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Gastrointestinal Drugs Advisory Committee MeetingApril 7, 2016
Obeticholic Acid (OCA)
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Kris Kowdley MD, FACP, FAASLDDirector, Liver Care Network and Organ Care ResearchSwedish Medical CenterSeattle, WA
PBC: Diagnosis, Natural History and Role of Current Therapy
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Outline Epidemiology Diagnosis Associated conditions Natural history UDCA Treatment
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PBC Newly Named Primary Biliary Cirrhosis renamed to Primary Biliary
Cholangitis Reflects earlier diagnosis: majority of patients without
cirrhosis Name change endorsed by patient groups, physicians
and societies (AASLD, EASL)
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Causes and Markers of PBC Autoimmune disease thought to be due to a
combination of genetic predisposition and environmental triggers
Lymphocytic inflammation targeting intrahepatic bile ducts
Serologic hallmark of PBC is the AMA, a highly disease-specific autoantibody found in 90-95% of patients and less than 1% of healthy blood donors
Serum biochemical tests show a cholestatic patternAlkaline Phosphatase >> ALT/ASTElevated serum bilirubin in late stage
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Features of PBC Chronic cholestatic disease with a progressive
course which may extend over many decades Rate of progression varies greatly Asymptomatic in early disease Often leads to fatigue, pruritus Concomitant autoimmune diseases Affects about 1/1000 women age >40 years Is an important indication for liver transplantation
in this population
Kumagi T, Heathcote EJ. Orphanet J Rare Dis. 2008;3:1.
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PBC Prevalence
Prevalence rates for the NetherlandsBoonstra K, Kunst A, Stadhouders P, et al. Rising Incidence and Prevalence of Primary Biliary Cirrhosis: A Large Population-base Study. Liver International. 2014;34:e35.
2000 2001 2002 2003 2004 2005 2006 2007 2008Year
Per 1
00,0
00 In
habi
tant
s
0
5
10
15
20
25WomenMen
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Global Temporal Trends in PBC Prevalence
Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review. Journal of Hepatology. 2012; 56(5): 1181-1188.
Prev
alen
ce P
er 1
00,0
00 In
habi
tant
s
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Year
0
10
20
30
40ErikssonMyszorRemmelJamesMetcalfBobergPlaMyers
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PBC Incidence
2000 2001 2002 2003 2004 2005 2006 2007Year
Inci
denc
e pe
r 100
,000
0.0
0.5
1.0
1.5
2.0
3.0WomenMen
2.5
Prevalence rates for the NetherlandsBoonstra K, Kunst A, Stadhouders P, et al. Rising Incidence and Prevalence of Primary Biliary Cirrhosis: A Large Population-base Study. Liver International. 2014;34:e35.
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Author, Year Study Period Country ES (95% CI) Weight
Predominant Recruitment Before 1990
Remmel, 1995 1976-1992 Estonia 0.23 (-0.30, 0.76) 7.13
Sevenet, 1986 1975-1984 France 0.26 (0.17, 0.35) 7.56
Danielsson. 1990 1973-1982 Sweden 1.33 (1.04, 1.62) 7.44
Lofgren, 1985 1976-1983 Sweden 1.40 (0.75, 2.05) 6.93
Myszor, 1990 1965-1987 United Kingdom 1.98 (1.37, 2.59) 7.00
Hamlyn, 1983 1972-1977 United Kingdom 1.00 (0.81, 1.19) 7.52
Triger, 1980 1977-1979 United Kingdom 0.58 (0.21, 0.95) 7.35
Kim, 2000 1975-1995 United States 2.70 (1.92, 3.48) 6.67
Subtotal (I-squared=95.1%, p=0.000) 1.12 (0.65, 1.59) 57.60
Predominant Recruitment After 1990
Myers, 2009 1996-2002 Canada 3.03 (2.52, 3.54) 7.16
Rautiainen, 2007 1988-1999 Finland 1.70 (1.23, 2.17) 7.22
Ngu, 2008 2008 New Zealand 0.80 (0.02, 1.58) 6.67
Pla, 2007 1990-2002 Spain 1.72 (1.37, 2.07) 7.37
James, 1999 1987-1994 United Kingdom 2.86 (2.61, 3.11) 7.47
Metcalf, 1997 1987-1994 United Kingdom 4.30 (3.44, 5.16) 6.50
Subtotal (I-squared=93.4%, p=0.000) 2.38 (1.66, 3.11) 42.40
Overall (I-squared=97.9%, p=0.000) 1.68 (1.10, 2.26) 100.00
Incidence of Primary Biliary Cirrhosis: Systematic Review and Meta-analysis
Mathivanan et al: Hepatology 2012; 56 (supplement S1):1140A-2 -1 0 1 2 3 4 5 6
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Incidence and Prevalence of PBC: Olmstead County, MN
Age-adjusted (1990 US whites) incidence/100,00: 2.71975-1995: women: 4.5 (3.1-5.9), men 0.7 (0.1-1.3)
Age and sex-adjusted prevalence (as of 1995): 40.265.4 (43-87.9) women, 12.1 (1.1-23.1) men
Kim Gastroenterology 2000;119:1631-1636Age Group
80+70-7960-6950-5940-4930-3920-290
2
4
6
8
10
12
14
16
18
Inci
denc
e (p
er 1
00,0
00 P
erso
n-Ye
ars)
Female Male
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PBC is a Chronic, Progressive Autoimmune Disease
Factors possibly associated with onset and perpetuation of bile-duct injury in PBC
Poupon R. J Hepatol. 2010;52(5):745-758. Selmi C, et al. Lancet. 2011;377(9777):1600-1609.Carey EJ, et al. Lancet. 2015;386(10003):1565-1575.
