Leveraging Clinical Pharmacology to Optimize Drug ... · our regulatory review, policy development,...

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Leveraging Clinical Pharmacology to Optimize Drug Development for

Nonalcoholic Steatohepatitis (NASH) and Cholestatic Liver Diseases

Sheraton Silver Spring Hotel | Magnolia Ballroom | Silver Spring, MDDecember 9, 2019

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Welcome & OverviewMark McClellan, MD, PhDDirector, Duke-Margolis Center for Health Policy

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Opening RemarksPatrizia Cavazzoni, MDDeputy Center Director for Operations, Center for Drug Evaluation and Research (CDER)

Opening Remarks from FDA

Leveraging Clinical Pharmacology to Optimize Drug Development for Nonalcoholic Steatohepatitis (NASH) and Cholestatic Liver Diseases

Patrizia Cavazzoni, M.D.Deputy Center Director for Operations

CDER/FDADecember 9, 2019

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NASH—A Public Health Concern• The incidence of

NASH is on the rise in the U.S.

• Given the ever-increasing patient population for NASH, the time is now to collectively derive solutions for this public health issue.

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Challenges in NASH• Timely identification of patients: there is an absence of

clear clinical, biochemical, or histological criteria that can identify patients with NAFL who are at risk for progression to NASH

• Development of noninvasive methods for diagnosis and staging

• Inclusion of appropriate study population• Translation of early phase results to late phase success

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CDER Initiatives

www.fda.gov

OCP actively contributes to CDER Initiatives aimed

at facilitating drug development through our regulatory review, policy development,

research programs, and strategic engagement.

• 21st Century Review Initiative• Computational Science Center• Critical Path Initiative• Equal Voice Initiative• Modernizing FDA's New Drugs

Regulatory Program• Pharmaceutical Quality for the 21st

Century• Safety First Initiative• Safe Use Initiative• Scientific Public Private

Partnerships and Consortia• Sentinel Initiative• Transparency Initiative• Unapproved Drugs Initiative

OCP actively contributes to CDER Initiatives aimed

at facilitating drug development through our regulatory review, policy development,

research programs, and strategic engagement.

• 21st Century Review Initiative• Computational Science Center• Critical Path Initiative• Equal Voice Initiative• Modernizing FDA's New Drugs

Regulatory Program• Pharmaceutical Quality for the 21st

Century• Safety First Initiative• Safe Use Initiative• Scientific Public Private

Partnerships and Consortia• Sentinel Initiative• Transparency Initiative• Unapproved Drugs Initiative

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OCP’s Innovative Solutions to Support CDER Initiatives

MODEL-INFORMED DRUG DEVELOPMENT (MIDD)MIDD Pilot Program ongoing to advance the use and potential of model-based approaches to accelerate drug development and patient access to safe and effective drugs

LEVERAGING COLLECTIVE ACTIONHelping to advance clinical trial design and strategies by leveraging collective action (C-PATH, etc.) to address contemporary regulatory challenges

THE INTERSECTION OF NEW TECHNOLOGIES AND REGULATORY SCIENCEKeeping up with the latest advances at the intersection of technology/approaches and regulatory science, such as machine learning/artificial intelligence and harnessing the power of RWD/RWE

OCPSUPPORTING

CDER THROUGH

INNOVATION

www.fda.gov

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Driving Innovation Through Translational Medicine:FDA/OCP Workshops

Workshops provide an unparalleled opportunity

to engage thought-leaders and create

dialogue on the latest in scientific methods and modern challenges in

drug development.

www.fda.gov

Select FDA/OCP Workshops in 2019:• Development of Best Practices in

Physiologically Based Pharmacokinetic Modeling to Support Clinical Pharmacology Regulatory Decision-Making

• Enhancing the Accessibility and Utility of Drug Interaction Information Labeling Workshop

• Leveraging Clinical Pharmacology to Optimize Drug Development for Nonalcoholic Steatohepatitis (NASH) and Cholestatic Liver Diseases

• Precision Dosing: Defining the Need and Approach to Deliver Individualized Drug Dosing in the Real World Setting

• Topical Drug Development-Evolution of Science and Regulatory Policy

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Driving Innovation Through Engagement: Vision for Today’s Workshop

ENGAGE in two-way scientific dialogue to share, educate, and

inform

DRIVEexpeditious

drug development in

this area

BRAINSTORM on creative solutions to some of the most pressing challenges

in NASH

Clinical Development of Drugs for the Treatment of NASH: General Considerations, Challenges, and the

Role of Clinical Pharmacology

Shirley K. Seo, Ph.D.Director, Division of Cardiometabolic and Endocrine Pharmacology

Office of Clinical PharmacologyOTS/CDER/FDA

Leveraging Clinical Pharmacology to Optimize Drug Development for Nonalcoholic Steatohepatitis (NASH) and Cholestatic Liver Diseases

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Disclaimer• The opinions contained in this presentation are my own and do

not necessarily represent the views of the FDA.

www.fda.gov

www.fda.gov

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most

common chronic liver condition in the U.S.1

Because most patients are asymptomatic in the initial

stages, NAFL can progress to NASH and other serious complications without

identification and treatment

Up to 25% of all adults in the U.S. have NAFLD. And 20% of

those adults have NASH 1

NASH is the leading cause of liver transplant in women and the 2nd leading cause in men 2

Yet, no approved treatment currently exists in the U.S.

The Urgency

1American Liver Foundation: https://liverfoundation.org accessed 12/4/192Noureddinm M et al, Am J Gastroenterol (2018) ,113(11): 1549-1659

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Complexities of the Liver as Both the Pharmacologic Target and the Clearing Organ

www.fda.gov

Drug Metabolismand Transport

SyntheticFunctionLiver Blood

Flow and DrugDistribution

Efficacy—Healed Liver

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Building Blocks of Clinical Pharmacology and Confidence in Proof of Concept

PK and PD

• Target exposure• Target engagement• Target modulation

Adapted from Vicini & van der Graaf, Clinical Pharmacology & Therapeutics (2013); 93:5, 379-381.

CONFIDENCEIN PROOF OF

CONCEPTFULL CHARACTERIZATION OFFULL CHARACTERIZATION OF

DRUG COMPOUND

FULL CHARACTERIZATION OFFULL CHARACTERIZATION OFPHARMACOLOGICPHARMACOLOGIC

TARGET

Quantitative Systems Pharmacology

• Pathway modulation• Pathophysiological

regulation• Disease modification

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General Considerations and Questions for Today

• NASH can be a “silent disease”– Need better early diagnostic tools – Ideally, should have predictive biomarkers to better forecast the

benefit of pharmacologic therapy • Pharmacologic target(s)

– Identification of the appropriate target– Should combination therapy be the mainstay?

• Dose of selected therapeutic agents– Is proper dose selection performed in all cases?– Is the right dose being given to the right patient population?

www.fda.gov

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Using Clinical Pharmacology to Poise Development for the Best Chance of Success

www.fda.gov

Clinical efficacy trials: Ensuring right population, right dose, and/or drug combination are studied

Early phase studies: Ensure well-designed and timely studies are properly informing Phase 3. Translatability of Phase 2 results to

Phase 3

Preclinical: Need to consider species translatability and appropriate characterization of target engagement

Phase 3

Preclinical

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Using Clinical Pharmacology to Poise Development for the Best Chance of Success

www.fda.gov

Data on hepatic impairment is critical

Given all the complexities of the liver, it is vital to study individuals with hepatic impairment

Represent a non-trivial subset of the NASH patient population

Hepatic dysfunction can impact either safety or efficacy, depending on the underlying mechanism for the change in drug disposition differential risk/benefit calculus

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Potential Challenges and Areas of Opportunity

www.fda.gov

• Beginning with nonclinical: no single ideal preclinical model exists so it is imperative to find relevance/translatability of animal model data to humans.

• Target identification and engagement: is the right pharmacologic target being engaged at the right stage of disease? (PPAR agonist, FXR agonist, Apoptosis signal-regulating kinase 1 (ASK1), etc.)

• Biomarkers at all stages are needed: diagnostic, prognostic, and surrogate endpoints that are predictive of long-term benefit

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Potential Challenges: Good News/Bad News

www.fda.gov 23

Good News/Bad News

www.fda.gov

Good news:The liver is healing. Recovery of enzyme activity, transporter

function, protein synthesis, increased blood flow and better distribution of drug

molecule

Semi-bad news:Dynamic process occurring during treatment, presenting challenges for predictability

of drug disposition and continued dosing. Need to

consider these complexities and implications on intra-hepatic concs and DDIs

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Can We Leverage Experiences from Another Liver Disease?

www.fda.gov

HCV NASH

Complex pathophysiology Complex pathophysiology

Hepatotoxicity of liver-targeteddrug is a concern

Hepatotoxicity of liver-targeteddrug is a concern

Targeting multiple pharmacologic mechanisms led to success Need for targeting multiple mechanisms…?

Healing liver did not impact dose because of shorter-term treatment

Will the healing liver cause the doseto evolve over longer term treatment?

The extent and types of DDIs have been impacted by the healing liver

Could changes in DDIs occur overlong-term treatment?

???

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Acknowledgements• The entire workshop organizing

committee at the FDA:– Anand Balakrishnan– Jenny Cheng– Dilara Jappar– Insook Kim (steering member)– Tracey Lee– Steven Li– Martina Sahre– Elizabeth Shang– Donny Tran (steering member)– Jack Wang (steering member)– Yao-Yao Zhu

www.fda.gov

• All speakers and panelists who have contributed to the program

• The entire Duke-Margolis Workshop Organizing Team and C-PATH partners

• Issam Zineh (Office Director, OCP)

• Patrizia Cavazzoni (Deputy Center Director for Operations, CDER)

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Session 1: Liver Disease Pathophysiology and the Impact of Liver Dysfunction on Pharmacokinetics, Pharmacodynamics, Drug Safety and Efficacy 9:35 am – 10:35 am

Duke Margolis CenterDuke Margolis Center-Duke Margolis Center- FDA MeetingDuke Margolis CenterNASH and

Duke Margolis CenterDuke Margolis CenterDuke Margolis CenterNASH and NASH and Cholestatic

FDA MeetingFDA MeetingDuke Margolis CenterDuke Margolis Center FDA MeetingFDA MeetingCholestaticCholestaticCholestatic Liver Disease

Clinical Overview of NASH Clinical Overview of NASH and

Clinical Overview of NASH Clinical Overview of NASH and and Cholestatic

Clinical Overview of NASH Clinical Overview of NASH CholestaticCholestatic Liver Disease

Manal F. Abdelmalek, MD, MPH, FAASLD Professor of MedicineDivision of Gastroenterology & Hepatology

DISCLOSURE(S)

Research Support- NIH / NIDDK (NASH CRN) - Prometheus - Enyo- Gilead Sciences - Galmed - Celgene- Genfit Pharmaceuticals - Galactin - Durect- Conatus Pharma - Blade- TaiwanJ - Intercept- Bristol Meyers Squibb - NGM Biopharma- Poxel - Madrigal- Allergan - Novo Nordisk

Consultant /Scientific Advisory Board- Bristol Meyers Squibb - TaiwanJ - Medimmune- Allergan - NGM Pharma - Prometic- Novo Nordisk - Blade

Speaker’s Bureau- Alexion - Medscape- Clinical Care Options - NASH Education Program

No conflict of interest or financial disclosure for today’s presentation

Overview for Discussion NAFLD and Cholestatic Liver Disease in 15 min

Spectrum of DiseaseEpidemiology

Cohorts at Risk Diagnostic Approach

Leveraging Clinical Pharmacology to

Optimize Drug Development

My presentation….

Spectrum of NAFLD

Environmental Modifiers

Epigenetics

Genetic

Outcome

Dynamic process

Variations in Disease Natural History

Clark J. Clini Gastro.2006.Bellentani et al. Ann Intern Med. 2000.

Browning et al. Hepatology 2004.

NAFLD Is Endemic—A Global Epidemic

Progression of NAFLD

Tacke & Weiskirchen. Expert Review of Gastro & Hepatol. 2019.

Prognosis of NAFLD and NASH

Adams et al, Gastro. 2005; Angulo et al, Gastro. 2015

verall Survival in NA by ibrosis Stage

P<0.001

Surv

ival

(%)

xpected

bserved

Follow-up (years)

bserved

xpected

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 5 8 10 15

N=420, Mean f/u 7.6 yrs

P=0.03

verall Survival in NA vs. t e eneral opulation

N=619, Median f/u 12.6 yrs

HR 1.34 (95% CI 1.003-1.76)

Risk Stratification Hig Risk opulations • Sedentary life style / Western diet (high fructose consumption) • Overweight /obese• Metabolic syndrome (3 or more features)• Type 2 diabetes (T2DM)• Ethnicity (Hispanic/ Asian)• Dyslipidemia• Polycystic ovary syndrome• Endocrinopathies (Panhypopituitarism) • Obstructive sleep apnea • First degree relative with NASH cirrhosis

Age > 50 years and T2DM and/or 1st degree relative with NASH cirrhosisstrongest clinical predictors for NASH & fibrosis

NAFLD and Hepatic Fibrosis in Patients With vs Without T2DM By Diagnostic Approach

Bril F, et al. Diabetes Care. 2017;40:419-430.

