Recent Advances in Primary Biliary Cirrhosis · Recent Advances in Primary Biliary Cirrhosis...

Recent Advances in Primary Biliary Cirrhosis

Disease Pathways and Potential Targets of Therapy

Ulrich H.W. Beuers, MD Department of Gastroenterology & Hepatology

Tytgat Institute for Liver and Intestinal Research Academic Medical Centre University of Amsterdam

The Netherlands

Primary Biliary Cirrhosis Characteristics

Sex (f:m) 9 : 1 Age 40 - 60 Survival without treatm. 7.5-16 years Cholestatic enzyme pattern AP, γGT

Autoantibodies AMA (anti-PDC-E2)

Sherlock and Summerfield, 1991

Symptoms: •  Fatigue •  Itch •  “Dry eye, dry mouth“ •  …

Courtesy of Ulrich H. W. Beuers, MD.

Primary Biliary Cirrhosis

Beuers U, et al. Hepatology. 1998;28:1449-1453.

Immune-mediated bile duct

injury

Aggravation of bile duct

injury by hydrophobic

bile acids

Cholestasis with

retention of hydrophobic bile acids in

liver

Liver cell damage,

apoptosis, necrosis, fibrosis, cirrhosis

Liver failure

Pathogenesis

Primary Biliary Cirrhosis - Pathogenesis -

•  Genetic predisposition

•  Exogenous factors

•  Endogenous factors


•  Genetic predisposition Monozygotic twins: >60% PBC Family members: 6% PBC

GWAS*: HLA-DQ-B1, Il12A, Il12B2, STAT4,…



Selmi C, et al. Gastroenterology. 2004;127:485-492.

Hirschfield GM, et al. N Engl J Med. 2009;360:2544-2555.

*GWAS: Genome-wide association study.

Sequence Homology of the Human Pyruvate Dehydrogenase Complex (PDC-E2208-237) with Bacterial Proteins

Inner lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2)

(Left graphic) With permission from Migliaccio C, et al. Hepatology. 2001;33:792-801. (Right graphic) With permission from Selmi C, et al. Hepatology. 2003;38:1250-1257.

Model of AMA Formation and Cholangiocyte Damage in Primary Biliary Cirrhosis

IgA AMA transfer via cholangiocytes

With permission from Rieger R, Gershwin ME. J Autoimmun. 2007;28:76-84.


Sex (f:m) 9 : 1 Age 40 - 60 Survival without treatm. 7.5-16 years Cholestatic enzyme Pattern AP, γGT



Signs & symptoms: •  Fatigue •  Itch •  “Dry eye, dry mouth“ •  …

Too low HCO3

- ?

Courtesy of Ulrich H.W. Beuers, MD.

Prieto J, et al. Gastroenterology. 1993;105:572-578. Medina JF, et al. Hepatology. 1997;25:12-17. Prieto J, et al. Gastroenterology. 1999;117:167-172. Banales JM, et al. Hepatology. 2012;56:687-697.

Boyer JL. Mechanisms of bile secretion and hepatic transport. In: Andreoli TE, et al, eds. Physiology of Membrane Disorders. 2nd ed. New York: Plenum Publ Corp; 1986:609-636.

Bile Formation in Mice and Men

Contribution to bile formation

Mouse Human0

20

40

60

80

100

Species

appr

ox. c

ontr

ibut

ion

tobi

le fo

rmat

ion

%

Hepatocytes Hepatocytes

%

Cholangio- cytes

(HCO3

-)

Source of bile

Carey MC. Physical-chemical properties of bile acids and their salts. In: Danielsson H, Slövall J, eds. Sterols and Bile Acids. Amsterdam, The Netherlands: Elsevier; 1985:345-403.




Mouse Human0

20

40

60

80

100

Species

appr

ox. c

ontr

ibut

ion

tobi

le fo

rmat

ion

%

Cholangio- cytes

(HCO3

-)


Source of bile

%

Bile composition

Mouse Human0

20

40

60

80

100

Species

appr

ox. c

onju

gatio

n of

bile

aci

ds %

Glycine conjugates

Taurine conjugates

Taurine conjugates

Bile salt composition

%



Mouse Human0

20

40

60

80

100

Species

appr

ox. c

ontr

ibut

ion

tobi

le fo

rmat

ion

%

Cholangio- cytes

(HCO3

-)


Bile composition

Mouse Human0

20

40

60

80

100

Species

appr

ox. c

onju

gatio

n of

bile

aci

ds %

Glycine conjugates

Taurine conjugates

Taurine conjugates

pKa > 4

pKa 1-2

Bile salt composition Source of bile

%

%

Carey MC. Physical-chemical properties of bile acids and their salts. In: Danielsson H, Slövall J, eds. Sterols and Bile Acids. Amsterdam, The Netherlands: Elsevier; 1985:345-403.


