1
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
2
Welcome & OverviewMark McClellan, MD, PhDDirector, Duke-Margolis Center for Health Policy
4
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
6
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.
7
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
8
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
9
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
10
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
11
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
15
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
17
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
18
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
19
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
20
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
21
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
22
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
23
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
24
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?
???
25
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)
27
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%)
51
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
52
Hardwick et al., Drug Metab Dispos, 39:2395, 2011
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
53
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
54
• 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
55
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
57
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
58
Normal Steatosis (>5%) (<5%)
Normal Steatosis(>5%) (<5%)
~3-fold increase
MRP3
Hardwick et al., Drug Metab Dispos, 39:2395, 2011
Increased MRP3 Protein Levelsin Liver Tissue from Patients with NASH
NASH (fatty infiltration)
NASH (fatty infiltration)
59
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
Ferslew…Brouwer, Clin Pharmacol Ther, 97:419, 2015
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
Ferslew…Brouwer, Clin Pharmacol Ther, 97:419, 2015
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)
Healthy NASH Fibrosis(F1-F3)
NASH Cirrhosis(F4/CP-A)
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
Healthy NASH Fibrosis(F1-F3)
NASH Cirrhosis(F4/CP-A)
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
Healthy NASH Fibrosis(F1-F3)
NASH Cirrhosis(F4/CP-A)
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
Healthy NASH Fibrosis(F1-F3)
NASH Cirrhosis(F4/CP-A)
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
Healthy NASH Fibrosis(F1-F3)
NASH Cirrhosis(F4/CP-A)
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.
CONFIDENTIAL – For internal purposes onlyv6
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
CONFIDENTIAL – For internal purposes onlyv6
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)
CONFIDENTIAL – For internal purposes onlyv6
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 )
CONFIDENTIAL – For internal purposes onlyv6
• 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 )
CONFIDENTIAL – For internal purposes onlyv6
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
CONFIDENTIAL – For internal purposes onlyv6
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)
CONFIDENTIAL – For internal purposes onlyv6
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)
CONFIDENTIAL – For internal purposes onlyv6
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
CONFIDENTIAL – For internal purposes onlyv6
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)
CONFIDENTIAL – For internal purposes onlyv6
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
CONFIDENTIAL – For internal purposes onlyv6
• 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
CONFIDENTIAL – For internal purposes onlyv6
• 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
CONFIDENTIAL – For internal purposes onlyv6
• 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
CONFIDENTIAL – For internal purposes onlyv6
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)
CONFIDENTIAL – For internal purposes onlyv6
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
CONFIDENTIAL – For internal purposes onlyv6
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
CONFIDENTIAL – For internal purposes onlyv6
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
Session 2: Panel DiscussionEarly Discovery and Development—Treatment Mechanisms, Molecular Targets, and Biomarkers in Early Development of Therapies for NASH and Cholestatic Liver Diseases
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
160HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines.
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?
165HepQuant’s products are not FDA-approved and are for investigational use only in clinical trials under FDA IDE guidelines.
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
Session 2: Panel DiscussionEarly Discovery and Development—Treatment Mechanisms, Molecular Targets, and Biomarkers in Early Development of Therapies for NASH and Cholestatic Liver Diseases