Prevalence of NAFLD/NASH Prevalence of Fibrosis

Diagnosing and Staging NAFLD/ NASH Noninvasively• Metabolic syndrome (3 or more features)• Vague right upper quadrant pain• Hepatomegaly on exam• Little (< 20 gm/day) to no alcohol use• “Bright” liver on ultrasound• “Seronegative” chronic hepatitis (ALT> AST)

– Viral serologies (negative HBsAg, HCV Ab) – Iron profile– Autoimmune markers (ANA, ASMA, AMA)– Ceruloplasmin– Alpha-1 antitrypsin

• Elevated liver enzymes (normal F< 20 U/L; M< 30 U/L)• Concern for advanced liver disease or decreased function: Platelet count < 150K,

albumin < 3.5 /dl, increased bilirubin, MELD > 12, Fibroscan > 12 kPA, Fib-4 > 3.25, NFS > 0.67, MRE stiffness > 3.63

Clark JM, Am J. Gastro. 2003

Cholestatic Liver Diseases Intrahepatic • Drugs• Alcohol• Infiltrative liver disease• Pregnancy• Heart failure• Primary biliary cholangitis• Infection• Immunodeficiiency• Sarcoidosis• IschemiaExtrahepatic • Primary sclerosing cholangitis• Pancreatitis• Tumors• IgG4 cholangitis• Congenital biliary anomalies• Cystic fibrosis

Biologic Spectrum of Cholestatic Liver Disease

Primary Biliary Cirrhosis Cholangitis Male : Female 9:1Age Typically > 45 yearsLaboratory Increased ALP, GGT, AST, ALTExposures Bacterial mimics/ xenobiotic

chemicalsSerologies AMA + 95%, ANA + 35-50% ,

+/- ASMALiver Histology Lymphocytic infiltrate, inflammatory

“florid” duct lesion, granulaoms may be present

MRCP / ERCP Normal appearing biliary treeCo-existing IBD Not typically present Younossi Z et al. Am J Gastro. 2019

Carey EJ. et al. Lancet. 2015PouponR. J of Hepatol. 2010

Overview of utility of investigations in PBC

*Perinuclear rims, nuclear dot, centromere;† Except in patients with ductopenic non-cirrhotic variantEASL CPG PBC. J Hepatol 2017;67:145–72

• Elevated ALP is typical of PBCest inding Notes

A Values associated with disease progression

AS A May be suggestive of PBC with features of AIH

Reflects cholestatic liver injury

gM Elevated values associated with disease

AMA ( 1 0) Diagnostic in >90% of cases in correct clinical context

Specific ANA Specific immunofluorescence patterns* present in 30%

Anti-gp210 Specific immunoassays available

Anti-sp100 Specific immunoassays available

Anti-centromere Associated with portal hypertensive phenotype

Bilirubin Elevation at late stages frequently indicative of cirrhosis†

latelets Indicative of cirrhosis

NR Indicative of cirrhosis

Albumin Indicative of cirrhosis

Pathogenesis of Primary Sclerosing Cholangitis

Diagnostic Approach to Cholestasis

EASL CPG. J Hep. 2017.

Hurdles for NASH and Cholestatic Liver Disease

Lack of diagnostic / prognostic biomarkers

Limited pharmacologic therapies

Lack of tailored approaches

Promising Future Ahead……

THANK YOU

Altered Hepatic ransporter unction in atients wit NASH

mplications for rug isposition, fficacy and Safety

im . R. Brouwer, arm ,

William R. Kenan Jr., Distinguished ProfessorAssociate Dean for Research & Graduate Education

The University of North Carolina at Chapel Hill

Conflict of Interest Disclosure

• Commercial Financial Interest: Co-inventor of the sandwich-culturedhepatocyte technology for quantification of biliary excretion (B-CLEAR®)and related technologies, which have been licensed exclusively toQualyst Transporter Solutions, LLC, recently acquired by BioIVT

• Scientific Consultant: Merck Research Laboratories, IndaloTherapeutics, Inc.

• Grants/Research Support: National Institute of General MedicalSciences, National Institutes of Health (R35 GM122576); InterceptPharmaceuticals; Otsuka Pharmaceutical Development &Commercialization, Inc.; Gilead Sciences, Inc.

Outline

• Hepatic Transport Proteins in Health and Disease

• Altered Hepatic Transport in Patients with Nonalcoholic Steatohepatitis (NASH) and Pharmacokinetic Implications Clinical Probes to Assess Transporter Function

− 99mTc-Mebrofenin (MRP2 probe)

− Morphine/Morphine Glucuronides (MRP3 probe)

• Increased Bile Acid Concentrations and Impact on Hepatic Transporters OSTα/β Induction

• Implications for Drug Disposition, Efficacy and Safety, and Knowledge Gaps

Hepatic ptake and fflux ransporters

Köck and Brouwer, Clin Pharmacol Ther, 2:599, 2012(Adapted from Ho and Kim, Clin Pharmacol Ther, 8:260, 2005)

BSEP (Bile Salt Export Pump);NTCP (Sodium-Taurocholate Cotransporting Polypeptide);MRP (Multidrug Resistance–Associated Protein);OST (Organic Solute Transporter)

Hepatic ptake and fflux ransporters50

Clarke et al., J Hepatol, 61:139, 2014

Altered Hepatic Transport Protein Levels in Liver Tissue from Patients with NASH

Hepatic Uptake Transporters

Human Liver Tissue

Normal Steatosis

NASH (fatty infiltration)

MRP1

MRP3

MRP4

P-gp

BCRP

Pan-Cadherin

Hepatic Efflux Transporters

Hardwick et al., Drug Metab Dispos, 39:2395, 2011

(>5%) (<5%)

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Altered MRP2 Expression and Localization in Liver Tissue from Patients with NASH

Clarke et al., Liver Int, 37:1074, 2017

p<0.05 compared to Normal

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Immunohistochemical Staining of MRP2

NASH (<5% fatty infiltration)NASH (>5% fatty infiltration)

99mTc-Mebrofenin (Choletec®):Probe for Transporter-Mediated Hepatobiliary Excretion

● Used clinically as a hepatobiliary imaging agent● Liver uptake ~98%; negligible metabolism● Urinary excretion <2% of dose● Transporter-mediated hepatobiliary disposition

─ Hepatic uptake via OATP1B1 and OATP1B3─ Biliary excretion via MRP2─ Basolateral excretion via MRP3

NH

N

O

OO

Tc99 3+

O O

N

O

O

OO

CH3

CH3

CH3

Br

NH

CH3

CH3

CH3

OBr

-

Ghibellini…Brouwer, Pharm Res, 25:1851, 2008

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Simulations redict ncreased Hepatic xposure to MR 2 Substrates in atients wit NASH

OAT

PM

RP

3

MR

P4

MRP2Bile

Time (min)

Cliv

er

Liver

Time (min)

Cbl

ood

Blood

Köck and Brouwer, Clin Pharmacol Ther, 2:599, 2012

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• Healthy subjects (n=14) and biopsy-confirmed NASH patients [n=7; NAFLD activity score (NAS)≥4] admitted on morning of study after overnight fast

• Attenuation correction obtained with a cobalt-57 flood source • Subjects positioned supine under gamma camera

• Subjects discharged following exit exam

Clinical Study Design: 99mTc-Mebrofenin

99mTc-mebrofenin PK

attenuationcorrection continuous γ-scintigraphy urine

collection

Scre

en/

Info

rmed

Con

sent

270

blood sampling

urine collection

300 min 180 210 240

Safety questionnaire &

discharge

140 1601201008060402010 15 7.552.50

2.5 mCii.v. dose

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Hepatic m c-Mebrofenin xposure was ncreased in atients wit NASH

2-fold in exposure

Control (n = 14) NASH (n = 7)

t1 2 0 min

t1 2 38 min

Mean ± SD

Ali…Brouwer, Clin Pharmacol Ther, 10 :749, 2018

0 5 0 1 0 0 1 5 0 2 0 01 0 0

1 0 0 0

1 0 0 0 0

1 0 0 0 0 0

1 0 0 0 0

1 0 0 0 0 0

5 0 1 0 0 1 5 0 2 0 0

na Ali

1. -fold in max

1. -fold in exposure

1. -fold in max

1. -fold in exposure

iverBlood

56

Model Scheme Describing 99mTc-Mebrofenin Disposition and Parameter Estimates

Parameters Healthy(n=14)

NASH(n=7)

CLuptake(L/min)

1.14(0.73-2.27)

0.731 **(0.382-1.04)

CLefflux (L/min)

0.00800(0.00481-0.0139)

0.00579(0.00475-0.00903)

CLbile (L/min)

0.0354(0.0157-0.0728)

0.0171 **(0.0110-0.0207)

Vcentral(L)

11.1(9.55-12.5)

6.32 **(5.69-9.69)

Vliver(L)

0.958(0.527-1.39)

0.891(0.648-1.43)

Observed Data and Model Predictionsfor Individual Subjects

Median (range); **p<0.001

Ali…Brouwer, Clin Pharmacol Ther, 104:749, 2018

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99mTc-Mebrofenin Hepatic Uptake Clearance was Lower in NASH Patients even with “Normal Function” SLCO1B1 Genotype

SLCO1B1

Genotype

Healthy(# of

subjects)

NASH(# of

subjects)Function

*15/*15 1 Low (LF)

*1A/*15 3 Intermediate (IF)

*1A/*14 1

Normal (NF)

*14/*14 1

*1A/*1A 2 3

*1B/*1B 2

*1B/*14 1

*1A/*1B 2 1

Ali…Brouwer, Clin Pharmacol Ther, 104:749, 2018

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Normal Steatosis (>5%) (<5%)

Normal Steatosis(>5%) (<5%)

~3-fold increase

MRP3


Increased MRP3 Protein Levelsin Liver Tissue from Patients with NASH



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Hepatic isposition of Morp ine and Metabolites

blood flow

blood flow

bile bileMR 2(ABCC2)

ATP

Morp ine

ATP

MR 3(ABCC3)

Morp ine lucuronides

Morp ine

Morp ine-3- (M3 ) and Morp ine- - (M )

lucuronide

1(SLC22A1)

UGT2B7

Brian erslew

60

• Healthy subjects without insulin resistance: n=14• Biopsy confirmed NASH patients [NAFLD activity score (NAS)≥4]: n=7

Urine Collection

Urine Collection

Urine Collection

Bile Acid Profiling Blood Sample

Morphine Blood Sample

Bile Acid Profiling Morphine Disposition

0.5, 1, 1.5, 2 h (0, 5, 10, 15, 30, 45 min), 1, 1.5, 2, 3, 4, 5, 6, 7, 8 h

Ferslew…Brouwer, Clin Pharmacol Ther, 97:419, 2015

Clinical Study Design: Morphine / Glucuronides61

MG Parameters Healthy (n=14)

NASH (n=7)

Cmax(nM)

225(194-261)

343**(284-413)

AUC0-last(µM*min)

37(32-44)

59 **(42-83)

Half-life (min)

187(153-229)

146(104-205)

Geometric mean (95% CI); ** p<0.01 t-test on log transformed data


Increased Morphine-3-Glucuronide (M3G) and Morphine-6-Glucuronide (M6G) Serum Concentrations in Patients with NASH

(M3G)

(M6G)

62

0 2 4 6 8 10 121

10

100

1000

Time (h)

Mor

phin

e (n

M)

No hydrolysis in gut

Normal gut hydrolysis

0 2 4 6 8 10 121

10

100

1000

Time (h)

M3G

(nM

)

0 2 4 6 8 10 121

10

100

1000

Time (h)

Mor

phin

e (n

M)

0 2 4 6 8 10 121

10

100

1000

Time (h)M

3G (n

M)

Simulations Predict Reduced Enterohepatic Recycling (EHR) of Morphine 3-Glucuronide (M3G) in Patients with NASH

Obese subjects

Obese subjectswith NASH-related

transporter changes

Without EHR, 11% decrease in

M3G AUC

Without EHR, 21% decrease in

M3G AUC

Serum concentrations were simulated after 3.76 mg morphine i.v. in 10 x 10 obese virtual subjects (age 33 – 63, 50% female)

Sjöstedt…Brouwer, in preparation, 2020

63

EHRNo EHR

0 2 4 6 8 10 121

10

100

1000

Time (h)

Mor

phin

e (n

M)

No hydrolysis in gut

Normal gut hydrolysis

0 2 4 6 8 10 121

10

100

1000

Time (h)

M3G

(nM

)0 2 4 6 8 10 12

1

10

100

1000

Time (h)

Mor

phin

e (n

M)

0 2 4 6 8 10 121

10

100

1000

Time (h)M

3G (n

M)

Noora Sjöstedt

Total Bile Acids Glycocholate TaurocholateParameter β P-value β P-value β P-value

NAS+Fibrosis 0.43(0.10)

0.0040.03

(0.01)0.001

0.02(0.01)

0.006

Increased Conjugated Bile Acids in Serum of NASH Patients

Ferslew…Brouwer, Clin Pharmacol Ther, 97:419, 2015β: regression parameter estimate (SE)

64

Mean ± SEM; *p<0.05

Mean ± SEM, Healthy: n=15 (13 for urine), NASH: n=7

Serum Urine

Serum and Urine Bile Acids at Screening

CDCA = Chenodeoxycholic AcidCA = Cholic AcidDCA = Deoxycholic AcidLCA = Lithocholic AcidUDCA = Ursodeoxycholic Acid Ferslew et al., Dig Dis Sci, 60:3318-3328, 2015

65

rganic Solute ransporter ( S ) SLC51A/Bis pregulated in atients wit iver isease

atients wit Nonalco olic Steato epatitis (NASH) and rimary Biliary irr osis ( B )

MelinaMalinen

Is OSTα/β an Overlooked “Safety Valve” for Hepatocellular Efflux of Bile Acids?