OH HO

COOH

OH HO

COO- HCO3

- H2CO3

•  Glycochenodeoxycholic acid induces mucosal injury in mouse gastric mucosa at pH 1 and 3, but not pH 5

Chenodeoxycholic acid Chenodeoxycholate

pKa and pH Determine Protonation, Polarity and Toxicity of Bile Acids

Eastwood GL. Gastroenterology 1975;68:1456-1465. Slide courtesy of Dr. Ulrich Beuers.

Bile Acids, but Not Bile Salts, Invade Cholangiocytes at Low pH

OH HO

COOH

OH HO

COO- HCO3

- H2CO3

Calculated protonation rate of bile salts GCDCA in human H69 cholangiocytes With permission from Hohenester S, et al. Hepatology. 2012;55:173-183. Top graphic courtesy of Dr. Ulrich Beuers.

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is

F ibros ing / scleros ing cholangitis

C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

The Cholangiocyte Secretes HCO3- Upon Various Stimuli

Minagawa N, et al. Gastroenterology. 2007;133:1592-1602.

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

Hypothesis: The Biliary HCO3- Umbrella

Bile

Apoptosis

Fibrosing cholangiopathy

Beuers U, et al. Hepatology. 2010;52:1489-1496. Hohenester S, et al. Hepatology. 2012;55:173-183.

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

Defect of the Biliary HCO3- Umbrella in PBC ?

Bile

Apoptosis


PBC

Poupon R, et al. J Hepatol. 2008;49:1038-1045.

Prieto J, et al. Gastroenterology. 1993;105:572-578. Medina JF, et al. Hepatology. 1997;25:12-17. Prieto J, et al. Gastroenterology. 1999;117:167-172. Banales JM, et al. Hepatology. 2012;56:687-697.

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

PDC-E2-like Peptides are Aberrantly Expressed on Apoptotic and Senescent Cholangiocytes

Bile

Apoptosis Senescence


PBC

Lleo A, et al. Hepatology. 2010;52:987-998. Sasaki M, et al. Liver Int. 2013;33:312-320. van de Graaf S, Beuers U. Liver Int. 2014;34:481-483.

PDC-E2

Primary Biliary Cirrhosis


?


injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure

Pathogenesis

Beuers U, et al. Hepatology. 1998;28:1449-1453. European Association for the Study of the Liver. J Hepatol. 2009;51:237-267.

Primary Biliary Cirrhosis: Therapy


injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure

Ursodeoxycholic acid (13-15 mg/kg/d)

Pathogenesis

Effect of UDCA on Survival in PBC “Paris I Criteria”

•  10-year survival without transplantation, according to 1-year biochemical response to UDCA: –  Responders (n=179): 90% (95% CI: 81% to 95%) –  Nonresponders (n=113): 51% (95% CI: 38% to 64%) –  p<0.0001; RR, 0.4; 95% CI: 0.3-0.5

Paris I Criteria

• Bilirubin: ≤1 mg/dL • ALP: ≤3 x ULN • AST: ≤2 x ULN

Corpechot C, et al. Hepatology. 2008;48:871-877.

Beuers U, et al. Hepatology. 2010;52:1489-1496. Hohenester S, et al. Hepatology. 2012;55:173-183.

Apoptosis Necrosis

Stimulation of cholangiocellular

secretion

Stimulation of hepatocellular

secretion

Bile acids

Reduction of bile toxicity

Potential Mechanisms and Sites of Action of UDCA in Cholestatic Liver Diseases

Antiapoptotic effects

Biliary HCO3- umbrella

With permission from Beuers U. Nat Clin Pract Gastroenterol Hepatol. 2006;3:318-328.

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

Medina JF, et al. Hepatology. 1997;25:12-17. Prieto J, et al. Gastroenterology. 1999;117:167-172.

