Leaders in Pharmaceutical Business Intelligence (LPBI) Group

LIVE 9/21 8AM to 2:40PM Targeting Cardio-Metabolic Diseases: A focus on Liver Fibrosis and NASH Targets at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

#BostonDOT16

@BostonDOT

 

Nonalcoholic Steatohepatitis (NASH)

 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14^th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

 

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

• Epidemic of NASH,
• approaches to treating NASH – Fibrosis
• NASH is a metabolic Disease of the Liver
• Treating the HCV will treat the Fibrosis

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

• Silent, Serious and Growing
• Obesity the Disease = BMI>30: Medical Complicastions for BMI >%) – On ANti-Obisity and Bariatric SUrgery, Type 2 Diabetis .. NAFLD .. NASH .. Cirrhosis .. HCC
• Parkinson’s Disease
• HIV/AIDS

1. Medical Complications of Obisity =197 :
2. NAFLD – Nonalcoholic Fatty Liver Disease >>> Liver transplantation replacing HCV
3. Associated with obesity and type 2 diabetes
4. NAFLD is UP 90% wiht Severe Obesity
5. Viral hepatitis and Hemochromatosis
6. NAFLD: Steatosis, Inflamamtion, Hepatocellular Necrosis, Fibrosis, Cirrhosis
7. NASH: insulin resistence .. metabolic syndrom .. interaction
8. Alternative Model: Metabolis Syndrom.. Steatosis .. NASH … FIbrosis
9. Genetics of Liver DIsease
10. PNPLA3 Associated with NAFLD – Not Weight Gain
11. Other genes: A Partial List:
12. Diagnosis of NASH: Liver biopsy macrovescicular fatty change: InflammationMollery bodies
13. 75% Patients with Cirrhousis have obisity
14. Alcoholoc hepatisis >> Progression to Cirrhousis
15. Macrovesicular Steatosis
16. NASH – inflammation
17. Sinusoidal Pericellular Fibrosis –
18. LAB Features of NAFLD

• Transaminase elevation
• Akaline phosphate

1. Biomarkers – NASH – associated cirrhousis with lower rate 30% of elevation
2. Fibrosure

• Clinical Features of NASH: none presentation, Bright, Echo Fibroscan FibroscanScreen for HCC, Varices if Gray zone: Biopsy
• Treatment of NASH
• Treat liver disease: Treat steatosis then Inflamamtion and fibrosis

1. NAFLD Treatment Strategy: Stepwise Approach

• Treat the steatosis Piodlitazone
• PPARalpha, delta,
• Treat Inflammation: ANtioxidant
• CCR2/CCR% inhibitors
• Metabolic SUrgery
• Weigh-independent for bariatric
• Bariatic: improvrment of steatosis,effect on inflammationless clear
• dramatic on weigh loss
• NO clear is surgery improved cirhousis
• If NASH developed >>>> progression s the rule
• No great treatment of NASH

Medication-assciated NASH: Glucocorti

 

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.

Non-Alcoholic Steatohepatisis and CVD – Meta inflammatory disease

• NAFL — abnormal Lipid accumulation
• NASH >> Balooning, FIbrosis inflamation
• Resolution of NASH is associated with reduction of Fibrosis (Golden – 505 trial)

CVD is linked to NAFLD: Lipids elevated and therosclerosis

• TG – elevated, APO B elevated, VLDL – elevated HDL decrease
• PPAR Alpha
• Gamma
• PPAR Beta/Delta agonist: GENFIT – Elafibranor
• SPPARM

Trans-activation: Lipid and Glucose homeostasis: Trans-repression – anti-inflammatory properties

• Hapatic mitochondrial activity deseases upon progression from NAFL to NASH: Obese NAFL and NASH

1. Upregulated hepatic respiratory in obese humans with or without NAFL
2. Impaired
3. Hepatic PPARalpha Expression Decreases upon Progression of Nash and Fibrosis
4. hepatic PPARalpha expression – target genes increase in patients with improved NASH histology after 1 year
5. Metabolic Regualtion by thehepatic JNK Signaling Pathway
6. Target gene transcription – miR-21 expression increases in human
7. PPAR Delta: Elafibbranor: – effect on plasma lipids: A Dual PPAR alpha/Delts (GFT505): 80mg vs placebo and 120mg vs placebo, improves plasma apolipolipids and glucose HbA1C – insulin sensitivity
8. efficacy in NASH acting on: Steatosis, fibrosis and cirrhosis
9. inflammatory markers: RESOLVE-IT Phase 3 Study Desing: NASH ressolution without adverse on FIbrosis and Cirrhosis

GOLDEN505 Trial: Improves plasma lipid levels: Triglycerides

Inclusion Criteria:

ALT, AST, GGT, ALP

Improve atherogenic dyslipidemia

• APOC3 – associated with CVD

9:10 PANEL DISCUSSION: Liver Fibrosis and NASH Targets

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

Panelists:

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

• FDA’s view on surrogate endpoints
• Biomarkers of NASH
• Regulatory challenges

1. Liver biopsy: gold standard, invasive direct measure of endpoints pros/cons
2. non-invasive functional tests – plasma bioamrkers
3. non-invasisve liver imaging techniques: MRI to assess hepatic fat content MRE to assess hepatic fibrosis, Fibroscan,
4. Endpoints acceptable by FDA: Current vs Future

• Pre clinical Translational animal models

Discussion by Panel members

Progression from NAFLD to NASH: Oxidative stress and toxic lipids

NASH and Steatosis are different populations

Alcoholoc Steatosis vs Non-Alcoholic Steatosis

• Obesity cause of Fatty liver
• NASH in Diabetes
• NASH progresses
• Steatosis is associated with NASH
• Different types of NASH: HTN, Dislipedemia,
• GENETICS underlining factors, more genes are discovered
• Limitations of Animal Studies for inference on Humans – careful in over generalizing results
• Metabolic SYndrom -not all progresses to NASH
• Nonalcoholic Steatohepatitis (NASH) depend on Steatosis

 

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).

• Medical complications of obisity: NASH and DM-2
• energy consumption
• white adipose tissue – energy storage
• brown adipose tissue matochondia’s energy
• FGF21 – Human activation of protein cleavage: A Homone beneficial on metabolic health circulation, weigh loss
• it suppreses hepatic Steatohepatitis
• One singleinjection in mice — leads to energy expenditure induced weigh loss and metabolic improvement in Obese Humans
• Negative FGF21 is Rapidly Eliminated from the body – renal degradation and Inactivation of FGF21 Endopeptidase Cleavage Site – Fibroblast Activation Protein Matched FAP Endopeptidease Specificity
• Closest relative of DPP4 upregulted during tissue injury in NASH
• FAP is SUfficient to Cleave FGF21
• Recombinant FGF21 with Recombinant FAP in Serum or Plasma
• FAP Protease – Serum Immunodepleted Ablates FGF21 Cleavage Activity: Peptide IgG vs anti-FAP
• FAP Cleavage Inactivates Human FGF21 dependent on KLB-FGFR1c placed on the site
• hFGF21 in Not Cleaved in FAP KO Mice
• Fc-hFGF21 is more stable in FAP KO mice
• FAR cleaves Endogenously Produced FGF21 In Vivo in monkeys and in dogs
• The FAP Cleavage Consensus GLY-Pro is COnserved in most mammalian FGF21
• FAP Does not Cleave the C-Terminal Residues of Mouse FGF21
• Human: FAP, DPPIV
• Mouse: FAP, DPP4
• FAP INhibition
• FAP is Overexpressed in Liver with Steatohepatitis: Early NASH vs Late NASH
• Proposal: FAP Inhibition for FGF21 Stabilization in NASH

1. Fatty hepatocytes – e.g. NASH
2. Activated stellate cells, e.g. 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.

Madrigal Portfolio of drugs:

• MGL-3196: First-in-Class THR-Beta Agonist – discovered first at ROCHE – THR-beta selective targeted to the Liver – regulated by THR-Alpha  – in Phase II – no side effects on bone
• Large & underserved Markets in NASH
• Phase 2 HeFH Patients

1. Hypothyroidism common in NASH patients
2. Liver-specific Hypothyroidism present in human NASH degradation of thyroid hormone increases deiodised 9DIO) 3 produced by Stelllate cells in NASH liver
3. Treating NASHrather than fibrosis is key in addressing the disease – approvable endpoint
4. THR – Thyroid hormone reduces Cholesterol
5. Thyroid hormone T3 thyroxine – treatment amy cause osteoporosis
6. MGL 0 3196: Liver size, Live Triglycerides, Improve Insulin tolerance, decrease ALT
7. Reduction of key NASH, Fibrosis Pathway Genes at Human Comparable Drug levels
8. THR-beta: Decreased Liver Fibrosis, Apoptosis in mice:

HUMAN DATA

• Single ascending dose study
• Multiple – ascending studies: LDL and TG decrease
• decrease Non-HDL CHolesterol
• Decrease Apolipoprotein B
• Pleiotropic Pioglitazone Effect in NASH at 6 month treatment and biopsy of liver – dramatic effect in NASH – ten years ago study
• PPAR gamma agonist – NEGATIVE SIDE EFFECTS: weight gain, CHF, Bone osteoporosis
• Anti-inflammatory: well tolerated

No Single NASH Therapeutics – Conbination agents

MGL – 3196 Phase 2 – Study: Proposed Phase 2 Proof of COncepts NASH Protocol

• Unmet needs in FH, a severeGenetic Dyslipedemia
• Weight loss in 6 weeksreduction in cholesterol and TG
• Likelihood of Success
• second study after 9 months
• is different on NASH Patients in 12 weeks using MRI on Liver
• prevalence
• HeFH, PCSK9 inhibitors plus standard care
• Unique and Complementary Lipid Lowering Profile

1. Lowers Lp(a) and severely atherogenic practice
2. Proposed Phase 2 HeFH Patients

 

11:25 Enjoy Lunch on Your Own