66

Malinen…Brouwer, Am J Physiol, 31 :G597, 2018

Köck and Brouwer, Clin Pharmacol Ther, 2:599, 2012(Adapted from Ho and Kim, Clin Pharmacol Ther, 8:260, 2005)

Altered Hepatic ransporter unction in atients wit NASH mayncrease Hepatic and or Systemic xposure to rugs and

Susceptibility to rug- nduced iver n ury

↑Bile Acids

67

• Altered hepatic transporters (↓OATP1B1 and OATP1B3, ↓MRP2, ↑MRP3, ↑OSTα/β)in patients with NASH may impact the systemic and/or hepatic exposure to substrates [drugs, metabolites, and endogenous compounds (e.g., bile acids)]

• Systemic concentrations may not accurately reflect hepatic exposure

• Patients with NASH may be predisposed to bile acid-mediated drug-induced liver injury by medications that inhibit hepatic efflux transporters

Altered Hepatic Transporter Function in Patients with NASH: Implications for Drug Disposition, Efficacy and Safety

68

• Impact of disease progression (NAFLD NASH Cirrhosis) on hepatic transporter function

• Pathophysiologic changes in input parameters for physiologically-based pharmacokinetic (PBPK) models during disease progression

• Altered transporter function in other key organs of drug absorption/elimination (e.g., intestine, kidney)

• Relationship between systemic concentrations and tissue exposure

Knowledge Gaps in Predicting Drug Disposition,Efficacy and Safety in Patients with NASH

69

AcknowledgementsGraduate Students/ Postdoctoral Fellows/ Visiting Scholars Izna Ali James Beaudoin Jacqueline Bezençon Brian Ferslew Giulia Ghibellini Curtis Johnston Josh Kaullen Kathleen Köck Melina Malinen Noora Sjöstedt Jason Slizgi Eleftheria Tsakalozou

Collaborators Sid Barritt Arlene Bridges Marija Ivanovic Wei Jai Mikko Niemi Mary Paine Paul Stewart Paul Watkins

Funding Sources National Institutes of Health Grants

R01 GM41935, R35 GM122576, T32 GM86330(NIGMS); UL1 TR001111 (NCATS)

Finnish Cultural Foundation, Orion Research Foundation, Sigrid Jusélius Foundation Erasmus+ Programme

IQVIA Clinical PK/PD Fellowship

UNC Hospitals Nuclear Medicine & Radiology Staff Clinical & Translational Research Center

Kathleen Köck, PhD

Lake et al., Toxicol Appl Pharmacol, 268:132, 2013

Bile Acid Synthesis in Human NASH

Orthogonal partial least squares discriminant analysis (OPLS-DA) (R2Xcum=0.380, R2Ycum = 0.077, Q2Ycum = 0.0419) scores plot discriminating the serum bile acid profiles over time

OPLS-DA Scores Plot Discriminates Patients with NASH


Clinical Pharmacology Questions for Drug Development for NASH and Cholestatic

Liver Diseases

Insook Kim, Ph.D.Team Leader, Gastroenterology and Hepatology Products

Division of Inflammation and Immune PharmacologyOffice of Clinical Pharmacology

OTS/CDER/FDA

75

Disclaimer

The views and opinions expressed here are my own and do not represent official guidance from the FDA

76

Outline• Current trends of clinical trials for liver diseases• Draft NASH guidances• Major Clinical Pharmacology Questions at the

IND Stage• Summary

77

Unmet needs• Limited number of approved drug products for non-

viral, non-oncology liver diseases– Ursodeoxycholic acid for primary biliary cirrhosis (1997)– Rifaximin for reduction in risk of overt hepatic

encephalopathy recurrence (2010)– Obeticholic acid for primary biliary cholangitis (2016;

Subpart H based on ALP reduction) • No approved drugs for NASH or PSC

ALP: Alkaline PhosphatasePSC: Primary sclerosing cholangits

78

Number of IND Submission

05

1015202530354045

2012 2013 2014 2015 2016 2017 2018 2019 (Q3)

NASH/NAFLD Other Liver Dz

www.fda.govAR S BM

NM

BR

N S

BM

Courtesy of Dr. Yao-Yao Zhu

NASH Guidances

79

Submission Trends• Development Program

– Commercial IND #• 132 (73 active) for NASH/NAFLD, 32 (14 active) for PBC/PSC

– Mostly in phase 1 and 2; a few completed phase 3– Many phase 2 study protocols to open an IND

• Investigational Treatment– NME (small molecules >>> biologics)– Repurposing of previously approved/studied drugs

• e.g. T2DM agents, anti-hyperlipidemia, weight loss– Combination therapy– One drug for both NASH and cholestatic liver diseases in some cases

• Recent late phase attritionwww.fda.gov PBC: Primary biliary cholangitis

80

Draft Guidances for NASH• Noncirrhotic NASH with Liver Fibrosis (2018)

– Accelerated approval pathway based on liver histology • Improvement in fibrosis stage > 1 and no worsening of steatohepatitis

OR• Resolution of steatohepatitis and no worsening of liver fibrosis OR• Both resolution of steatohepatitis and improvement in fibrosis

• NASH with Compensated Cirrhosis (2019)– Efficacy: Time to clinical outcome events– Compensated cirrhosis by histology (e.g., F4 fibrosis); – Exclusion of MELD score > 12

www.fda.gov

81https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM627376.pdf

Biomarkers

82

Early Clinical Trials for Dose Selection• Proof of mechanism

– Identification of target engagement biomarkers– PK/PD for biomarkers

• Proof of concept in patient population– Biomarkers that correlate with liver histology

• Histology for NASH (reasonably, likely predict clinical outcome)– POC for each component for a combination product– Exposure-response relationship

Relationship among MOA, disease-specific biomarkers, imaging biomarkers, and histology should be evaluated and established throughout the program

MOA: mechanism of action

83

Major Clinical Pharmacology Questions at the IND Stage

• Dose selection• Drug-drug interactions with concomitant medications for patients

in clinical trials

• Inclusion/exclusion criteria based on renal and hepatic function– Drug ADME, and impact of hepatic and renal impairment on PK

Patients with liver diseases often have comorbidities that require medications

Patients with liver diseases can have concurrent HI and RI

ADME: absorption, distribution, metabolism, excretion

84https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM627376.pdf

Early evaluation of the effects of hepatic impairment on PK to support dosing across the spectrum of NASH liver disease

85

Importance of Right Dosage for Patients with Hepatic Impairment

Ocaliva Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207999s003lbl.pdf

86

Hepatic impairment study• Single or multiple dose PK study• Initial tolerability in subjects with hepatic

impairment• Cirrhosis patients • Degree of HI based on Child-Pugh score

• Mild HI: Child-Pugh Class A (score 5-6)• Moderate HI: Child-Pugh Class B (score 7-9)• Severe HI: Child-Pugh Class C (score 10-15)

• Other classification may be used with collection of Child-Pugh score

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072123.pdf

To support the dosing for patients with cirrhosis in clinical trials

To support clinical trials for patients with non-cirrhotic NASH and cholestatic liver diseases• Patients may asymptomatically progress to compensated cirrhosis

during the trials

PK in patients with non-cirrhotic NASH or cholestatic liver disease need to be collected in the clinical trials

87

Case: Repurposing of Drug A• Approved for a non-liver disease• Proposed for non-cirrhotic NASH with fibrosis (stage F2/F3)

– Patients with cirrhosis on biopsy excluded from efficacy trials

• To study the same dose as the approved dose for the non-liver disease

Risk mitigation strategy for patients who may asymptomatically progress to cirrhosis during the trial is needed

Biomarkers for progression to cirrhosisBiomarkers correlated with the PK change

• In a legacy HI study, 5-fold higher AUC in subjects with compensated cirrhosis than in subjects with normal liver function

88

Summary• Unmet medical needs in the area of NASH and

cholestatic liver diseases• Early characterization of ADME of the drug and

impact of hepatic impairment on PK– To support dosing in patients with liver diseases– To mitigate safety concerns if the liver disease

progresses during the trials

89

Opportunities• Better understanding of relationship between drug

concentrations in plasma and liver

• Better characterization of physiologic parameters that reflect the pathophysiological changes due to liver dysfunction and that may impact PK

• Simultaneous assessment of PK and biomarkers in target patient population to understand and establish the relationship between PK, PD, and disease biomarkers

90

Acknowledgements• Clinical pharmacology review

team for GI/Liver products• Anand Balakrishnan• Jenny Cheng• Dilara Jappar• Hyewon Kim• Elizabeth Shang• Sojeong Yi

• Former members• Jack Wang • Xiaohui Li • Christine Hon

• DGIEP colleagues for liver products• Clinical review team• Pharm/Tox review team

• OCP senior leadership• Shirley Seo (DCEP) • Donny Tran (DCEP)• Chandrahas Sahajwalla (DIIP)• Suresh Doddapaneni (DIIP)• Issam Zineh (Office Director)

92

https://ir.conatuspharma.com/press-releases/detail/168/conatus-announces-top-line-results-from-encore-nf-phase-2bhttps://www.gilead.com/news-and-press/press-room/press-releases/2019/4/gilead-announces-topline-data-from-phase-3-stellar3-study-of-selonsertib-in-bridging-fibrosis-f3-due-to-nonalcoholic-steatohepatitis-nashhttps://ir.stockpr.com/cymabay/press-releases/detail/476https://ir.stockpr.com/cymabay/press-releases/detail/476

95

Session 2: Early Discovery and Development—Treatment Mechanisms, Molecular Targets, and Biomarkers in Early Development of Therapies for NASH and Cholestatic Liver Diseases10:50 am – 12:15 pm

An Overview of Treatment Mechanisms, Molecular Targets, and Biomarkers in

Early Development of Therapies in NASH and Cholestatic Liver Diseases

Naga Chalasani, MDIndiana University School of Medicine

isclosure (12 1 )

• Ongoing paid consulting activities (or had in preceding 12 months) with NuSirt, Abbvie, Allergan, Madrigal, Siemens, La Jolla, Foresitelabs, Axcella, Zydus, Galectin, and Genentech.

• Research grant support from Exact Sciences, DSM, and Intercept where his institution receives the funding.

• No speaking fees since 1999

Major causes of morbidity and mortality of NAFLD sub-phenotypes

Sample Footer.

NAFL NASH w/ F0 &F1

NASH with F2 & F3

NASH Cirrhosis

Cardiovascular Cardiovascular Liver disease Liver disease

Non-hepatic malignancies

Non-hepatic malignancies

Cardiovascular disease

Cardiovascular disease

?Renal disease Liver disease Hepatic & non-hepatic malignancies

Hepatic & non-hepatic malignancies

iver directed p armacot erapy

NAFL NoNASH w/F0 & F1 Probably NotNASH w/F2&F3 YesNASH Cirrhosis Yes

NASH w/ F2 and F3Major causes of morbidity and mortality

Desired Outcomes Valid surrogate(s)

Liver failure Prevention of progression to cirrhosis

Resolution of NASH with no worsening of fibrosis ORSignificant improvement in fibrosis with stable steatohepatitis

NASH Cirrhosis: Early vs Late Stage

arly cirr osis• Thin septa• No CSPH • Preserved synthetic function• Active SH

Reversal of cirrhosis (≤ 2point drop in Fibrosis

score

Prevention of development of complications of

cirrhosis

Study duration ≥ 2 yrsCombination Rx

Longer study duration Combination Rx

Prevention of Reversal of

Study duration ≥ 2 Longer study duration

ate Stage cirr osis• Thick septa• CSPH (Plts <100k, splenomegaly, LSM

>18 kPa)• MELD < 13• ± Active SH

Prevention of development of complications of cirrhosis

Longer study duration Combination Rx

Currently Available Drugs for Treatment of NASHTargeting insulin resistance

Compound

Targeting Oxidative stress

Metformin

Pioglitazone

Liraglutide

Compound

Vitamin E

Mechanism of action

Multiple

PPAR agonist

GLP-1 receptor agonist

Mechanism of action

Antioxidant

Trials

Multiple studies

PIVENS*

Multiple studies

LEAN*

Trial

PIVENS*

TONIC*

Primary endpoint(s)

Various

Improvement in NAS ≥ 2 without fibrosis worseningResolution of NASH without fibrosis worsening

Primary endpoint(s)

Improvement in NAS ≥ 2 without fibrosis worsening

AASLD recommendation as NASH treatment

Not recommended

May be used in patients with biopsy-proven NASHPremature to considerGLP-1 receptor agonists

AASLD recommendation as NASH treatment

May be used in non-diabetic adults with biopsy-proven NASH

Slide Courtesy from Peter Traber, MD - Alacrita

SAR425899/Sanofi

ase 1

DS102/Afimmune RG-125/Regulus

A4250/Albiero

IONIS-DGAT2Rx/Ionis O304/BetagenonKBP-042/Nordic Bioscience

INT-767/Intercept

O304/Betagenon

CAT-2054/Catabasis

CER-002/Cerenis

DUR-928/Durect

semaglutide/Novo NordiskMGL-3196/Madrigal

cenicriviroc/Allergan obeticholic acid/Intercept

elafibranor/Genfit

Subpart H

ase 2

ase 3

ertugliflozin/Merck, Pfizer sotagliflozin/LexiconVBY-376/Virobay

ND-L02-s201/Nitto Denko, BMS bertilumab/MedImmune PF-06835919/Pfizer

PF-06835919/Pfizer DUR-928/Durect

norUCDA/Falk Pharma GmbH

lobal ipeline for NASH

MSDC-0602K/Metabolic Solutions, Octeca NGM282/NGM BioGS-0976/Gilead LMB763/Novartis

GS-9674/GileadBMS-986036/BMS

ND-L02-s201/Nitto Denko, BMS

bertilumab/MedImmune NC101/Naia

solithromycin/Merck, CempraIMM-124E/Immuron MT-3995/Mitsubishi Tanabe

Full Approval

IVA337/Inventiva BI 1467335/BI PF-05221304/Pfizer

CM101/ChemomAb

DRX065/POXEL

EDP305/Enanta

Namacizumab/Birdrock

TERN201/Terns

VAP1/Sucampo

?