UDCA Stimulates Impaired HCO3- Secretion in PBC

Bile

UDCA



Beuers U, et al. Hepatology. 1998;28:1449-1453. European Association for the Study of the Liver. J Hepatol. 2009;51:237-267.

Primary Biliary Cirrhosis: Therapy


injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure


Liver transplantation

Pathogenesis


Primary Biliary Cirrhosis: Future Therapy


injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure



RCT (Phase 3)

Budesonide ?

Pathogenesis

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

Combined UDCA and Glucocorticoids Upregulate an Alternate AE2 Promoter in Human Liver Cells

Bile

Arenas F, et al. J Clin Invest. 2008;118:695-709.

UDCA + Gluco- corticoid






injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure



RCT (Phase 3)

Budesonide? norUDCA?

Pathogenesis

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

NorUDCA is a Potent HCO3- Secretagogue in Man and Rodents

Bile

norUDCA



Hofmann AF, et al. Hepatology. 2005;42:1391-1398. Fickert P, et al. Gastroenterology. 2006;130:465-481. Halibasic E, et al. Hepatology. 2009;49:1972-1981. Denk GU, et al. Hepatology. 2010;52:1758-1768.




injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure



RCT (Phase 3)


Nuclear receptor agonists? - FXR: obeticholic acid?

RCT (Phase 3)

Pathogenesis

The Farnesoid X Receptor (FXR) Protects Against Toxic Effects of Hydrophobic Bile Acids

MRP2 MDR3

BSEP NTCP

OATP

CFTR

Bile acids

Org. anions

Phospholipids

HCO3

CI CI

FIC1 Aminophospholipids

ABCG5/G8 Cholesterol

FXR

CYP7A1

FXR HCO3-

CA

BSEP: ABCB11 MRP2: ABCC2 MDR3: ABCB4 FIC1: ATP8B1 CA, Carboanhydrase

For details, see: Baghdasaryan A, et al. Mol Asp Med. 2014: epub.

OST α/β

SULT2E1

CYP3A4

UGT2B4

Slide courtesy of Dr. Ulrich Beuers.

The Farnesoid X Receptor (FXR) Protects Against Toxic Effects of Hydrophobic Bile Acids

MRP2 MDR3

BSEP NTCP

OATP

CFTR

Bile acids

Org. anions

Phospholipids

HCO3

CI CI

FIC1 Aminophospholipids

ABCG5/G8 Cholesterol

FXR

CYP7A1

FXR HCO3-

CA

BSEP: ABCB11 MRP2: ABCC2 MDR3: ABCB4 FIC1: ATP8B1 CA, Carboanhydrase

OST α/β

SULT2E1

CYP3A4

UGT2B4

For details, see: Baghdasaryan A, et al. Mol Asp Med. 2014: epub.

Slide courtesy of Dr. Ulrich Beuers.

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

FXR Agonists Stimulate Biliary HCO3- Secretion in Rodents

Bile

FXR agonist



Baghdasaryan A, et al. Hepatology. 2011; 54:1303-1312. Baghdasaryan A, et al. Mol Asp Med. 2014: epub

FXR




injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure



RCT (Phase 3)


Nuclear receptor agonists? -  FXR: obeticholic acid? -  PPARα: beza-, fenofibrate?

RCT (Phase 3)

RCT (Phase 3)

Pathogenesis

HC O3-‐

C l-‐

CFTR

CaCl

C l-‐ C l-‐

S ecretinAC h

ATP

ATP

P2Y AE2

InsP 3

InsP 3 E R

C a++

cAMP

TGR-5

+

C a++

+

P2Y

ATP

C l-‐

C l-‐C l-‐

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is


C DC A

B ile

C holang ioc yte

HCO3-‐

H2O + C O2

+ H+

S R

C A

FXR Agonists Stimulate Biliary HCO3- Secretion in Rodents

Bile

PPARα agonist



Phospholipids Mixed micel formation

Ghonem A, et al. Hepatology. 2014;59:1030-1042.




injury



bile acids

Cholestasis with


liver

Liver cell damage,


Liver failure



RCT (Phase 3)


Nuclear receptor agonists? -  FXR: obeticholic acid? -  PPARα: beza-, fenofibrate?

