saul j. karpen, m.d., ph.d. - virology...
TRANSCRIPT
![Page 1: Saul J. Karpen, M.D., Ph.D. - Virology Educationregist2.virology-education.com/presentations/2017/... · 2017-12-07 · Saul J. Karpen, M.D., Ph.D. Raymond F. Schinazi Distinguished](https://reader030.vdocument.in/reader030/viewer/2022013022/5f59c6f767c3d563620e0b97/html5/thumbnails/1.jpg)
Saul J. Karpen, M.D., Ph.D.Raymond F. Schinazi Distinguished Biomedical Chair
Professor of PediatricsHepDart Kona, Hawaii
December 6, 2017
The Re-vival of Bile Acid Based Therapeutics for Children and Adults
FXRRXRα
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Disclosures
• Consultant– Intercept Pharmaceuticals– Retrophin– Albireo– Regulus
• NIH NIDDK Consortia– ChiLDReN (14 NA sites children with biliary atresia & other cholestatic diseases)
– NASH CRN (8 US sites adults & children with NASH)
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Topics
• Bile acid (BA) primer: FXR, TGR5, ASBT, NTCP
– Including the microbiome …
• BA Roles & Targets in Cholestasis– FXR activators– ASBT (SLC10A2) & NTCP (SLC10A1) inhibitors– Cholic Acid (CA), UDCA & NorUDCA – FGF19 analogues– Potentiators & Chaperones
• BA Roles & Targets in NAFLD– FXR activators & inhibitors– ASBT inhibitors– TGR5 activators
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• Cholesterol Bile acids (~ 14 enzymes)• > 95 % efficient• Specific BA transporters in Liver & Intestine• Each BA circulates 8-10 times a day• Luminal bacterial modifications• BA flux is relevant for:
• Feedback regulation of BA synthesis
• Bile flow
• Absorption of Fats & Vitamins ADEK
• Metabolism
ASBT
COOH
OH
OHH
HO
Cholic acidCA
HO
COOH
OHH
Chenodeoxycholic acid
CDCA
3 7
7
The enterohepatic circulation of bile acids
COOH
HO
OH
H
Deoxycholic acid
DCABacterialModification
HO
COOH
OHH
Ursodeoxycholic acid
UDCA
7β
Non-human,Rx
Primary
Primary
Key bile acids
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Key Components of the Enterohepatic Circulation of Bile Acids
Fickert & Wagner J Hepatol 2017 Ridlon J Lipid Res 2006
Certain bacteria metabolize bile
acids and change active biliary components
CA + CDCA:70% of BAs in bile4% of BAs in feces
Biliary Bile acids
Fecal Bile acids
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LXRFXR
MAPK
PI3K
PKC
TGR5
AP1FASTRAIL
PGC1α
CAR
VDR
PXR
CellSignaling
Apoptosis
NuclearReceptors
JNKp38MAPK
ERK1/2
SHPFGF19
S1PR2
Multiple Molecular Roles for Bile Acids
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Bile acid based approaches
Trauner M, Fuchs CD, Halilbasic E, Paumgartner G. New therapeutic concepts … . Hepatology. 2017
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Topics
• Bile acid (BA) primer: FXR, TGR5, ASBT, NTCP
– Including the microbiome …
• BA Roles & Targets in Cholestasis– FXR activators– ASBT (SLC10A2) & NTCP (SLC10A1) inhibitors– Cholic Acid (CA), UDCA & NorUDCA – FGF19 analogues– Potentiators & Chaperones
• BA Roles & Targets in NAFLD– FXR activators & inhibitors– ASBT inhibitors– TGR5 activators
See Ghosh. Abst 14, Thursday 10:30
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NTCP
⬇BA import
BSEP
ost α & β
cyp7aLRH-1
shpSHPRXR FXR
bsep
OST α/β
RXR FXR
RXR LXR
RXR RAR
RXR FXR
ntcp
⬇BA synthesis
Hepatic FXR targeting to improve adaptation to BA retention
RXRα FXR
⬆BA export
⬆BA sinusoidal export
Thomas Pharm Res 2013
Mouse Liver ChIP-SEQ:• FXR: 7800 sites
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FXR Deficiency Neonatal Cholestasis/Liver Failure
Nature Commun. 2016
2 Families:• Presentation at birth6 w of age
• ⬆ Direct Bilirubin • Coagulopathy• Mild ⬆ ALT & AST• Low GGT
• 2 died (5 weeks, 8 months)• 2 transplanted (4 & 22 months)
NR1H4: ARG176*
Absent BSEP expression
BSEPRXR FXR
New disease discovered
through exome sequencing.
