two types of peptide inhibitors of PCSK9 using phage display: an engineered calcium-independent EGF(A) domain of LDLR and a 13-amino acid linear peptide Pep2-8, both with Kd ~ 0.7 µM and could fully restored LDL receptor surface levels in PCSK9-treated HepG2 cells. The mechanism of inhibition for Pep2-8 was clearly defined by structure.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:35 Small Molecule PCSK9 Binders and Allosteric Modulation of PCSK9 Function

Yusheng Xiong, Ph.D., Director, Exploratory Chemistry, Merck Research Laboratories

Screening of the Merck sample collection identified a small molecule PCSK9 binder of 20 uM affinity. The X-ray structure revealed that it binds at the junction between the catalytic domain and C-terminal domain of PCSK9. This binding site is close to multiple loss-of-function natural mutation sites, and therefore we hypothesized that a potent binder may have the potential of modulating PCSK9 function either intra- or extracellularly. This talk will present our effort in improving this class of binders in terms of binding affinity, selectivity, and cell permeability to interrogate the potential of modulating PCSK9 function.

11:05 Protection from Cardiac Ischemia by Inhibiting Phosphorylation of a Specific PKC Substrate

Nir Qvit, Ph.D., Postdoctoral Fellow, Department of Chemical and Systems Biology, Stanford University

Delta protein kinase C (delta-PKC) activation after a heart attack leads to cardiac damage. To determine if of the many substrates of delta-PKC, PDK is the substrate that mediates this injurious effect in the heart, we designed a short protein-protein interaction inhibitory peptide (PPIIP) to selectively inhibit delta-PKC phosphorylation of PDK. The peptide selectively inhibited phosphorylation of PDK without affecting phosphorylation of several other delta-PKC substrates. Further, PDK/delta-PKC PPIIP treatment led to a 50% reduction in infarct size, in release of cardiac enzyme and in JNK phosphorylation, all markers of cardiac injury.

11:35 GPR40 Full Agonists for Type 2 Diabetes

Sanath Meegalla, Ph.D., Principal Scientist, Cardiovascular and Metabolic Therapeutic Area, Janssen Research & Development, LLC

The medicinal chemistry efforts that led to the discovery of a series of GPR40 full agonists and its biological activities will be the focus of this presentation. The structure activity relationships, G-protein signaling due to the engagement of the GPR40 receptor, insulin secretion from human islets and rat oral glucose tolerance test results of a full agonist series will be presented.

12:05 pm Lunch on Your Own

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing


2:05 Chairperson’s Remarks

Weilin Xie, Ph.D., Senior Principal Scientist, Biotherapeutics, Celgene Corp.

2:15 Challenges and Opportunities in NASH Therapy Development

Weilin Xie, Ph.D., Senior Principal Scientist, Biotherapeutics, Celgene Corp.

2:45 Inhibiting ASK1 and Implications for Liver Disease

Frank Lovering, Ph.D., Associate Research Fellow, World Wide Medicinal Chemistry, Pfizer 

Apoptosis signal-regulating kinase 1 (ASK1),  a member of the MAP3K kinase family,  plays a role in activating c-Jun N-terminal kinase (JNK) and p38 MAP kinase signaling pathways in response to various stress stimuli including reactive oxygen species (ROS) and endoplasmic stress. Inhibition of ASK1 is expected to have implications in a number of pathological situations including COPD, diabetic nephropathy and NASH.

 CrownBio NEW3:15 Advances in Preclinical Models for Cardio-Metabolic and Liver Disease

Thyagarajan_AmarAmar Thyagarajan, Ph.D., Associate Director Product Marketing, Crown Bioscience


3:45 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:25 FXR Agonist, Obeticholic Acid, Attenuates Fibrosis Development in a More Translational NASH Mouse Model

Martine Morrison, Ph.D., Research Scientist, Metabolic Health Research, The Netherlands Organization of Applied Scientific Research (TNO)

While obeticholic acid treatment has shown promising results in clinical studies, currently most data available on the effects of obeticholic acid and FXR activation in the liver are derived from animal models that have limited translational value to the human situation. The LDLr-/-.Leiden mouse is a translational, diet-inducible model for non-alcoholic steatohepatitis (NASH) with associated fibrosis, which displays many clinically relevant features of NASH.

4:55 Late Breaking Presentation

5:25 Welcome Reception in the Exhibit Hall with Poster Viewing

6:25 End of Day

Day 1 | Day 2 | Download Brochure

Wednesday, September 21

7:30 am Registration Open and Morning Coffee

8:00 Chairperson’s Opening Remarks

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

8:10 FEATURED PRESENTATION: The Epidemic of Fatty Liver Disease: Silent, Serious and Still Growing?

Lee Kaplan, M.D., Ph.D., Director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School

8:40 Non-Alcoholic Steatohepatitis and Cardiovascular Disease: Modulation by Novel PPAR Agonists

Bart Staels, Ph.D., Professor, INSERM, University of Lille, Pasteur Institute

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. In this presentation, we will review recent findings on the pathophysiological role of PPARs in the different stages of non-alcoholic fatty liver disease (NAFLD), from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidences for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis towards irreversible, more advanced lesions. Large controlled trials of long duration to assess the long-term clinical benefits of PPAR agonists in humans are ongoing.

9:10 PANEL DISCUSSION: Liver Fibrosis and NASH Targets

Moderator: H. James Harwood, Ph.D., Delphi BioMedical Consultants, LLC



Lee Kaplan, M.D., Ph.D., Director, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School

Bart Staels, Ph.D., Professor, INSERM, University of Lille, Pasteur Institute

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

Weilin Xie, Ph.D., Senior Principal Scientist, Biotherapeutics, Celgene Corp.


  • FDA’s view on surrogate endpoints
  • Biomarkers of NASH
  • Translational animal models

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Targeting Fibroblast Activation Protein (FAP) and FGF21 to Treat Fatty Liver Disease

Diana Ronai Dunshee, Ph.D., Department of Molecular Biology, Senior Scientific Researcher, Genentech, Inc.

FGF21 is a hormone with anti-obesity and hepatoprotective properties. However, the beneficial effects of FGF21 are limited by a relatively short half-life in circulation. We discovered that fibroblast activation protein (FAP), an endopeptidase overexpressed in liver with cirrhosis, cleaves and inactivates FGF21. Pharmacological inhibition of FAP increases endogenous levels of active FGF21, thus making FAP a promising target for the treatment of non-alcoholic-steatohepatitis (NASH).

10:55 Thyroid Hormone Receptor Beta (THR-ß) Agonist for NASH: Correcting a Primary Deficiency in NASH Livers

Rebecca Taub, M.D., Ph.D., CEO, Madrigal Pharmaceuticals

NASH patients typically have metabolic syndrome including diabetes, dyslipidemia, obesity, and primarily die of cardiovascular disease. Hypothyroidism at the level of the thyroid gland and liver-specific hypothyroidism are common in NASH. Based on clinical and preclinical data, Thyroid receptor beta agonists decrease insulin resistance, reduce LDL-C, triglycerides fatty liver, inflammation and fibrosis in NASH. The target will also provide CV benefit to patients with NASH. MGL-3196 is a highly THR-ß selective liver-directed once daily oral medication that has shown excellent safety and lipid-lowering efficacy in humans; unlike prior thyroid receptor agonist(s), no cartilage findings in chronic toxicology or ALT increases in human studies. MGL-3196 is being advanced in Phase II studies in patients with genetic dyslipidemia or NASH.

11:25 Enjoy Lunch on Your Own

2:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:20 End of Conference

Day 1 | Day 2 | Download Brochure