RCT (Phase 3)

RCT (Phase 3)

Pathogenesis


Sex (f:m) 9 : 1 Age 40 - 60 Survival without treatm. 7.5-16 years Cholestatic enzyme pattern AP, γGT



Symptoms: •  Fatigue •  Itch •  “Dry eye, dry mouth“ •  …

Courtesy of Ulrich H.W. Beuers, MD.

Molecular size: <3 kD

Amphiphilic upon protonation: hydrophobicity ↑

No peptide G-protein coupled receptor

Lysophosphatidic acid (LPA)

Kremer AE, et al. Gastroenterology. 2010;139:1008-1018.

Identification of a Neuronal Activator in Serum of Pruritic Patients

*

SMB1

SMB2

*Ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2). Abbreviations: LPC, lysophosphatidylcholine; SMB1, somatomedin B1; SMB2, somatomedin B2. With permission from Nishimasu H, et al. Trends Pharmacol Sci. 2012;33:138-145.

Lysophosphatidic Acid (LPA) is Formed by Autotaxin in Serum

*P <.05. ***P <.001 (ANOVA). With permission from Kremer AE, et al. Hepatology. 2012;56:1391-1400.

Increased Autotaxin (ATX) Activity is Specific for Pruritus of Cholestasis

0

50

100

150

200

beforetherapy(n=18)

aftertherapy(n=18)

p<0.05

Itch

inte

nsity

[%]

0

50

100

150

200

beforetherapy

(n=6)

aftertherapy

(n=6)

p<0.01

Itch

inte

nsity

[%]

0

50

100

150

200

beforetherapy

(n=8)

aftertherapy

(n=8)

p<0.01

Itch

inte

nsity

[%]

0

50

100

150

200

beforetherapy(n=18)

aftertherapy(n=18)

p<0.05

ATX

activ

ity [%

]

0

50

100

150

200

beforetherapy

(n=6)

aftertherapy

(n=6)

p<0.05

ATX

activ

ity [%

]

A B C D

0

50

100

150

200

beforetherapy

(n=8)

aftertherapy

(n=8)

p<0.01

ATX

activ

ity [%

]

Colesevelam-18%

MARS-62%

Nasobiliary Drainage-87%

0

50

100

150

200

beforetherapy

(n=5)

day 3 oftherapy

(n=5)

p<0.005

ATX

activ

ity [%

]

0

50

100

150

200

beforetherapy

(n=5)

day 3 oftherapy

(n=5)

p<0.005

Itch

inte

nsity

[%]

Rifampicin-65%

E F G HColesevelam

-13%MARS-29%

Nasobiliary Drainage-50%

Rifampicin-32%

Itch

Abbreviations: ATX, autotaxin; MARS, molecular absorbance recirculating system. Kremer AE, et al. Hepatology. 2012;56:1391-1400.

Autotaxin Activity Mirrors Therapeutic Efficacy in Pruritus of Cholestasis

-85%

ATX

(n=17) (n=17)

(n=17) (n=17)

Potential Pruritogens in Cholestasis

Accumulate in the systemic circulation

Are secreted into bile

Are (biotrans-)formed in the liver and/or gut

Affect the endogenous serotonergic and

opioidergic system

Autotaxin LPA X

Pruritogens…

Beuers U, et al. Hepatology. 2014. [Epub ahead of print] Slide courtesy of Dr. Ulrich Beuers.

Accumulate in the systemic circulation

Are secreted into bile

Affect the endogenous serotonergic and

opioidergic system

X Rifampicin

Naltrexone Sertraline

Cholestyramine

Nasobiliary drainage

Pruritogens…

Rifampicin Albumin dialysis etc.

Pathogenesis of Pruritus in Cholestasis Targets for Interventional Therapies: Summary

Autotaxin LPA

Are (biotrans-)formed in the liver and/or gut

Beuers U, et al. Hepatology. 2014. [Epub ahead of print] Slide courtesy of Dr. Ulrich Beuers.

Challenges and New Opportunities in the Clinical Management of PBC

David E.J. Jones, MD, PhD Dean of Research and Innovation

Newcastle University Newcastle upon Tyne, United Kingdom

Survival Is Still Significantly Impaired in PBC in the UDCA Era

Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Jones DE, et al. J Hepatol. 2010;53:911-917.