Aramchol/Galmed

Resmetriom/Madrigal

Slide Courtesy from Michael Charlton, MD

Categorization of NASH Development Compounds

Slide Courtesy from Peter Traber, MD - Alacrita

Targeted Metabolic Insulin sensitizers

(GLP-1) FGF21/19 SGLT-1 inhibitors

KHK inhibitor PUFAs IBAT inhibitors DGAT-2 inhibitors

ROS stress reduction Vitamin E mTOT inhibitors

Anti-Steatosis ACC inhibitors SCD1 inhibitors FASN inhibitors Omega-3 fatty acid

Multifactorial Metabolic PPAR agonists FXR agonists THRβ agonists LXR agonists Mito pyruvate carrier modulators

Intestinal permeability

Larazotide Lubiprostone

Anti-Inflammatory/Fibrotic

CCR2/5 inhibitor ASK-1 inhibitors Caspase inhibitors Galectin-3 inhibitors 5-lipogenase inhibitors

CB1 inhibitors A3AR antagonists LOXL2 inhibitors NOX1/4 inhibitors ROCK2 inhibitors αvβ6/1 integrin inhibitors

Nuclear HormoneReceptors

InsulinResistanc

e

Obesity↑ lipids

MetabolicSyndrome

T2D

Advanced Phase Monotherapy Programs in Pre-Cirrhotic NASH

Slide Courtesy from Dr. Peter Traber

Obeticholic Acid (FXR agonist) Elafibranor (PPAR α/δ)

Resmetrion (THRβ agonist) Cenicriviroc (CCR2/5 inhibitor) Aramchol (SCD-1 inhibitor) MSDC-0602K (mito pyruvate carrier

modulator) Selonsertib (ASK-1 inhibitor) **

Tropifexor/cilofexor/Nidufexor/EDP-305* (FXRs)

Seladelpar (PPAR δ)*/Lanifibranor (PPAR α/δ/ɣ)/PXL770 (deut pio)/Saroglitazar (PPARα/γ)

VK2809 (THRβ agonist) Semaglutide (GLP-1 agonist) MEDI0382 (GLP-1/glucagon

agonist) Firsocostat/PF-05221304 (ACC

inhibitor) NGM 282 (FGF19 agonist) NGM 313 (KLB receptor agonist) Pegbelfermin (FGF21 agonist)

BIO89-100, AKR-001 PF-06835919 (KHK inhibitor) Elobixibat (IBAT inhibitor)

* Failed primary endpoint in phase 2 trial ** Failed primary endpoint in phase 3 trial

Phase 3 initiated/completed/posted

Namodenoson (A3 adenosine receptor agonist)

IMM-124-E (bovine colostrum) CORT118335 (Glucocorticoid Receptor

Modulators) Licoglifozin (SGLT2 inhibitor) Icosabutate (SCFA) AZD4017 (11-βhydroxysteroid

dehydrogenase inh) CC-90001 (JNK inhibitor) TVB-2640 (fatty acid synthase

inhibitor) ISIS 703802 (ANGPTL3 antisense) AZD4076 (microRNA-103/107) Emricasan (Caspase inhibitor)* Simtuzumab (LOXL-2 inhibitor)*

Phase 2 initiated/completed/posted

Drug (Company) MOA Phase Study Description Data (estimate)

Obeticholic acid (Intercept)

FXR Agonist 3 REGENERATE: NASH with F2/F3 fibEndpoint: Fibrosis OR Resolution; Composite outcomes

Met primary endpoint

Elafibranor(Genfit)

PPAR α/δ agonist 3 RESOLVE-IT: NASH with F1-3 fibrosis (n=2000)Endpoints: Resolution [72 wks]; Composite outcomes

Recruit completed

Resmetriom (Madrigal)

THR β agonist 3 MAESTRO-NASH: NASH with F2-3 fibrosis (n=2000)Endpoint: Resolution [52 wks]; Composite outcomes

Recruiting

Cenicriviroc(Allergan)

CCR2/5 inhibitor 3 AURORA: NASH with F2-3 fibrosis (n=2000)Endpoints: Fibrosis [12 months); Composite outcomes

Recruiting

Aramchol(Galmed)

SCD1 inhibitor 3 ARMOR: NASH with F2/F3 fib (n=~2000)Endpoint: Fibrosis OR Resolution [52 wks]; Composite outcomes

Recruiting

MSDC-0602K(Cirius)

Mitochondrial pyruvate carrier modulator

3 NASH with fibrosis (n=3600)Endpoint: HbA1c [6 mo] and Resolution [12 mo]Composite hepatic and cardiac outcomes [31 mo]

Not yet recruiting

Selonsertib (Gilead)

ASK-1 inhibitor 3 STELLAR-3: NASH with F3 fibrosisEndpoints: Fibrosis; Composite outcomes

Failed primaryTerminated**

Phase 3 Clinical Trials in Pre-Cirrhotic NASH*

* Includes trials that have been initiated and have information on trial posted on clinicaltrials.gov

** Continuing evaluation in combination clinical trial (ATLAS; NCT03449446)Slide Courtesy from Peter Traber, MD - Alacrita

Drug (Company) MOA Phas

e Study Description Data Status

Selonsertib (GILD)

ASK-1 inhibitor

3 STELLAR-4: Comp NASH cirrhosisEP: Fibrosis; composite outcomes

Failed primary

Also failed STELLAR3 (stage 3 NASH); ATLAS P2 combination trial ongoing

Obeticholic acid (ICPT)

FXR Agonist 3 REVERSE: Comp NASH cirrhosisEP: Fibrosis; composite outcomes

JUN 2021

Trial ongoing; In Aug 2019 increased patients from 540 to 900 and extended Rx 12 to 18 mo

Simtuzumab(GILD)

LOXL2 inhibitor

2 Comp NASH cirrhosisEP: Change in HVPG

Failed primary

Also failed in pre-cirrhotic NASH to improve fibrosis. Program discontinued

Belapectin (GALT)

Galectin-3 inhibitor

2 NASH-CX: Comp NASH cirrhosisEP: Change in HVPG

Failed primary

Post-hoc difference in HVPG without varices and reduced development of varices; no effect on fibrosis; P3 trial planned**

Emricasan(CNAT/Novartis)

Pan-caspase inhibitor

22

ENCORE-PH Change in HVPGENCORE-LF Complications

Failed primary

Post-hoc analysis showed some effect in high HVPG sub-group; Currently not progressing

Pegbelfermin (BMS)

PEG-FGF21 2 Comp NASH cirrhosisEP: Fibrosis

JAN 2020

Completed trial enrollment

Phase 3 and 2 Clinical Trials in NASH Cirrhosis

Selected Biomarkers – NAFLD and NASH

Solublebiomarkers

Imaging Function tests

ALTK18 fragmentsOwl NASH testELFProC3

VCTE (Fibroscan)MRI PDFFMR spectroscopyMR elastographyMultiparametric MRI

HepaquantC13 Methacetin breath test

LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis)

NIMBLE

Coordinator: Prof Quentin M. Anstee

€46.5 m illion(2017-2022)

N MB rogram eam StructureNIMBLE Program Leadership

Project Co-chairs: Arun Sanyal, Sudha Shankar, Roberto CalleMembers: Claude Sirlin, Anthony Samir, Rohit Loomba, Sarah Sherlock

Scientific Program Manager: Tania KamphausTeam

Circulating & Functional Markers Work Stream

Rohit Loomba (UCSD) – Co-chair Sudha Shankar (Astra Zeneca) – Co-

chair Roberto Calle (Pfizer)

Academic collaborators

Imaging Markers Work Stream

Claude Sirlin (UCSD)– Co-chairAnthony Samir (Harvard/MGH) – Co-chair Sarah Sherlock (Pfizer) – Co-ChairAcademic collaborators

Pathology Expert Team

Cynthia Guy (DCRI) Melissa Contos (VCU)Others TBD

Data Analysis & Modeling Expert Team

Nancy Obuchowski (Cleveland Clinic)Santos Carvajal-Gonzalez (Pfizer)Cytel

Molecular targets and ongoing studies in PBC

• UDCA is the first line agent approved for PBC. Serum AlkP response to UDCA is predictive of long-term outcomes of patients with PBC.

• Obeticholic acid is approved for treating PBC unresponsive, or partially responsive, or intolerant to UDCA

• Ongoing trials: FXR agonist, PPAR agonists, and FGF19 for Alk P and disease course. IBAT inhibitor (Linerixibat) and kappa opioid receptor agonist (Korsuva) for itching.

PPAR-α PPAR-ɣ PPAR-δ

Bezafibrate ++++ +++ +++

Seledelpar Negligible ++++

Saroglitazar ++++ +

Elafibranor +++ ++

Molecular targets and ongoing studies in PSC

• No approved therapy. UDCA and endoscopic therapies are used clinically.

• norUDCA and Cilofexor (FXR) are being tested in phase3 clinical trials

• Other ongoing trials: PPAR agonists (fenofibrate), FGF19, IBAT inhibitor, HTD 1801, Vancomycin, FMT etc.

Clinical Pharmacology of OCA in Health and Liver Disease

Jeffrey E. Edwards Ph.D.Executive Director of Clinical Pharmacology

Intercept Pharmaceuticals, Inc.

Obeticholic Acid: Background

• Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist

• OCA is a modified bile acid derived from the primary bile acid chenodeoxycholic acid (CDCA), the natural human FXR ligand

• OCA has received marketing authorization in the United States, Europe, Canada, and several other countries for the treatment of primary biliary cholangitis (PBC)

• New Drug Application to the US FDA for OCA in patients with fibrosis due to NASH has been submitted

Pharmacokinetics and Pharmacodynamics of OCA

• Absorption in the gut followed by conjugation to glycine and taurine in the liver (highly extracted by the liver)

• Extensive enterohepatic recirculation with the drug primarily residing within the liver-gut axis (primary location of FXR)

• Approximate 4-day half-life

• Bile acid like toxicity observed at high daily doses of OCA (250 mg) in healthy subjects

Ileum

FGF-19

Enterocytes

Systemic Circulation

Cholesterol

Bile AcidsBile Acids

Bile acid

Jejunum

Duodenum

Colon

Port

al V

ein

nterocyte

ASBTOSTα/β

FXRβ

Duodenum

Jejunum

Ileum

allbladder

SHPIBABP

Inhibition

SHPCholesterolCholesterol

SHP

A1FXRFXR

SHP

A1

FGF-19

Edwards J. Certara (Producer). 2017 . Obeticholic Acid – From PK Model to Drug Label [webinar]. Retrieved from: https://www.certara.com/webinar-archive/obeticholic-acid-from-pk-model-to-drug-label.

PK of OCA in Healthy Subjects versus Cirrhosis

• Higher systemic exposure of endogenous bile acids with moderate and severe hepatic impairment

• Similar proportional increase in systemic exposure of OCA

0

50

100

150

Mea

n (S

D) To

tal B

ile A

cids (

µM) Bile Acids

0

20000

40000

60000

80000

Mea

n (S

D) To

tal O

CA

AUC 0

-t(h

*ng/

mL)

OCA

Normal Liver Function

Mild ImpairmentChild-Pugh A

Moderate ImpairmentChild-Pugh B

Severe ImpairmentChild-Pugh C

13-fold

6.4-fold

1.6-fold

17-fold

4.2-fold

1.1-fold

Edwards J. Certara (Producer). 2017 . Obeticholic Acid – From PK Model to Drug Label [webinar]. Retrieved from: https://www.certara.com/webinar-archive/obeticholic-acid-from-pk-model-to-drug-label.

Systemic and Liver Exposure of Bile Acids in End-Stage Liver Disease

• Higher systemic concentrations of bile acids

• Modestly higher liver exposure with hepatic impairment

N o r m a l L i v e r

F u n c t i o n

C i r r h o s i s0

5 0

1 0 0

1 5 0

En

do

ge

no

us

Bil

e A

cid

s (

M) L i v e rP l a s m a

Figure: Fischer, et al. Clinica Chimica Acta. 1996;251:173 Edwards J. Certara (Producer). 2017 . Obeticholic Acid – From PK Model to Drug Label [webinar]. Retrieved from: https://www.certara.com/webinar-archive/obeticholic-acid-from-pk-model-to-drug-label.

Effects of Cholestasis on Systemic and Liver Bile Acid Exposure

Higher liver exposure of bile acids with cholestasis

*Fischer, et al. Clinica Chimica Acta. 1996;251:173 Edwards J. Certara (Producer). 2017 . Obeticholic Acid – From PK Model to Drug Label [webinar]. Retrieved from: https://www.certara.com/webinar-archive/obeticholic-acid-from-pk-model-to-drug-label.

*Fischer, et al. Clinica Chimica Acta. 1996;251:173.