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Cholic Acid Chenodeoxycholic acid
Lithocholic AcidZ-Guggulsterone
FXR Agonists
FXR Antagonists
GW4064EC50: 4-10 µM 37-80 nM≈ 20 µM
IC50:
Deoxycholic acid19-50 µM
6-α-ethyl-CDCA (Obeticholic acid)99 nM
≈ 10 µM
Makishima Science 1999Parks Science 1999Wang Mol Cell 1999Urizar Science 2002Yu JBC 2002Pellicciari J Med Chem 2002Hawkins JCI 2002Dussault JBC 2003Downes Mol Cell 2003Carter Ped Res 2007
≈ 10-30 µMStigmasterol≈ 10 µM
Fexaramine25 nM
Fexarine38 nM
Fexarene36 nM
AGN312 µM
(also RXR)
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Cholic Acid Therapy in BA Synthesis Defects (3 β HSD Deficiency): ⬇ hepatotoxic atypical bile acid intermediates
Adapted from Setchell KD. Adolf Windaus Prize Lecture 2004. In: Paumgartner G et al, eds. Bile Acid Biology and Its Therapeutic Implications. Proceedings of the Falk Symposium 141 (XVIII Internationale Bile Acid Meeting) held in Stockholm, Sweden, June 18-19, 2004. Netherlands: Springer; 2005:1-15.
Atypical Bile Acids(URINE)
cyp7aLRH-1
shpSHPRXR FXR
RXR LXR
⬇BA synthesisCholic acid is an FXR agonist ↓ CYP7A (↓ BA synthesis)
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NEJM 2016: NCT01473524
93% Female
56 ±10 y
73 ±13 kgAlk Phos 324 ± 174 Serum BA 48±68
93% on UDCAPruritus Scores: Itch, PBC-40, 5-D Itch
OCA
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NTCP Inhibition: Blocking Bile Acid Return to Hepatocytes
Karpen: adapted from: Liver Diseases in ChildrenSlijepcevic D, et al Hepatology. 2017; online 5.12.2017
• Myrcludex B: Potent NTCP inhibitor• Peptide derived from aa 2-47 of pre-S1 HBV sequence• Inhibits HBV (& HDV) entry into hepatocytes
• Note: NTCP (SLC10A1) S267F variant in 10% of Chinese resists HBV infection.
Li & Urban J Hepatology 2016
Myrcludex B in Human Volunteers
x
xx
xx
See Foster Abst. 22, CRV431
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Fickert P. J Hepatol. 2017
NorUDCA for PSC: 12 week Phase 2 Trial
38 Sites12 European countries
159 Participants:• 40 UDCA naïve • 58 UDCA responders• 55 UDCA non-responders
Exclusions:• < 18 or > 80 y• Concurrent immunosuppressive meds• Recent endoscopic Rx• T Bili > 3, etc…
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NorUDCA for PSC: Change in Alk Phos as Primary Endpoint
* : p < 0.01 compared to Placebo
# : p < 0.025 comparing 1500 to 500 mg
Plans for Phase 3 Study
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ASBT inhibitors:
FXR & LXR Modulators
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ASBT
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A4250 Maralixibat; SHP625Elobixibat; A3309
Volixibat; SHP626 GSK2330672
ASBT inhibitors in clinical trials
Clinical trials.gov
Diseases:Alagille SyndromePFIC1PFIC2Biliary Atresia
PBCPSC
NASH
Constipation
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ASBT inhibition in the Abcb4-/- mouse: 2 mouse models of PFIC3
Miethke, Hepatology 2015
ASBTi fecal BA loss & & altered Liver BAs
Baghdasaryan, Journal of Hepatology, 2016
ASBTi Fibrosis & Inflammation
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Lancet 2017: NCT01899703
11 pts
10 pts
19 F/ 2 M 52 ±10 y 73 ±13 kgAlk Phos 264 ± 174 IU/LSerum BA 48±68 µMPruritus Scores: Itch, PBC-40, 5-D Itch
Dose escalation: 45 mg po BID Days 1-390 mg po BID Days 4-14