Transplant-free survival of all NE1-25 cohort PBC patients vs case controls

Suboptimal Therapy in PBC—What Are the Potential Causes?

l  Drugs are not as effective as we think they are and/or our biomarkers of response don’t accurately predict real response

l  Effectiveness may not be as universal as we think it is l  Drugs are effective but we aren’t using them optimally l  Drugs are effective but aren’t actually getting to people l  Some combination of the above

Abbreviations: PBC, primary biliary cirrhosis.

Suboptimal Therapy in PBC—What Are the Potential Causes?

l  In UK-PBC national cohort, 20% of PBC patients are not treated with ursodeoxycholic acid (UDCA)

l  Significant percentage of patients are treated with doses in 10- to 12-mg/kg range

l  Some issues with adherence (weight gain, nausea, hair loss?)

l  Simple and consistent message is needed about UDCA

Abbreviations: PBC, primary biliary cirrhosis.

UDCA Is an Effective Therapy in PBC

Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Poupon RE, et al. Gastroenterology. 1997;113:884-890.

Criteria for “Response” to UDCA in PBC

Paris Criteria

•  Bilirubin ≤1 mg/dL + AST ≤2 x ULN +ALP ≤3 x ULN after 12/12 UDCA at 13-15 mg/kg

•  Responder: 96% survival vs 99% control population at 5 years

•  Nonresponder: 69% survival vs 68% Mayo Predicted Survival

•  ALP decrease by 40% or normalized After 12/12 UDCA at 13-15 mg/kg

Barcelona Criteria

Issues

•  Reciprocity •  “Virtual” controls (the 65-year-old woman paradox) •  Generalizability •  Dichotomizes a continuous variable

Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Corpechot C, et al. Hepatology. 2008;48:871-877.

Criteria for “Response” to UDCA in PBC Early-Stage Patients

70

10 11

76

8 20

53

5 16

86

1

18

71

7 17

0

20

40

60

80

100

Rate of biochemical response

Adverse outcome in responders

Adverse outcome in nonresponders

Barcelona Paris I Paris II Rotterdam Toronto

Patie

nts (

%)

•  Early stage defined as normal albumin and bilirubin •  Paris II criteria: ALT and ALP ≤1.5 x ULN after medical therapy

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; NS, not significant; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Corpechot C, et al. J Hepatol. 2011;55:1361-1367.

P = NS for Barcelona, Paris I, Rotterdam, and Toronto; P <.05 for Paris II.

Criteria Chi-‐square statistic P-‐valueBarcelona 7.3 6.73E-‐03Paris I 106 <1E-‐16Toronto 24.2 8.78E-‐07Paris II 45.7 1.40E-‐11

RESULTS: Log-‐rank test for time free from LT for PBC, PBC-‐related death or Bilirubin ≥ 100µmol/L

Abbreviations: LT, liver transplant; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Carbone M, et al. Gastroenterology. 2013;144:560-569.e7.

UDCA-Response Criteria in the UK-PBC Patient Cohort—Independent Validation

Responders Nonresponders

Factors Predicting Outcome in PBC in the UK-PBC Patient Cohort

Mul%variate %me-‐to-‐event analysis (baseline variables only) Variable Es%mate SE HR L95 U95 P Baseline Sodium -‐0.086 0.035 0.918 0.857 0.983 0.014 Crea7nine -‐0.0158 0.005 0.984 0.975 0.994 0.001 LN Bilirubin 1.407 0.15 4.085 3.046 5.477 <2e-‐16 LN (AST or ALT ra7o) -‐0.53 0.164 0.588 0.427 0.811 0.001 LN ALP 0.477 0.152 1.611 1.195 2.172 0.002 Platelets -‐0.004 0.002 0.996 0.993 0.999 0.006

Mul%variate %me-‐to-‐event analysis (including "Paris I response" at 12 months) Variable Es%mate SE HR L95 U95 P Baseline Sodium -‐0.076 0.031 0.927 0.871 0.986 0.016 LN Bilirubin 1.157 0.139 3.181 2.423 4.177 <2e-‐16 LN (AST or ALT ra7o) -‐0.455 0.165 0.634 0.459 0.877 0.006 Platelets -‐0.003 0.001 0.997 0.994 0.999 0.020 12 months Treatment failure 2.124 0.308 8.361 4.574 15.278 5.10E-‐12

Cox Proportionate Hazards Model: Time-to-Event Analysis

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HR, hazard ratio; LN, natural log; PBC, primary biliary cirrhosis; SE, standard error. Carbone M, et al. J Hepatol. 2013;58:S43-S44. Abstract 99. Slide courtesy of David E. J. Jones, MD, PhD.