Port

al V

ein

Normal

Bile Acids

Bile low

ptake

olestasisolestasisolestasis

Port

al V

ein

Bile lowecreased

ptake

0

0

1 0 0

1 0

2 0 0

2 0

nd

og

en

ou

s

Bi

le

A

ci

ds

(

M)

iver xposure

Normal iverunction

olestasis

Dose/Exposure-Response of OCA in PBC

• Clear dose- and plasma exposure-response for OCA in PBC patients for reductions in alkaline phosphatase (ALP) and total bilirubin (BILI)

ALP Total Bilirubin

1 10 100 1000

10 mg QD

5 mg QD

Trough Total OCA (ng/mL)

-40

-30

-20

-10

0

%

in A

LP fr

om B

asel

ine

Observed*Predicted

1 10 100 1000

10 mg QD

5 mg QD

Trough Total OCA (ng/mL)

-20

-10

0

10

%

in B

ILI f

rom

Bas

elin

e

Observed*Predicted

Edwards J, et al. Presented at EASL, The International Liver Congress, 2016. Barcelona, Spain. (Poster 394).

Dosing of OCA in PBC Patients with Moderate and Severe Hepatic Impairment

• Alternative dosing in PBC patients with moderate or severe hepatic impairment

• 5 mg once weekly 5 mg twice weekly 10 mg twice weekly

Edwards J, et al. Presented at AASLD The Liver Meeting, 2017. Washington DC (Poster 296).

0

1 0 0 0

2 0 0 0

3 0 0 0

ota

l A

a

ve

,ss

(n

gm

) la s m a iv e r

M o d e ra te S e v e r e M o d e ra te S e v e r eN o rm a l H e p x n

m g 1 0 m g m g m g m g 1 0 m g m g m go n c e d a ily o n c e w e e k ly o n c e d a ily o n c e w e e k ly

N o rm a l H e p x n0

1 0 0 0

2 0 0 0

3 0 0 0

ota

l A

a

ve

,ss

(n

gm

) la s m a iv e r

S e v e r eM o d e ra te S e v e r e M o d e ra teN o rm a l H e p x n

m g 1 0 m g m g m g m g 1 0 m g m g m g

o n c e d a ily tw ic e w e e k ly o n c e d a ily tw ic e w e e k ly

N o rm a l H e p x n0

1 0 0 0

2 0 0 0

3 0 0 0

ota

l A

a

ve

,ss

(n

gm

) la s m a iv e r

M o d e ra te S e v e r e M o d e ra teN o rm a l H e p x n

m g 1 0 m g 1 0 m g 1 0 m g m g 1 0 m g 1 0 m g 1 0 m g

o n c e d a ily tw ic e w e e k ly o n c e d a ily tw ic e w e e k ly

S e v e r eN o rm a l H e p x n

Effects of Fibrosis/Cirrhosis due to NASH on the Hepatic Uptake of OCA/Bile Acids

• Liver extraction of OCA and bile acids are decreased with NASH fibrosis

• Systemic exposure of OCA/bile acids are expected to increase in fibrosis; however, liver is not expected to change significantly

Port

al V

ein

Bile Flow

Hepatic Vein

1%

Normal

NTCP

Hepatic Uptake

2 %Spill OverSpill Over

Porta

l Vei

n

Hepatic Vein

NASH ibrosis 1

Hepatic Vein

%Spill Over

%Hepatic Uptake

NTCP

Bile Flow

Porta

l Vei

n

Hepatic Vein

NASH ibrosis 2

Hepatic Vein

NTCP

%Spill Over

%Hepatic Uptake

Bile Flow

Porta

l Vei

n

Hepatic VeinHepatic

NASH ibrosis 3

NTCP

Hepatic Vein

8%Spill OverSpill Over

2%Hepatic Uptake

Bile Flow

Bile Flow

Porta

l Vei

n

Hepatic Vein

2%

8%Spill Over

NASH ibrosis ( irr osis ild- ug A)

NTCP

Vein

Hepatic Uptake

Plasma Exposure of OCA and Bile Acids in Subjects with Fibrosis or Cirrhosis due to NASH

• Increase in plasma exposure but no clear differences in liver exposure with NASH fibrosis (Stage F1-F3) and minimal increase in cirrhosis (Child-Pugh A [F4])

1 2 310

100

1000

ibrosis Stage

Stea

dy-S

tate

ose-

Nor

mal

ied

lasm

a ot

al

A A

0- (

ngm

mg)

n=12 n=8 n=15 n=181 2 3

10

100

1000

ibrosis StageSt

eady

-Sta

teos

e-N

orm

ali

ediv

er

otal

A

ro

ug (n

gm

mg)

n=2n=7 n=9 n=9

Alkhouri N, et al. Presented at AASLD The Liver Meeting, 2019. Boston, Massachusetts (Poster 2294).

Plasma Liver

-100

0

100

200

300

400

600

700

Med

ian

(IQR

) Per

cent

Cha

nge

from

Bas

elin

e FG

F-19

7 12 4 3127 16 32 5n= 153 16

Healthy NASH Fibrosis(F1-F3)

NASH Cirrhosis(F4/CP-A)

PBO PBO5 5 510 10 1025 25 25

Dose (mg)

-100

-50

0

Med

ian

(IQR)

Per

cent

Cha

nge

from

Bas

elin

e C4

7 12 4 3127 16 32 5n= 153 16

PBO PBO5 5 510 10 1025 25 25

Dose (mg)



Dose Response of OCA for Markers of FXR Activation in NASH

• OCA plasma exposure: Healthy < NASH F1-F3 < NASH F4 • Results consistent with liver exposure being similar or minimal higher in subjects

with fibrosis or cirrhosis due to NASH, respectively • Similar dose responses for FXR activation between healthy and NASH subjects

7α-Hydroxy-4-cholesten-3-one (C4) Fibroblast Growth Factor 19 (FGF-19)

Dose Response of OCA for Markers of Liver Injury and Function

• Similar dose response between OCA 10 mg and OCA 25 mg, less for OCA 5 mg

-50

-25

0

2575

125

Med

ian

(IQR)

Per

cent

Chan

ge fr

om B

asel

ine

ALT

7 12 11 3127 16 32 5n= 153 16



PBO PBO5 5 510 10 1025 25 25

Dose (mg)

-50

0

150

250

Med

ian

(IQR)

Per

cent

Cha

nge

from

Bas

elin

e AS

T

7 12 11 3127 16 32 5n= 153 16



PBO PBO5 5 510 10 1025 25 25

Dose (mg)

ALT AST

Dose Response of OCA for Markers of Liver Injury and Function

• Increase in plasma exposure but no clear differences in liver exposure with NASH fibrosis (stage F1-F3) and minimal increase with cirrhosis (Child-Pugh A [stage F4])

-60

-40

-20

0

20

Med

ian

(IQR)

Per

cent

Cha

nge

from

Bas

elin

e G

GT

7 12 11 3127 16 32 5n= 153 16

PBO PBO5 5 510 10 1025 25 25



Dose (mg)

-50

0

50

Med

ian

(IQR)

Per

cent

Chan

ge fr

om B

asel

ine

BILI

7 12 11 3127 16 32 5n= 153 16



PBO PBO5 5 510 10 1025 25 25

Dose (mg)

GGT Total Bilirubin

Dose Response of OCA for Livers Function Based on HepQuant

• Clear dose response for improvement in liver function (HepQuant) • Results appear more consistent with the improvement in fibrosis from

REGENERATEREGENERATE (F2/F3 Population)2

Fibrosis Improvement with No Worsening of NASHStudy 747-117 (F2/F3 Population)

Functional Improvement ( DSI ≥2)

Placebo OCA 10 mg OCA 25 mg0

10

20

30

40

50

60

70

80

% P

atie

nts

17.6%23.1%

n=311 n=308

p=0.0002

11.9%

n=312

p=0.0446

Placebo OCA 10 mg OCA 25 mg0

10

20

30

40

50

60

70

80

% P

atie

nts

36%

73%

n=5 n=11

0%

n=11

Alkhouri N, et al. Presented at EASL, The International Liver Congress, 2019. Vienna, Austria. (Poster LBP-18).

Potential Pitfall of Using Liver Biomarkers

• Increases in ALP with OCA and other non-steroidal FXR agonist have been observed

• OCA does not directly transcriptionally regulate ALP • OCA does regulate gene(s) involved in ALP homeostasis (ie, PLD)

MS 0.

1%

A 100

M

MS 0.

1%

A 0.1

M

A 0.31

M

A 1.0

M

A 3.1

M

A 10.0

M

A 31.

M

A 100

M0

1

2

3

Alkaline osp atase (A )

A m

RN

A

MS 0.

1%

A 100

M

MS 0.

1%

A 0.1

M

A 0.31

M

A 1.0

M

A 3.1

M

A 10.0

M

A 31.

M

A 100

M0

10

1

op olipase ( )

mR

NA

OCA Therapeutic Concentrations

OCA Therapeutic Concentrations

ALP Phospholipase D (PLD)

Potential Indirect Effect of OCA on Alkaline Phosphatase

Hepatocyte

AAAAAAA

AAAAAAA

A

A

AAAAA

AAA

AAA

S edding

leavageby leavage leavage

Membrane-bound A

Soluble A

eneeneR eneeneR

RR

RR

RRR

A

leavageby

GPI-anchored PLD

GPI-anchored ALP

Soluble PLD

Soluble ALP

Mechanism II

AAA

leavage

etergent (e.g. Bile Acids)

AA

leavage

Conclusions

• Liver disease, cholestatic and non-cholestatic, may have significant effects on the PK and disposition of drugs used in NASH

• OCA shows significant improvement in biomarkers associated with NASH

• Dose-response not always matching Phase 3 results• Non-invasive technologies may help in aiding dose selection

• Important to determine if changes in biomarkers of liver disease are only due to disease modification

irculating Biomarkers in arly rug evelopment in NASH

Session 2: Early Discovery and Development: Treatment Mechanisms, Molecular Targets, and Biomarkers in Early Development of Therapies for NASH and Cholestatic Liver Diseases

Saurab upta, akeda armaceuticals nternational o.

CONFIDENTIAL – For internal purposes onlyv6

Disclosure

Working at Takeda Pharmaceuticals International Co. at Department of Translational Biomarker Research at Gastrointestinal Drug Discover Unit.


Contents

– Background & need for non-invasive biomarkers in drug development in NASH

– Pro-C3 and other extracellular matrix biomarkers in early drug development in NASH:

• Diagnosis, disease Severity • Fast and slow progressing patients• Responder and non-responder• Prognostic biomarkers for liver related Complications• Translatability

– Conclusion & future perspective


Rationale for use of Non-invasive Biomarkers in NASH Drug Development

• Liver biopsy is still a reference standard for staging fibrosis and steatohepatitis

• Biopsy invasive and painful, may lead to severe complications including bleeding, injury to other organs & death

• Costly, lack of specialists to cater huge patient numbers• Not suitable for frequent or longitudinal assessment • May not adequately represent disease phenotype as fibrosis in NASH is heterogenous • High inter-observer variability in histological scoring even highly skilled & trained pathologists

• Noninvasive, cost effective, readily available, accurate & reproduceable biomarker/s will be desirable for diagnosis, patient stratification, response and prognosis

133

www.niddk.nih.gov/health-information/liver-disease/nafld-nash/diagnosis

Fibrosis Scoring System NAS Scoring System

(Anstee et al., Heptaology 2019; Rockey et al., Hepatology 2009, Ratziu et al., Gastroenterology 2005)


Current Landscape of Clinical Endpoints in NASH

Early Phase 2 studies: • In proof of concept studies biomarkers associated with steatosis, steatohepatitis, and fibrosis are used as endpoints

– e.g.: MRI-PDFF, CK-18, ALT, MRE, ELF, Pro-C3– Histological endpoints can be used, provided trial is run for sufficient duration – Opportunity to characterize non-invasive biomarkers

Late Phase 2 studies: • Evidence of efficacy on a histological endpoint (i.e., reduction of inflammatory changes, improvement in fibrosis, or both)• Scope of Biomarkers

– Biomarkers that can increase likelihood of confirmatory biopsy– Biomarkers that can provide evidence of disease progression– Prognostic biomarkers which may robustly predict liver related complications

Phase III studies:• Resolution of steatohepatitis on overall histopathological reading & no worsening of liver fibrosis on NASH CRN fibrosis score. OR • Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) & no worsening of steatohepatitis (defined

as no increase in NAS for ballooning, inflammation, or steatosis); • Or Both

Additional Clinical Endpoints used in NASH studies • Composite long-term outcome composed of all-cause mortality, cirrhosis & liver-related clinical outcomes

134(Adapted from Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry Dec 2018; NASH trials at ClinicalTrial.gov )


• NASH patients with hepatic inflammation and hepatocellular injury are at increased risk of progressive fibrosis

• Hepatic fibrosis is the only predictor of clinical disease progression

• Fibrosis is abnormal connective tissue turn over, damages structure and function of organ/tissue

• Core protein of fibrosis is collagen and other structural proteins like laminins and elastin

• Formation and degradation of collagen and other extracellular matrix (ECM) proteins leads to release of peptide fragments which can be detected in circulation as fibrogenesis and fibrolysis biomarkers (BMs) respectively

135

NASH Biomarkers: Pro-C3 and Other ECM Turn Over Markers

(Schuppan et al., J Hepatol 2017)

Soluble peptide fragments can be detected in serum/ plasma via ELISA based assay

(Karsdal et al., Biochemistry of Collagens Laminins and Elastins 2018; Anstee et al., Heptaology 2019 )


136

Learnings from HCV: ECM Remodeling Markers for Diagnosis of Fibrosis

Fibrogenesis Markers

Fibrolysis Markers

aaaaaaaaaaaaaaaaaaaa(Nielsen et al., PloS One 2015)

A B

• In a cross sectional study in 403 chronic hepatitis (HCV) patients with biopsy were included in analysis

• Along with ECM markers other biochemical measures including AST and ALT were measured