ASBT Inhibitors for Pruritus
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5-D Itch ScaleSerum BA
C4
PBC: 14 days of ASBT inhibition pruritus & serum BA levels
Note:ASBTi serum UDCA & DCA
No change in liver indices
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Topics
• Bile acid (BA) primer: FXR, TGR5, ASBT, NTCP
– Including the microbiome …
• BA Toxicity & Targets in Cholestasis– FXR activators– ASBT (SLC10A2) & NTCP (SLC10A1) inhibitors– Cholic Acid (CA), UDCA & NorUDCA – FGF19 analogues– Potentiators & Chaperones
• BA Roles & Targets in NAFLD– FXR activators & inhibitors– ASBT inhibitors– TGR5 activators
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NHANES data: 1988 to 2010 Prevalence of NAFLD among U.S. Adolescents
0
2
4
6
8
10
12
1988-94 1999-02 2003-06 2007-10
% S
uspe
cted
NA
FLD
ALT >25.8 U/L for boys; >22.1 U/L for girls
Welsh, Karpen, Vos, J Ped 2013Source: Dr. Miriam Vos
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Obese (& Normal) Adolescents Adults with CV Disease
NEJM 2016
• Israeli Army Recruits• 1967-2010• Mean Age: 17 yo• 60% Male BMI %ile CV Mortality
Hazard Ratio • 50th-74th 1.32 (1.2-1.5)• 75th-84th 1.76 (1.5-2.0)• 85th-94th 2.25 (2.0-2.6)• > 95th 3.46 (2.9-4.1)
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J Hepatol. 2016;65:363–368.
BMI > 25 is a risk factor for the development of
liver disease
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Roles for bile acid signaling in addressing NAFLD & NASH
FXRTGR5ASBTGLP1
CholestasisGlucose MetabolismFat MetabolismCholesterol KineticsInsulin Resistance
LiverIntestineVisceral FatMuscle
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OCA
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J Clin Invest. 2015;125:386–402.
Intestinal FXR Antagonism improves NASH in mice
Intestinal FXR Agonism improves NASH in mice
Essential, but seemingly contradictory effects of FXR & BA signaling in NAFLD
Intestinal FXR ko protects against HFD-induced hepatic steatosis
Nat Med. 2015;21:159–165.
Fexaramine (Intestinal FXR agonist) improves HFD-induced hepatic steatosis
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NAFLD & NASH:
FXR Agonism or FXR Antagonism
Both work Why?
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Intact Enterohepatic BA Recirculation
ASBT
Ileal ASBTInhibition
ASBT
Interrupted EnterohepaticBA Recirculation
Ileal ASBT inhibition will improve the hepatic
and whole body response to HFD in
mice
Hypothesis:
ColonBA’sMicrobial BA metab.TGR5 signaling
BA Pool size
LiverBA Synthesis Cholesterol
IleumBA UptakeFXR-FGF15/19 signaling
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ALIOS (45% fat; 0.2% cholesterol), + Added Sugars in the Drinking Water
Chow
HFD
ASBTi [SC-435] x 16wk
HFDASBTi
HFD:
ASBTi: 0.006% SC-435, 10 mg/kg/day
Mice: Male, C57BL6J, 4-6 weeks, n=7-16/group
4 8 12 16. . . ..0Weeks • Weekly Body Weights
• Weekly Caloric & fluid intake
• Week 15 GTT, ITT
• Week 16• Serum Liver Indices• Feces Bile Acids• Ileum RNA• Colon RNA• Liver Histology
• Lipids & Bile Acids
• RNA-Seq• RNA & Protein• Hydroxyproline
• Statistics: Mean ± SD• ANOVA
Tetri LH. Am J Physiol GI 2008 Nov;295(5):G987–95.
Mells JE J Nutr Biochem. 2015 Mar;26(3):285–92.
Study Design & Endpoints
Rao A et al. Sci Transl Med 2016; 357: ra122.