Just How Effective Is UDCA in PBC? The Conventional Model

l  79.7% of UDCA-treated patients are UDCA-

responsive (Paris I) l  797 beneficiaries per 1000 patients in UK-PBC

cohort l  UDCA is highly effective!

BUT l  Significant proportion of patients meet response

criteria before therapy is commenced

Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.

Just How Effective Is UDCA in PBC?

80% 20%

74%

80%

1000 patients

800 UDCA-treated 200 UDCA-untreated

640 responders 160 nonresponders

20%

474 “respond” without therapy 166 true responders

UDCA has a beneficial effect in 166/1000 patients with PBC in the UK-PBC cohort For every 100 genuine responders, there are 96 genuine nonresponders

Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Slide courtesy of David Jones, MD.

Treatment Failure in the UK-PBC Patient Cohort

>50% of patients in the UK-PBC patient cohort who presented before the age of 50 have failed primary therapy (in a state of UDCA nonresponse or already transplanted) by the time of study

Abbreviation: UDCA, ursodeoxycholic acid. With permission from Pells G, et al. J Hepatol. 2013;59:67-73.

Potential Mechanisms for UDCA Nonresponse in PBC and Possible Options for Therapeutic Advance

l  Different severity or nature of immune response –  Targeted immunosuppression (biologics)

l  Different bile pool/microbiota –  “Second-line” bile acid therapies

l  Different biliary epithelial response –  Biliary epithelial protectant agents

l  Pre-existing fibrosis/cirrhosis –  Earlier diagnosis allowing treatment window for UDCA! –  Antifibrotics


Challenges for Trial Design for Second-Line Therapy in PBC

•  Definition of the “at-risk” population requiring second-line therapy

•  Outcome measures (do UDCA response criteria apply to other therapies?)

•  Lack of relevant biomarkers •  Impossibility of carrying out a hard endpoints trial due to

prolonged disease •  Difficulty in performing a histology-based trial (acceptability

and lack of scoring systems)


Drugs Under Evaluation for PBC

l  Rituximab (B-cell depletion) l  Fibrates (PPAR-α agonists) l  Obeticholic acid (6-ethyl chenodeoxycholic acid,

FXR agonist) l  Nor-ursodeoxycholic acid (bicarbonate “umbrella,”

anti-inflammatory, anti-fibrotic)

Abbreviations: FXR, farnesoid X receptor; PBC, primary biliary cirrhosis; PPAR, peroxisome proliferator-activated receptor.

Biochemical Effects of Rituximab in Patients with PBC and an Incomplete Response to UDCA

l  Open-label study of rituximab treatment in patients with PBC and incomplete responses to UDCA (n = 6)

l  Rituximab was well tolerated and associated with reductions in serum immunoglobulins (IgA; IgM) and antimitochondrial antibodies

l  Significant reductions in serum ALP levels were observed up to 36 weeks following rituximab treatment

Abbreviations: ALP, alkaline phosphatase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Tsuda M, et al. Hepatology. 2012;55:512-521.

Fenofibrate Improves Liver Biochemistry Values in PBC Patients

l  Peroxisome proliferator-activated receptor (PPAR)-α agonist, fibric acid derivative

l  PPAR-α activity –  Regulation of bile acid synthesis and detoxification –  Modulates phospholipid secretion, which helps protect bile duct

epithelium by formation of micelles l  Open-label study to evaluate efficacy and safety of fenofibrate in

patients with PBC and incomplete response to UDCA (n = 20) l  ALP levels decreased significantly; rebound in ALP levels occurred

following fenofibrate discontinuation l  Contraindicated in patients with hepatic or severe renal disfunction,

including PBC Abbreviations: ALP, alkaline phosphatase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Levy C, et al. Hepatology. 2009;50(suppl 4):995A-996A. Zollner G, Trauner M. Br J Pharmacol. 2009;156:7-27. Tricor PI. 2010. Abbott Laboratories.