• Multiple ordered logistic regression models for the detection of fibrosis stratified according to Metavir F stages: A) Model 1 combining Pro-C3, C4M, AST, and ALT

B) Model 2 combining Pro-C3, C4M, age, BMI, and gender


Pro-C3 Correlation with Fibrosis Score and NAS

137

Pro-C3 levels in F3 (n=31) =24.6 ng/mL (13-41.2)Pro-C3 levels in F4 (n=29) =23.5 ng/mL (15.3-38.5)

• Pro-C3 is increased in NAFLD subjects as compared to healthy

• Increase in Pro-C3 according to severity of fibrosis as well as NAS observed in number of studies

• Pro-C3 is an ADAMTS (a disintegrin and metalloproteinase with a thrombospondin type 1 motif) generated neo-epitope marker of type III collagen formation

• Not a liver specific marker of fibrogenesis

NVH NVH NVH

(Gupta et al., Hepatology 2017; Sanyal et al., EASL 2019 Poster # LBP-30; Yi et al., Sci Rep. 2018)


Fibrogenesis biomarkers in NASH, Simple Steatosis and NHV

ProC3XPro-C3 Pro-C6

Pro-C4Pro-C5

NHV NHV

NHV NHV NHV

• Besides Pro-C3 other fibrogenesis markers may offer additional information:o Pro-C4 ↑ indicates increase in basement fibrosis whereas Pro-C3 ↑ indicates interstitial fibrosis

• Type VI collagen pro‐peptide, endotrophin, stimulates fibroblasts and ↑ Pro-C3 in scar in a jar modelo Collagen fragments also have signaling capabilities

(Gupta et al., Hepatology 2017; Morten et al., Hepatology 2019)

All graphs values are Mean + SEM (ng/mL)


Fibrolysis biomarkers in NASH, Simple Steatosis and NHV

C3M C4M2

EL-NEBGM

NHV NHV

NHV NHV

Mean + SEM values in ng/mL

(Gupta et al., Hepatology 2017; Unpublished Data, 2019)

• Fibrolysis biomarkers markers may have limited value in discrimination b/w NASH and SS

• However fibrolysis biomarker are also elevated in NASH as compared to simple steatosis and NHV;

• A direct quantification of the tissue turnover balance (i.e. the ratio between fibrogenesis and fibrolysis), may provide more comprehensive information on a specific collagen

• Ratio of Pro-C3/C3M was significantly ↑(p<0.03) in NAFLD (1.81+0.21) patients vs. NHV (0.86+0.05)

• For collagen IV also formation/degradation ratio was significantly ↑ (p<0.01) in NAFLD patients (12.05+0.25) vs. NHV ((10.61+0.37

• Fibrosis is a high turn over component of NASH pathogenesis


Ethnic Translatability of ECM Turnover Biomarkers in Caucasians and Japanese subjects

140

Inhouse Data on Pro-C3FibrosisScore

Yohkohoma collaboration (ng/ml+SD)

Univ. Birmingham collaboration (ng/ml+SD)

F0 16.9 ± 9.8 (N=39) 21.2 ± 22.6 (N=8)

F3 25.8 ± 16.2 (N=9) 26.2 ± 17.3 (N=20)

F4 55.4 ± 38.7 (N=3) 27.3 ± 12.4 (N=6)

• While designing a global trial it is important to establish the levels of biomarkers in different ethnicities

Pro-C3 Levels in Caucasians (L) vs Japanese (R)

ECM markers in NH Japanese vs. NH Caucasians

(Gupta et al., Hepatology 2017; Unpublished Data, 2019)

All graphs values are Mean + SEM (ng/mL)


Effect of Pharmacological intervention on Pro-C3 levels: Potential for Patient Enrichment?

• In phase –II study, 16 wks. treatment with BMS-986036, a FGF21 analogue F1-F3 NASH patients led to beneficial effects on steatosis (MRI-PDFF), markers of liver injury (ALT, AST) & fibrosis (Pro-C3, MRE)

• Higher ↓ in Pro-C3 was observed in patients with higher >20 ng/mL

• In phase 2 study NGM-282, a FGF 19 analogue, was treated in biopsy confirmed NASH patients for 12 wks.

• In 3 mg cohort 63 % patients had >2 ↓ in NAS score and 42 ↓ their fibrosis score by >1

• In responder group Pro-C3 ↓ 56% & Pro-C3 correlated with histological changes

• NGM313, novel activator of beta-klotho/FGFR1c single dose significantly ↓ Pro-C3 by day 28

(Abdelmalek M. et al., 2017; AASLD #195650; Sanyal et al., Journal of Hepatology 2017 S89–S90; DePaoli, EASL 2019, PS-108; Sanyal et al., EASL 2019 Poster # LBP-30)

NGM-282BMS986036


• Farglitazar, PPARγ agonist, 52 wk treatment failed to improve overall histological fibrosis stage and morphometrical collagen in a Phase II CHC; Patients with baseline levels of Pro-C3 > 20.2 ng/mL showed efficacy

• Balaglitazone, PPAR γ agonist, was evaluated in type 2 diabetics with 26 wk. treatment in a phase III study; subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with ↓ in levels of alanine aminotransferase and Pro-C3

Pro-C3: Clinical Biomarker for Identification of Responders to Anti-fibrotic Treatment

142 (Morten et al., AJP-Gastrointest Liver Physiol 2016)

Phase II clinical trials Farglitazar in advanced hepatitis C patients Phase III study of Balaglitazone in patients with late-stage Type 2 diabetes

Disease specific threshold need to de defined for potential patient enrichment/patient stratification


• Serum Levels of Pro-C3 were significantly reduced at 2-12 wks both in PSC and NASH Patients wks post treatment• It will be important to understand how long the levels of Pro-C3 need to be lowered to be reliably observe improvement

in histological fibrosis scores

Time course of Change in Pro-C3

143(Hirschfield et al., EASL 2019 Poster # FRI-027; Harrison et al., Hepatology 2019; Hirshfeild et al., Journal of Hepatology, 2019 )

R Value

PSC study NASH Study

• 43 biopsy confirmed NASH SC treatment with NGM-282, significant decrease observed at both 1 and 3 mg

• NGM282 at 1 mg and 3 mg doses significantly reduced plasma Pro-C3 at all the time points assessed

• After 12 wks. of treatment Pro-C3 levels ↓ by 21 % and 27% with NGM282 1mg and 3mg dose respectively

PSC study


• 47 Liver transplant (LT) patients divided into fast, intermediate or non-progressors towards recurrent fibrosis (RC), RC within 1 yr, RC within 3-5 yrs and no fibrosis 5yrs post LT, respectively Pro-C3 measured at 3, 6, 12 months along with biopsy

• In 137 CHC patients Pro-C3 and C3M were measured at base line and 52 wks, plasma Pro-C3 predicts fibrosis progression

Potential of Pro-C3 to Predict Clinical Outcomes

144(Nielsen et al., EASL 2019 Poster # Thu-088; Nielsen et al., Liver Int. 2015)

Liver Transplant patients CHC Patients

Prognostic Performance of Pro-C3


145

Western diet-fed M R mice

Male MC4RKO mice 8 w drug ve . treatment8w

1w Habituation( ays)

Western diet-13W (11 weeks old)

Reverse ranslatability of M Biomarker reclinical ata in M R

• Most ECM biomarkers are translatable across species

• In MCR4KO mice there is significant increase in rPro-C3, Pro-C5, C3M and C4M

• ECM biomarkers are good tools to employ in preclinical settings and may be of value for PK-PD modelling in an more efficient manner

(Unpublished Data, 2019)


Conclusion and Future Perspective

Extracellular matrix turnover biomarkers especially Pro-C3 has shown promise for: NASH diagnosis, especially F3 and F4 Identifying NASH patients potentially in active fibrogenesis phase Stratification biomarker Response biomarker for fibro-static activity Demonstrates quick turnover Preclinical translation

Early phase NASH clinical trials should try to incorporate multiple non-invasive biomarkers as feasible, to provide further evidentiary strength to biomarkers and their association with endpoints

Non-invasive biomarker/s are key for expedited NASH drug development Various National and International NASH biomarkers consortia, like NIMBLE and LITMUS

are working towards the same objective

146 aaaaaaaaaaaaaaaaaaaa


Acknowledgements

Gastrointestinal Discovery Unit Takeda

• Shinji Ogawa, Hiroaki Yashiro, et al.

Statistics: Iwona Dobler, Jacob Zhang

University of Birmingham: Gideon Hirschfield et al.

Nordic Bioscience Team

147


148

Picture From : https://jpninfo.com/wp-content/uploads/2017/06/Climb-Mt-Fuji-featured.jpg

Thank You For Your Attention

149

Session 2: Panel DiscussionEarly Discovery and Development—Treatment Mechanisms, Molecular Targets, and Biomarkers in Early Development of Therapies for NASH and Cholestatic Liver Diseases

Biomarkers for NASH in Early Clinical Development

Roberto Calle, MDClinical Research Internal Medicine Research UnitPfizer, Inc.

FDA Public Workshop: Clinical Pharmacology in Drug Development for Liver Diseases

December 9, 2019

151

efinition of Non-Alco olic Steato epatitisHistology has helped to characterize and define the disease

• Steatosis (macro-vesicular)

• Ballooning

• Lobular inflammation

• Zone 3 distribution

Kleiner et al, Hepatology 2005

Stage 1 Stage 2 Stage 3 Stage 4Fibrosis Staging

Histology courtesy of Pierre Bedossa and Arun Sanyal

152

mplications of Biopsy Based ecision-makingHISTOPATHOLOGY-BASED ASSESSMENT IS NOT AN EFFICIENT STRATEGY FOR DRUG DEVELOPMENT

Sampling variability: Same biopsy, Two different grades of liver fibrosis

■ Patient perspective:o Invasiveo Painfulo Morbidity / Mortality

■ Technical drawbacks:o Sampling variabilityo Intra- & Inter-observer variabilityo Limited opportunity for repeat

assessment■ Operational feasibility challenges:

o Resource intense; needs hepatologist or radiologist and pathologist

153

onsortium approac is encouraged by AUpdated FDA Draft Guidance published January 2014

“Because of the substantial work needed to achieve qualification, CDER [Center for Drug Evaluation and Research] encourages the formation of collaborative groups to undertake these tool-development programs… A variety of projects undertaken by consortia have demonstrated the usefulness of this approach.”

Unmet Need for Drug Development

A major unmet need to advance drug development for NAFLD is the development of non-invasive biomarker or biomarker panels that 1. Identification of individuals with NASH (Diagnostic marker)

2. Identification of individuals at risk of progression to cirrhosis and in need of pharmacological or non-pharmacologic intervention (Prognostic marker)

3. Permits evaluation of effects of one or more pharmacologic interventions on disease progression in subjects at various stages of NASH (Response marker)

154

evelopment of New erapeutics for NASH

Phase 1

POC- Dose Ranging

Ph3 pivotal studies

Phase 2 Phase 3

onditionalregulatory approval

Studies based on circ. markers or imaging to

assess early inflammation and fibrosis effect

increased ability to properly dose range

Efficacy endpoints based on Non-invasive

markers – No Bx

2-6 wks studies• LFC if anti-steatotic• Marker of inflammation• Marker of fibrosis

turnover

Proof of Mechanism

Safety & PK

Future Desired State

↓ screen failure rates (<30%) @ Bx

LARGE INVESTMENT WITH HIGH

CONFIDENCE

Outcomes Ph4 Study

Recruitment based on Non-invasive

markers

↓ screen failure rates (<30%) @ Bx

155

e allenge is N ack of otential Biomarkers but Rat er ack of roperly ualified Biomarkers

Many blood-based and imaging-based

biomarkers being developed to diagnose

and stage NASH

Wang et al., Nature Reviews, 2018

156

N MB AN M S N N N B M M N AR B R A R M B MAR R NS R A

Academic Lead: Prof. Quentin Anstee (Newcastle)Industry Lead: Dr. Julia Brosnan (Pfizer)

Academic Lead: Dr. Arun Sanyal (Virginia Commonwealth)Industry Leads: Dr. Roberto Calle (Pfizer) & Dr. Sudha Shankar (AZ)

Liver Investigation: Testing Marker Utility in Steatohepatitis

Dr. Roberto Calle (Pfizer) & Dr. Sudha Shankar (AZ)

MRI

Circulating

Functional

US

157


158HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines.