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Liver
0
1
2
3
4
Chow HFD HFDASBTi
a
b
a
Cyp7a1
0
1
2
3
4 Cyp8b1
a
b
a
Chow HFD HFDASBTi
Rel
ativ
e ge
ne e
xpre
ssio
n
Colon
0
5
1 0
1 5
2 0 Ilbp
a a
b
Chow HFD HFDASBTi
Rel
ativ
e ge
ne e
xpre
ssio
n
ASBT
Feca
l Bile
Aci
ds (µ
M/2
4 hr
) Feces
HFD
a
b
0
1
2
3Fgf15
a
b
c
Chow HFD HFDASBTi
Ileum
Rel
ativ
e ge
ne e
xpre
ssio
n
HFDASBTi
Chow HFD
Shp
ab
a
SC-435 Inhibits Ileal ASBT Function
HFDASBTi
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Glu
cose
(mg/
dL)
Time (mins)
Chow
HFD + ASBTiHFD
*
ITT
AUC
a,bb* * *
a
**
*
Chow
HFD + ASBTiHFD
GTT
AU
C a
b
a
* Significantly different from HFD + Asbti
GTT
ITT
ASBTi Restores Glucose Tolerance
Chow HFD HFDASBTi
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Chow HFD HFD + ASBTi
NAFLD Activity Score (NAS)
Chow HFD HFDASBTi
a
b
c
ASBTi Improves Hepatic NAFLD Activity & Steatosis Scores
Triglycerides Cholesteryl Esters(µ
g/m
g liv
er)
(µg/
mg
liver
)
a
b
a
a
b
a
Chow HFD HFDASBTi
Chow HFD HFDASBTi
Chow HFD HFDASBTi
(pm
ol/m
g liv
er ti
ssue
)
Total Bile Acids
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FXR AntagonistFXR Agonist
HFD
58% 42%
HFD + Asbti
83%
17%
Bile
Aci
d (p
mol
/mg
tissu
e)
* * * * *α-TMCA β-TMCA ω-TMCA THDCA TUDCA α-MCA β-MCA
FXR Antagonist
HFDHFD + Asbti
TCA TCDCA TDCA TLCA CA
*
*
*
FXR Agonist
*
ASBTi Markedly Alters Hepatic BA Composition
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HFD
Insulin resistance
Hyperglycemia Hyperinsulinemia
ChREBP
Lipogenic genes TG
SREBP-1c LXR Hepatic cholesterol
FXR Hepatic BA Composition
ASBTi
ASBTi
ASBTi
Hepatic Steatosis
ASBT
Hypothesized Mechanisms of Action of ASBTi in Liver
FXR Antagonist
FXR Agonist
HFD
58% 42%
HFD + Asbti
83%
17%
Ileal ASBT inhibition Markedly Alters Hepatic BA Composition
TMCA’s THDCA TUDCA
TCA TCDCA TDCA
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Summary: Re-vival of Bile Acid Biology & New Therapeutics• Bile acid (BA) biology: FXR, TGR5, ASBT, NTCP
– Gut-Liver-Microbe-Gene Axis involves BAs
– Differential effects in Ileum, Colon, Liver, Fat, …
– Individual BA’s have distinct functional properties
• Cholestasis– Roles for FXR Agonism, ASBT inhibition, norUDCA
– ? NTCP Inhibition
• NAFLD– Complex roles for FXR Agonism & Antagonism– Roles for ASBT inhibition (Await human study: Shire, SHP626: NCT02787)– ? NTCP inhibition (CRV231)
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Saul Karpen, MD, PhDPaul Dawson, PhDAstrid Kosters, PhDAnuradha Rao, PhDAngelica Amanso, PhDJP Berauer, MDGina Ramirez
Funding (NIH)• R01 DK056239 • R01 DK047987• Philanthropies: • Alpard Foundation• Spain Fund• Moss Fund
Anya Mezina,MD MSCRCourtney FerrebeeJamie Mells, PhDKim PachuraJianing Li, PhDGrace WynnPrabhu Shankar, MD
Emory University (Saul-Paul Lab)
Hong Yin, MD (Pathology)
Dean Jones, PhD (Metabolomics)Sophia BantonShuzhao Li
Hao Wu, PhD (School of Public Health)
Emory University
Brad Keller, PhD (Lumena/Shire)
Ken Setchell, PhD
Wujuan Zhang, PhD
Cincinnati Children’s