FXR-Agonism as a Therapeutic Option in PBC—Properties of Obeticholic Acid

Shared Properties with Ursodeoxycholic Acid (UDCA) l  Choleresis l  Antiapoptosis l  Antioxidant

Additional Direct Properties l  Induced bile acid detoxification l  Induced bile acid conjugation l  Suppressed bile acid synthesis l  Modified bile acid transport

Additional Indirect Properties (via GI release of FGF-19) l  Suppressed bile acid synthesis

Could “UDCA nonresponse” addressed by OCA be a manifestation of indirect actions?

Abbreviations: FCF-19, fibroblast growth factor 19; FXR, farnesoid X receptor; GI, gastrointestinal; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.

FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)

Phase II Data in PBC Patients on Stable UDCA

*Primary efficacy endpoint was percent change in plasma ALP from pretreatment values; patients with a placebo-subtracted ALP reduction of ≥10% were defined as responders. Abbreviations: ET, end of treatment; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.

Patie

nts R

espo

ndin

g (%

)

Day 85/ET

Placebo 10 mg 50 mg0

20

40

60

80

10 mg50 mg

Placebo

p <0.0001 p = 0.0017

0%

70%

44%

Dose

% S

ubjec

ts

Placebo OCA 10 mg OCA 50 mg

OCA 50 mg

OCA 10 mg

Patie

nts R

espo

ndin

g (%

)*


Phase II Data

Abbreviations: ET, end of treatment; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.

Placebo 10mg 50mg0

10

20

30

40

50

Placebo10mg50mg

%Pa

tient

s With

draw

ing

D

ue to

Pru

ritu

s (%

)

Placebo OCA 10 mg OCA 50 mg

OCA 50 mg OCA 10 mg


Phase III (POISE)

M9 Screening

1 to 8 weeks

Entry ALP ≥1.67 x ULN

and/or bilirubin > ULN

but <2 x ULN

N = 216

Positive Response •  ALP <1.67 x ULN and bilirubin WNL,

and ≥15% ALP reduction

Continue pre-study UDCA

All Patients (N = 180) Long-term Safety Extension

5 years OCA Rx OCA 10 mg

Placebo

12 Months M12

& LTSE Visit 1

M6 W2 0

OCA 5 mg OCA 10 mg

M3

Abbreviations: ALP, alkaline phosphatase; FXR, farnesoid X receptor; LTSE, long-term safety extension; OCA, obeticholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; WNL, within normal limits. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.

*P <.0001 vs placebo; P-values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factor. Abbreviations: ALP, alkaline phosphatase; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis; ULN, upper limit of normal. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.


Phase III Data (POISE)

R e s p o n d e rs (% )

0

2 0

4 0

6 0P la c e b o (n = 7 3 )

T it ra te d O C A (n = 7 0 )

1 0 m g O C A (n = 7 3 )

1 2 m o n th s6 m o n th s

*

***

Primary Endpoint: Proportion of subjects achieving ALP <1.67 x ULN with bilirubin ≤ ULN

and ≥15% reduction in ALP



Time (months)

LS M

ean

(SE)

Δ in

ALP

(U/L

)fro

m B

asel

ine

-200

-150

-100

-50

0 Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)

0 6 12

P <.0001 vs placebo for all post baseline values of titrated OCA and 10 mg OCA groups. Abbreviations: ALP, alkaline phosphatase; FXR, farnesoid X receptor; LS, least squares; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.



Time (months)

LS M

ean

(SE)

Δ in

ALT

(U/L

)fro

m b

asel

ine

-40

-30

-20

-10

0 Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)

0 6 12

P <.0001 vs placebo for all post baseline values of titrated OCA and 10 mg OCA groups. Abbreviations: ALT, alanine aminotransferase; FXR, farnesoid X receptor; LS, least squares; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.



Time (months)

LS M

ean

(SE)

Δ in

Dire

ct B

ilirub

in( µ

mol

/L) f

rom

Bas

elin

e

-2

-1

0

1

2

3Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)

0 6 12

*

*

*

* *

**

*

*P <.05 vs placebo. Abbreviations: FXR, farnesoid X receptor; LS, least squares; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.



Placebo (n=73)

Titrated OCA (n=70)

10 mg OCA (n=73)

D/C due to pruritus, n (%) 0 1 (1%) 7 (10%) TEAEs without pruritus, n (%) 66 (90%) 62 (89%) 63 (86%) TEAE pruritus, n (%) 28 (38%) 39 (56%) 50 (68%) SAEs, n (%) 3 (4%) 11 (16%) 8 (11%)

Abbreviations: D/C, discontinuation; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SAE, serious adverse event; TEAE, treatment-emergent adverse effect. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.