Measuring the Liver’s Function

Metabolism DependentFlow Dependent

Functional tests can assess hepatocyte function, systemic inflow, portal inflow, and quantifies portal-systemic spillover

Clearance of IV [A] Clearance of PO [B] Clearance of IV [A] Clearance of PO [B]

HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines.Figure is from Poster at AASLD Liver Meeting 2016

Hepatic Impairment

LiverDisease

159


161

Function Values for Dual Clearance Test

50 40 30 25 22 20 19 18 17 16 15 14 13 12 11 10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 3.75 3.50 3.25 3 2.75 2.5 2.25 2 1.8 1.6 1.4 1.2 110 0.83 2.88 5.96 7.93 9.31 10.34 10.9 11.48 12.1 12.76 13.46 14.21 15.01 15.88 16.82 17.86 18.42 19 19.62 20.28 20.98 21.73 22.53 23.4 24.35 25.38 26.53 27.81 28.51 29.26 30.06 30.93 31.87 32.91 34.05 35.33 36.48 37.76 39.21 40.88 42.869 1.93 3.37 6.21 8.11 9.47 10.49 11.03 11.61 12.23 12.88 13.57 14.31 15.11 15.98 16.91 17.94 18.5 19.08 19.7 20.35 21.05 21.8 22.6 23.47 24.41 25.44 26.58 27.86 28.56 29.31 30.11 30.98 31.92 32.95 34.1 35.37 36.52 37.8 39.24 40.92 42.898 3.19 4.22 6.71 8.5 9.81 10.79 11.32 11.89 12.49 13.13 13.81 14.54 15.33 16.18 17.1 18.12 18.67 19.25 19.86 20.51 21.21 21.95 22.74 23.61 24.54 25.57 26.71 27.98 28.67 29.42 30.22 31.08 32.02 33.05 34.19 35.47 36.61 37.88 39.33 41 42.977 4.64 5.4 7.5 9.15 10.37 11.3 11.81 12.36 12.93 13.55 14.21 14.92 15.69 16.52 17.43 18.43 18.97 19.54 20.15 20.79 21.47 22.2 22.99 23.84 24.77 25.79 26.92 28.18 28.87 29.61 30.4 31.26 32.2 33.22 34.36 35.63 36.76 38.03 39.47 41.13 43.16 6.31 6.89 8.64 10.1 11.21 12.09 12.56 13.08 13.62 14.21 14.84 15.52 16.26 17.07 17.95 18.92 19.45 20 20.59 21.22 21.89 22.61 23.39 24.22 25.14 26.14 27.25 28.5 29.18 29.92 30.7 31.56 32.48 33.5 34.62 35.88 37.01 38.27 39.7 41.36 43.315 8.29 8.74 10.17 11.44 12.44 13.23 13.66 14.14 14.64 15.19 15.78 16.43 17.13 17.89 18.74 19.67 20.18 20.71 21.28 21.89 22.54 23.24 24 24.81 25.71 26.69 27.78 29 29.67 30.39 31.17 32.01 32.92 33.93 35.04 36.28 37.4 38.65 40.06 41.7 43.65

4.5 9.43 9.83 11.12 12.29 13.22 13.97 14.39 14.84 15.32 15.84 16.41 17.03 17.71 18.45 19.27 20.18 20.67 21.2 21.75 22.35 22.99 23.67 24.41 25.22 26.1 27.07 28.14 29.35 30.01 30.73 31.49 32.32 33.23 34.22 35.32 36.56 37.67 38.91 40.32 41.94 43.884 10.71 11.06 12.23 13.3 14.17 14.86 15.26 15.68 16.14 16.64 17.18 17.77 18.42 19.14 19.93 20.81 21.29 21.8 22.34 22.92 23.54 24.21 24.94 25.72 26.59 27.54 28.59 29.78 30.44 31.14 31.9 32.72 33.61 34.6 35.69 36.91 38.01 39.24 40.63 42.25 44.17

3.8 11.27 11.6 12.72 13.75 14.59 15.27 15.65 16.06 16.51 17 17.53 18.11 18.75 19.45 20.23 21.1 21.57 22.07 22.61 23.18 23.8 24.46 25.18 25.96 26.82 27.76 28.81 29.99 30.64 31.34 32.09 32.91 33.8 34.77 35.86 37.08 38.17 39.39 40.78 42.4 44.313.6 11.85 12.17 13.24 14.23 15.05 15.71 16.08 16.48 16.92 17.4 17.92 18.48 19.11 19.8 20.56 21.42 21.88 22.38 22.91 23.48 24.08 24.74 25.45 26.22 27.07 28 29.04 30.21 30.86 31.55 32.3 33.11 34 34.97 36.05 37.26 38.34 39.56 40.95 42.56 44.463.4 12.47 12.78 13.8 14.76 15.54 16.18 16.54 16.93 17.36 17.82 18.33 18.89 19.5 20.18 20.93 21.77 22.23 22.71 23.24 23.79 24.39 25.04 25.74 26.51 27.34 28.27 29.3 30.46 31.1 31.79 32.53 33.34 34.22 35.18 36.26 37.46 38.54 39.75 41.13 42.73 44.633.2 13.13 13.42 14.4 15.32 16.07 16.69 17.04 17.42 17.84 18.29 18.79 19.33 19.93 20.59 21.33 22.15 22.6 23.08 23.6 24.15 24.74 25.38 26.07 26.82 27.65 28.57 29.59 30.74 31.37 32.06 32.79 33.59 34.46 35.42 36.49 37.68 38.76 39.97 41.34 42.93 44.823 13.83 14.11 15.04 15.92 16.65 17.25 17.59 17.96 18.36 18.8 19.28 19.81 20.4 21.04 21.76 22.57 23.02 23.49 23.99 24.53 25.12 25.75 26.43 27.17 27.99 28.9 29.9 31.04 31.67 32.35 33.08 33.87 34.74 35.69 36.75 37.93 39 40.2 41.57 43.15 45.03

2.8 14.58 14.84 15.73 16.58 17.28 17.86 18.18 18.54 18.93 19.36 19.83 20.34 20.91 21.54 22.25 23.04 23.47 23.94 24.43 24.96 25.54 26.16 26.83 27.56 28.37 29.26 30.26 31.39 32.01 32.68 33.4 34.18 35.04 35.99 37.03 38.21 39.27 40.46 41.82 43.39 45.262.6 15.39 15.63 16.48 17.29 17.96 18.52 18.84 19.18 19.56 19.97 20.43 20.93 21.48 22.1 22.78 23.56 23.98 24.44 24.92 25.44 26 26.61 27.27 28 28.79 29.67 30.65 31.77 32.38 33.04 33.76 34.53 35.38 36.32 37.36 38.53 39.58 40.76 42.11 43.67 45.532.4 16.26 16.49 17.29 18.07 18.71 19.25 19.55 19.88 20.25 20.65 21.09 21.57 22.11 22.71 23.38 24.13 24.55 24.99 25.47 25.98 26.53 27.12 27.77 28.48 29.26 30.13 31.1 32.2 32.8 33.46 34.16 34.93 35.77 36.7 37.72 38.88 39.93 41.1 42.43 43.99 45.832.2 17.2 17.42 18.18 18.92 19.54 20.05 20.34 20.66 21.02 21.4 21.82 22.29 22.81 23.4 24.05 24.78 25.18 25.62 26.08 26.58 27.12 27.7 28.34 29.03 29.8 30.65 31.6 32.68 33.28 33.93 34.62 35.38 36.21 37.12 38.14 39.29 40.32 41.48 42.8 44.34 46.172 18.24 18.44 19.17 19.87 20.46 20.95 21.23 21.53 21.87 22.24 22.65 23.1 23.6 24.17 24.8 25.51 25.9 26.32 26.77 27.26 27.79 28.36 28.98 29.66 30.41 31.24 32.18 33.24 33.83 34.46 35.15 35.9 36.71 37.61 38.62 39.75 40.77 41.92 43.23 44.75 46.57

1.9 18.79 18.99 19.7 20.38 20.96 21.43 21.71 22.01 22.34 22.7 23.1 23.54 24.04 24.59 25.21 25.91 26.3 26.71 27.16 27.64 28.15 28.72 29.33 30 30.75 31.57 32.5 33.55 34.13 34.76 35.44 36.18 36.99 37.89 38.89 40.01 41.02 42.17 43.47 44.98 46.791.8 19.38 19.58 20.26 20.92 21.48 21.95 22.22 22.51 22.83 23.19 23.58 24.02 24.5 25.04 25.65 26.34 26.72 27.13 27.57 28.04 28.55 29.1 29.71 30.37 31.11 31.92 32.84 33.88 34.46 35.08 35.76 36.49 37.29 38.18 39.17 40.29 41.3 42.43 43.73 45.23 47.031.7 20 20.19 20.85 21.5 22.04 22.5 22.76 23.05 23.36 23.71 24.09 24.52 24.99 25.52 26.12 26.8 27.17 27.58 28.01 28.47 28.97 29.52 30.12 30.77 31.5 32.3 33.21 34.24 34.81 35.43 36.1 36.82 37.62 38.5 39.48 40.59 41.59 42.72 44 45.5 47.291.6 20.66 20.84 21.48 22.11 22.64 23.09 23.34 23.62 23.93 24.27 24.64 25.06 25.52 26.04 26.63 27.3 27.66 28.06 28.48 28.94 29.43 29.97 30.56 31.21 31.92 32.72 33.61 34.63 35.2 35.8 36.47 37.18 37.97 38.85 39.82 40.92 41.91 43.03 44.31 45.8 47.571.5 21.36 21.54 22.16 22.77 23.29 23.72 23.96 24.24 24.54 24.87 25.23 25.64 26.09 26.6 27.18 27.83 28.19 28.58 28.99 29.44 29.93 30.46 31.04 31.67 32.38 33.16 34.05 35.05 35.61 36.21 36.87 37.58 38.36 39.22 40.19 41.28 42.26 43.37 44.64 46.12 47.881.4 22.11 22.28 22.88 23.47 23.97 24.39 24.63 24.9 25.19 25.51 25.87 26.27 26.71 27.21 27.77 28.41 28.76 29.14 29.55 29.99 30.47 30.99 31.56 32.18 32.88 33.65 34.52 35.51 36.07 36.66 37.31 38.01 38.78 39.64 40.59 41.67 42.65 43.74 45 46.47 48.221.3 22.91 23.08 23.66 24.23 24.72 25.13 25.36 25.62 25.9 26.21 26.56 26.95 27.38 27.87 28.41 29.04 29.38 29.76 30.16 30.59 31.06 31.57 32.13 32.74 33.42 34.19 35.04 36.02 36.56 37.15 37.79 38.48 39.25 40.09 41.04 42.1 43.07 44.16 45.4 46.86 48.591.2 23.78 23.94 24.5 25.06 25.53 25.92 26.15 26.4 26.67 26.98 27.31 27.69 28.11 28.59 29.12 29.73 30.07 30.43 30.82 31.24 31.7 32.2 32.75 33.36 34.03 34.77 35.62 36.58 37.12 37.69 38.32 39.01 39.76 40.59 41.53 42.58 43.54 44.61 45.85 47.29 49.011.1 24.73 24.88 25.42 25.95 26.41 26.79 27.01 27.25 27.52 27.81 28.14 28.51 28.92 29.38 29.9 30.49 30.82 31.17 31.56 31.97 32.42 32.91 33.45 34.04 34.69 35.43 36.26 37.2 37.73 38.3 38.92 39.59 40.33 41.16 42.08 43.12 44.06 45.12 46.35 47.77 49.471 25.76 25.91 26.43 26.94 27.38 27.75 27.96 28.19 28.45 28.74 29.06 29.41 29.81 30.25 30.76 31.34 31.66 32 32.37 32.78 33.22 33.69 34.22 34.8 35.44 36.16 36.97 37.9 38.41 38.97 39.58 40.25 40.98 41.79 42.69 43.72 44.65 45.7 46.91 48.31 50

Not physiologically possible Range for Lean Controls Moderate Hepatic Impairment Late Portal hypertension Late Decompensation, Pre-Terminal DiseasePossible but not likely Mild Hepatic Impairment Early Portal Hypertension Decompensation 99999 Zone of Transition to Increase Portal-Systemic SHUNTing from Left to Right

Portal-Systemic SHUNT Values for Dual Clearance Test

50 40 30 25 22 20 19 18 17 16 15 14 13 12 11 10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 3.75 3.5 3.25 3 2.75 2.5 2.25 2 1.8 1.6 1.4 1.2 110 20.0% 25.0% 33.3% 40.0% 45.5% 50.0% 52.6% 55.6% 58.8% 62.5% 66.7% 71.4% 76.9% 83.3% 90.9% 100.0% 105.3% 111.1% 117.6% 125.0% 133.3% 142.9% 153.8% 166.7% 181.8% 200.0% 222.2% 250.0% 266.7% 285.7% 307.7% 333.3% 363.6% 400.0% 444.4% 500.0% 555.6% 625.0% 714.3% 833.3% 1000.0%9 18.0% 22.5% 30.0% 36.0% 40.9% 45.0% 47.4% 50.0% 52.9% 56.3% 60.0% 64.3% 69.2% 75.0% 81.8% 90.0% 94.7% 100.0% 105.9% 112.5% 120.0% 128.6% 138.5% 150.0% 163.6% 180.0% 200.0% 225.0% 240.0% 257.1% 276.9% 300.0% 327.3% 360.0% 400.0% 450.0% 500.0% 562.5% 642.9% 750.0% 900.0%8 16.0% 20.0% 26.7% 32.0% 36.4% 40.0% 42.1% 44.4% 47.1% 50.0% 53.3% 57.1% 61.5% 66.7% 72.7% 80.0% 84.2% 88.9% 94.1% 100.0% 106.7% 114.3% 123.1% 133.3% 145.5% 160.0% 177.8% 200.0% 213.3% 228.6% 246.2% 266.7% 290.9% 320.0% 355.6% 400.0% 444.4% 500.0% 571.4% 666.7% 800.0%7 14.0% 17.5% 23.3% 28.0% 31.8% 35.0% 36.8% 38.9% 41.2% 43.8% 46.7% 50.0% 53.8% 58.3% 63.6% 70.0% 73.7% 77.8% 82.4% 87.5% 93.3% 100.0% 107.7% 116.7% 127.3% 140.0% 155.6% 175.0% 186.7% 200.0% 215.4% 233.3% 254.5% 280.0% 311.1% 350.0% 388.9% 437.5% 500.0% 583.3% 700.0%6 12.0% 15.0% 20.0% 24.0% 27.3% 30.0% 31.6% 33.3% 35.3% 37.5% 40.0% 42.9% 46.2% 50.0% 54.5% 60.0% 63.2% 66.7% 70.6% 75.0% 80.0% 85.7% 92.3% 100.0% 109.1% 120.0% 133.3% 150.0% 160.0% 171.4% 184.6% 200.0% 218.2% 240.0% 266.7% 300.0% 333.3% 375.0% 428.6% 500.0% 600.0%5 10.0% 12.5% 16.7% 20.0% 22.7% 25.0% 26.3% 27.8% 29.4% 31.3% 33.3% 35.7% 38.5% 41.7% 45.5% 50.0% 52.6% 55.6% 58.8% 62.5% 66.7% 71.4% 76.9% 83.3% 90.9% 100.0% 111.1% 125.0% 133.3% 142.9% 153.8% 166.7% 181.8% 200.0% 222.2% 250.0% 277.8% 312.5% 357.1% 416.7% 500.0%