*p<0.05 vs placebo for LS mean change VAS score range: 0= no pruritus, 100= severe pruritus

T im e (m o n th s )

S c o re (m m )

0

1 0

2 0

3 0

4 04 0

1 0 0

P la c e b o (n = 7 3 )

0 6 1 2

T itra te d O C A (n = 7 0 )1 0 m g O C A (n = 7 3 )

* **

Pruritus Visual Analog Scale Score

Cholestyramine Placebo: 11% Titration OCA: 19% 10 mg OCA: 26%



Time (months)

Mea

n (S

E) L

DL C

hole

ster

ol(m

mol

/L)

3.0

3.2

3.4

3.6

3.8

4.0Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)

0 6 12

Abbreviations: FXR, farnesoid X receptor; OCA, obeticholic acid; LDL, low density lipoprotein; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.



Time (months)

Mea

n (S

E) H

DL C

hole

ster

ol(m

mol

/L)

1.0

1.5

2.0

2.5Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)

0 6 12

Abbreviations: FXR, farnesoid X receptor; HDL, high density lipoprotein; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.

Clinician Awareness Is a Challenge for Effective Therapy in PBC

Abbreviations: gastro, gastroenterologist; hep, hepatologist; PBC, primary biliary cirrhosis Bodenheimer HC, et al. J Hepatol. 2014:60(suppl): Abstract P399. Slide courtesy of David E. J. Jones, MD, PhD.

80

65

0

20

40

60

80

100

Heps Gastros

Competence: “Highly Competent”

Early Diagnosis/Treatment

88 87

Heps Gastros

Early Diagnosis

Practice Performance: “Always/Often”

76 65

Heps Gastros

Early Treatment

Res

pond

ers (

%)

Clinician Competence in and Use of Response Criteria for Assessing Treatment Response

in PBC


76

42

0

20

40

60

80

100

Heps Gastros

Practice Performance: “Always/Often”

36 30

0

20

40

60

80

100

Heps Gastros


Res

pond

ers (

%)

Effect of Untreated or Suboptimally Treated PBC on Disease Progression/Mortality


74

55 64

38

0

20

40

60

80

100

Heps Gastros Heps Gastros


Effect on Disease Progression

Res

pond

ers (

%)

Causes of Suboptimal Treatment

Overall Health Status and Quality of Life Are Also Impaired in PBC, UK-PBC

Cohort Data (n = 2300)

l  35% of primary biliary cirrhosis (PBC) patients report perceived QOL impairment vs 6% of healthy controls (P <.0001)

l  46% of PBC patients rated their perceived health status as fair or poor vs 15% of healthy controls (P <.0001)

l  In terms of change over time, 49% of PBC patients reported their health as worse compared with the previous year vs 14% of healthy controls (P <.0001)

Mells GF, et al. Hepatology. 2013;58:273-283.

Individual Symptom Domain Impacts UK-PBC Cohort Data (n = 2300)

Con PBC11

22

33

44

55p<0.0001

45%

PBC-

40 F

atig

ue D

omai

n

With permission from Mells GF, et al. Hepatology. 2013;58:273-283.

Individual Symptom Domain Impacts UK-PBC Cohort Data (n = 2300)

l  Fatigue is important symptom with significant impact on patient –  Fatigue had its greatest impact on perceived QOL when

accompanied by symptoms of social dysfunction

–  89% of patients with severe fatigue and poor QOL had symptoms of impaired social function compared with 11% of patients with severe fatigue and no QOL impairment (P <.0001)

l  Critical issue is how patients adapt and cope with fatigue as this will ultimately affect impact of fatigue on QOL

l  Disease management should ultimately target both the underlying biology of the disease as well as symptoms

Mells GF, et al. Hepatology. 2013;58:273-283.

Reaching the Goal—What We Need to do to Improve PBC Care

l  Improve community, patient, and first responder awareness of the disease and its presentations

l  Improve physician awareness of the need for therapy with UDCA and assessment of response

l  Systematic approach to management with triage built in for high-risk/nonresponding patients

l  Systematic approach to the evaluation of second-line therapy and implementation into stratified management pathways

l  Improved awareness of, assessment of, and treatment of symptoms in PBC using systematic approaches

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