4.5 9.0% 11.3% 15.0% 18.0% 20.5% 22.5% 23.7% 25.0% 26.5% 28.1% 30.0% 32.1% 34.6% 37.5% 40.9% 45.0% 47.4% 50.0% 52.9% 56.3% 60.0% 64.3% 69.2% 75.0% 81.8% 90.0% 100.0% 112.5% 120.0% 128.6% 138.5% 150.0% 163.6% 180.0% 200.0% 225.0% 250.0% 281.3% 321.4% 375.0% 450.0%4 8.0% 10.0% 13.3% 16.0% 18.2% 20.0% 21.1% 22.2% 23.5% 25.0% 26.7% 28.6% 30.8% 33.3% 36.4% 40.0% 42.1% 44.4% 47.1% 50.0% 53.3% 57.1% 61.5% 66.7% 72.7% 80.0% 88.9% 100.0% 106.7% 114.3% 123.1% 133.3% 145.5% 160.0% 177.8% 200.0% 222.2% 250.0% 285.7% 333.3% 400.0%

3.8 7.6% 9.5% 12.7% 15.2% 17.3% 19.0% 20.0% 21.1% 22.4% 23.8% 25.3% 27.1% 29.2% 31.7% 34.5% 38.0% 40.0% 42.2% 44.7% 47.5% 50.7% 54.3% 58.5% 63.3% 69.1% 76.0% 84.4% 95.0% 101.3% 108.6% 116.9% 126.7% 138.2% 152.0% 168.9% 190.0% 211.1% 237.5% 271.4% 316.7% 380.0%3.6 7.2% 9.0% 12.0% 14.4% 16.4% 18.0% 18.9% 20.0% 21.2% 22.5% 24.0% 25.7% 27.7% 30.0% 32.7% 36.0% 37.9% 40.0% 42.4% 45.0% 48.0% 51.4% 55.4% 60.0% 65.5% 72.0% 80.0% 90.0% 96.0% 102.9% 110.8% 120.0% 130.9% 144.0% 160.0% 180.0% 200.0% 225.0% 257.1% 300.0% 360.0%3.4 6.8% 8.5% 11.3% 13.6% 15.5% 17.0% 17.9% 18.9% 20.0% 21.3% 22.7% 24.3% 26.2% 28.3% 30.9% 34.0% 35.8% 37.8% 40.0% 42.5% 45.3% 48.6% 52.3% 56.7% 61.8% 68.0% 75.6% 85.0% 90.7% 97.1% 104.6% 113.3% 123.6% 136.0% 151.1% 170.0% 188.9% 212.5% 242.9% 283.3% 340.0%3.2 6.4% 8.0% 10.7% 12.8% 14.5% 16.0% 16.8% 17.8% 18.8% 20.0% 21.3% 22.9% 24.6% 26.7% 29.1% 32.0% 33.7% 35.6% 37.6% 40.0% 42.7% 45.7% 49.2% 53.3% 58.2% 64.0% 71.1% 80.0% 85.3% 91.4% 98.5% 106.7% 116.4% 128.0% 142.2% 160.0% 177.8% 200.0% 228.6% 266.7% 320.0%3 6.0% 7.5% 10.0% 12.0% 13.6% 15.0% 15.8% 16.7% 17.6% 18.8% 20.0% 21.4% 23.1% 25.0% 27.3% 30.0% 31.6% 33.3% 35.3% 37.5% 40.0% 42.9% 46.2% 50.0% 54.5% 60.0% 66.7% 75.0% 80.0% 85.7% 92.3% 100.0% 109.1% 120.0% 133.3% 150.0% 166.7% 187.5% 214.3% 250.0% 300.0%

2.8 5.6% 7.0% 9.3% 11.2% 12.7% 14.0% 14.7% 15.6% 16.5% 17.5% 18.7% 20.0% 21.5% 23.3% 25.5% 28.0% 29.5% 31.1% 32.9% 35.0% 37.3% 40.0% 43.1% 46.7% 50.9% 56.0% 62.2% 70.0% 74.7% 80.0% 86.2% 93.3% 101.8% 112.0% 124.4% 140.0% 155.6% 175.0% 200.0% 233.3% 280.0%2.6 5.2% 6.5% 8.7% 10.4% 11.8% 13.0% 13.7% 14.4% 15.3% 16.3% 17.3% 18.6% 20.0% 21.7% 23.6% 26.0% 27.4% 28.9% 30.6% 32.5% 34.7% 37.1% 40.0% 43.3% 47.3% 52.0% 57.8% 65.0% 69.3% 74.3% 80.0% 86.7% 94.5% 104.0% 115.6% 130.0% 144.4% 162.5% 185.7% 216.7% 260.0%2.4 4.8% 6.0% 8.0% 9.6% 10.9% 12.0% 12.6% 13.3% 14.1% 15.0% 16.0% 17.1% 18.5% 20.0% 21.8% 24.0% 25.3% 26.7% 28.2% 30.0% 32.0% 34.3% 36.9% 40.0% 43.6% 48.0% 53.3% 60.0% 64.0% 68.6% 73.8% 80.0% 87.3% 96.0% 106.7% 120.0% 133.3% 150.0% 171.4% 200.0% 240.0%2.2 4.4% 5.5% 7.3% 8.8% 10.0% 11.0% 11.6% 12.2% 12.9% 13.8% 14.7% 15.7% 16.9% 18.3% 20.0% 22.0% 23.2% 24.4% 25.9% 27.5% 29.3% 31.4% 33.8% 36.7% 40.0% 44.0% 48.9% 55.0% 58.7% 62.9% 67.7% 73.3% 80.0% 88.0% 97.8% 110.0% 122.2% 137.5% 157.1% 183.3% 220.0%2 4.0% 5.0% 6.7% 8.0% 9.1% 10.0% 10.5% 11.1% 11.8% 12.5% 13.3% 14.3% 15.4% 16.7% 18.2% 20.0% 21.1% 22.2% 23.5% 25.0% 26.7% 28.6% 30.8% 33.3% 36.4% 40.0% 44.4% 50.0% 53.3% 57.1% 61.5% 66.7% 72.7% 80.0% 88.9% 100.0% 111.1% 125.0% 142.9% 166.7% 200.0%

1.9 3.8% 4.8% 6.3% 7.6% 8.6% 9.5% 10.0% 10.6% 11.2% 11.9% 12.7% 13.6% 14.6% 15.8% 17.3% 19.0% 20.0% 21.1% 22.4% 23.8% 25.3% 27.1% 29.2% 31.7% 34.5% 38.0% 42.2% 47.5% 50.7% 54.3% 58.5% 63.3% 69.1% 76.0% 84.4% 95.0% 105.6% 118.8% 135.7% 158.3% 190.0%1.8 3.6% 4.5% 6.0% 7.2% 8.2% 9.0% 9.5% 10.0% 10.6% 11.3% 12.0% 12.9% 13.8% 15.0% 16.4% 18.0% 18.9% 20.0% 21.2% 22.5% 24.0% 25.7% 27.7% 30.0% 32.7% 36.0% 40.0% 45.0% 48.0% 51.4% 55.4% 60.0% 65.5% 72.0% 80.0% 90.0% 100.0% 112.5% 128.6% 150.0% 180.0%1.7 3.4% 4.3% 5.7% 6.8% 7.7% 8.5% 8.9% 9.4% 10.0% 10.6% 11.3% 12.1% 13.1% 14.2% 15.5% 17.0% 17.9% 18.9% 20.0% 21.3% 22.7% 24.3% 26.2% 28.3% 30.9% 34.0% 37.8% 42.5% 45.3% 48.6% 52.3% 56.7% 61.8% 68.0% 75.6% 85.0% 94.4% 106.3% 121.4% 141.7% 170.0%1.6 3.2% 4.0% 5.3% 6.4% 7.3% 8.0% 8.4% 8.9% 9.4% 10.0% 10.7% 11.4% 12.3% 13.3% 14.5% 16.0% 16.8% 17.8% 18.8% 20.0% 21.3% 22.9% 24.6% 26.7% 29.1% 32.0% 35.6% 40.0% 42.7% 45.7% 49.2% 53.3% 58.2% 64.0% 71.1% 80.0% 88.9% 100.0% 114.3% 133.3% 160.0%1.5 3.0% 3.8% 5.0% 6.0% 6.8% 7.5% 7.9% 8.3% 8.8% 9.4% 10.0% 10.7% 11.5% 12.5% 13.6% 15.0% 15.8% 16.7% 17.6% 18.8% 20.0% 21.4% 23.1% 25.0% 27.3% 30.0% 33.3% 37.5% 40.0% 42.9% 46.2% 50.0% 54.5% 60.0% 66.7% 75.0% 83.3% 93.8% 107.1% 125.0% 150.0%1.4 2.8% 3.5% 4.7% 5.6% 6.4% 7.0% 7.4% 7.8% 8.2% 8.8% 9.3% 10.0% 10.8% 11.7% 12.7% 14.0% 14.7% 15.6% 16.5% 17.5% 18.7% 20.0% 21.5% 23.3% 25.5% 28.0% 31.1% 35.0% 37.3% 40.0% 43.1% 46.7% 50.9% 56.0% 62.2% 70.0% 77.8% 87.5% 100.0% 116.7% 140.0%1.3 2.6% 3.3% 4.3% 5.2% 5.9% 6.5% 6.8% 7.2% 7.6% 8.1% 8.7% 9.3% 10.0% 10.8% 11.8% 13.0% 13.7% 14.4% 15.3% 16.3% 17.3% 18.6% 20.0% 21.7% 23.6% 26.0% 28.9% 32.5% 34.7% 37.1% 40.0% 43.3% 47.3% 52.0% 57.8% 65.0% 72.2% 81.3% 92.9% 108.3% 130.0%1.2 2.4% 3.0% 4.0% 4.8% 5.5% 6.0% 6.3% 6.7% 7.1% 7.5% 8.0% 8.6% 9.2% 10.0% 10.9% 12.0% 12.6% 13.3% 14.1% 15.0% 16.0% 17.1% 18.5% 20.0% 21.8% 24.0% 26.7% 30.0% 32.0% 34.3% 36.9% 40.0% 43.6% 48.0% 53.3% 60.0% 66.7% 75.0% 85.7% 100.0% 120.0%1.1 2.2% 2.8% 3.7% 4.4% 5.0% 5.5% 5.8% 6.1% 6.5% 6.9% 7.3% 7.9% 8.5% 9.2% 10.0% 11.0% 11.6% 12.2% 12.9% 13.8% 14.7% 15.7% 16.9% 18.3% 20.0% 22.0% 24.4% 27.5% 29.3% 31.4% 33.8% 36.7% 40.0% 44.0% 48.9% 55.0% 61.1% 68.8% 78.6% 91.7% 110.0%1 2.0% 2.5% 3.3% 4.0% 4.5% 5.0% 5.3% 5.6% 5.9% 6.3% 6.7% 7.1% 7.7% 8.3% 9.1% 10.0% 10.5% 11.1% 11.8% 12.5% 13.3% 14.3% 15.4% 16.7% 18.2% 20.0% 22.2% 25.0% 26.7% 28.6% 30.8% 33.3% 36.4% 40.0% 44.4% 50.0% 55.6% 62.5% 71.4% 83.3% 100.0%

Not physiologically possible Normal Range for SHUNT Moderately Increased SHUNT Markedly Increased SHUNTPossible but not likely Minimally Increased SHUNT Nearly Complete to Complete SHUNT

Clearance Clearance 2

Clearance 1 Clearance 2

Should Function be the New Gold Standard?

HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines. 162

• Treatment should improve how a person/patient FEELS, FUNCTIONS, or SURVIVES

• A person with a disease that progressively damages the liver -FEELS, FUNCTIONS, or SURVIVES based upon how the liver functions; and not based upon the surrogate of scar/fibrosis.

• If treatment improves the liver, the test must detect and quantify this improvement.

Change in Ishak Fibrosis Stage (IFS) from Baseline to Yr 2(174 Paired Liver Biopsies from HALT-C Subjects)

4.11 ± 1.31 4.09 ± 1.51∆IFS = 0.02 ± 1.10p = 0.84

HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines.

Change in Function from Baseline to Yr 2(188 Paired Function Tests in HALT-C subjects)

19.37 ± 5.42 21.00 ± 7.39∆Test = 1.64 ± 5.21p < 0.00003

HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines.

Can Function Testing become a

Clinical Reality?


Function Testing Clarifies Liver HealthCutoff for Significant Clinical Risk

Clinical outcomes (variceal bleed, ascites, encephalopathy, liver-related death)High likelihood of cirrhosisHepatocellular carcinoma (HCC)

Defines Global Liver HealthPatients and providers can track function over time or with treatment Improved function leads to significant improvement in liver disease Improvement in function defines improvement in Pharma trialsWorsening of function implies worsening of liver disease

HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines. 166

167


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