PBC is characterized by destruction of the interlobular and septal bile ducts that may lead to cirrhosis
Immune response
Bile duct damage
Environment
Genetics
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Concomitant Autoimmune Disease in Women with PBC
Carey EJ, Ali AH, Lindor KD. Primary Biliary Cirrhosis. The Lancet. 2015 Oct.; 386(10003):1565-1575.
Frequency (%)Sjögren’s syndrome 7-34
Raynaud’s syndrome 9-13
Hashimoto’s thyroiditis 11-13
Rheumatoid arthritis 3-8
Psoriasis 6
Scleroderma or CREST 1-2
Inflammatory bowel disease 1
Any autoimmune disease 33-55CREST (calcinosis, Raynaud phenomenon, esophogeal dymotilitly, sclerodactyly, and telangiectasia syndrome) is a limited type of scleroderma.
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Clinical Features Vary Greatly Between Patients
Fatigue1,2
Pruritus1,2
Concurrent autoimmune diseases1,2
Reduced bone density1,2
Hypercholesterolemia1,2
PBC can range from asymptomatic and slowly progressive to symptomatic and rapidly evolving.1
1Selmi C, et al. Lancet. 2011;377(9777):1600-1609.2Carey EJ, et al. Lancet. 2015;386(10003):1565-1575.
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Pruritus Is Common Among PBC Patients
Prevalence reported as high as 69%1
Unknown etiology1,2
Bile salts, endogenous opioids, histamine, serotonin, progesterone/ estrogen, and autotaxin/lysophosphatidic acid are suspected pruritogens2
Diurnal variation – most intense itch in the late evening2
Localization reported at limbs – soles of feet, palms of hands2
Exacerbated by pregnancy or contact with wool/heat3
1. Imam MH, et al. J Gastroenterol Hepatol. 2012;27(7):1150-1158.2. Beuers U, et al. Hepatology. 2014;60(1):399-407. 3. Lindor KD, et al. Hepatology. 2009;50(1):291-308.
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Numerous Treatment Options Exist to Help Patients Manage Their Pruritus
General Recommendations1
Skin moisturizerWet, cooling, or moist wrapsTopical agents with symptomatic relief (eg, camphor, menthol)Relaxation techniquesTraining to stop the cycle of itch, scratch, itch
First-line2-4Bile acid sequestrants• Cholestyramine• Colestipol, colesevelam
The following agents may be used for pruritus that is refractory to bile acid sequestrantsSecond-line2-4 Rifampicin
Third-line2-4Oral opioid antagonists• Naltrexone • Nalmefene
Fourth-line2-4 Selective serotonin reuptake inhibitors:• Sertraline
1. Weisshaar E, et al. Acta Derm Venereol. 2012;92(5):563-581. European Association for the Study of the Liver. J Hepatol. 2009;51(2):237-267.
2. Lindor KD, et al. Hepatology. 2009;50(1):291-308. 4. Hohenester S, et al. Semin Immunopathol. 2009;31(3):283-3
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Bile duct
Inflammation
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Diagnosis of PBC: Is Biopsy Needed? If:AMA
ALP >1.5x ULN
AST <5x ULN
Then:Positive predictive value for PBC >98%
‒ Sensitivity 80%, specificity 92%
Zein CO, Angulo P, Lindor K. When is liver biopsy needed in the diagnosis of primary biliary cirrhosis? Clin Gastro and Hepatol 2003;1(2):89-95
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PBC Disease Progression: Preclinical Stage
DecompensatedManifestAsymptomaticPreclinical
Intact bile ductsCholestasis
Disease Progression by Stage1,2
Graphic adapted from Selmi C, et al. Lancet. 2011;377(9777):1600-1609.1. Selmi C, et al. Lancet. 2011;377(9777):1600-1609.2. Silveira MG, et al. Hepatology. 2010;52(1):349-359.
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PBC Disease Progression: Asymptomatic Stage
DecompensatedManifestAsymptomaticPreclinical
Intact bile ductsCholestasis
Disease Progression by Stage1,2
Graphic adapted from Selmi C, et al. Lancet. 2011;377(9777):1600-1609.1. Selmi C, et al. Lancet. 2011;377(9777):1600-1609.2. Silveira MG, et al. Hepatology. 2010;52(1):349-359.
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PBC Disease Progression: Manifest Stage
DecompensatedManifestAsymptomaticPreclinical
Intact bile ductsCholestasis
Disease Progression by Stage1,2
Graphic adapted from Selmi C, et al. Lancet. 2011;377(9777):1600-1609.1. Selmi C, et al. Lancet. 2011;377(9777):1600-1609.2. Silveira MG, et al. Hepatology. 2010;52(1):349-359.
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PBC Disease Progression: Decompensated Stage
Without intervention A substantial number of patients progress to liver failure, transplant, or
death within 10 years2
DecompensatedManifestAsymptomaticPreclinical
Intact bile ductsCholestasis
Disease Progression by Stage1,2
Graphic adapted from Selmi C, et al. Lancet. 2011;377(9777):1600-1609.1. Selmi C, et al. Lancet. 2011;377(9777):1600-1609.2. Silveira MG, et al. Hepatology. 2010;52(1):349-359.
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Many Patients With PBC Also Suffer from Cholestasis-and/or Cirrhosis-Associated Complications
1Carey EJ, et al. Lancet. 2015;386(10003):1565-1575.2Lindor KD, et al. Hepatology. 2009;50(1):291-308.
% of Patients AffectedComplications of chronic cholestasis1
Osteoporosis 20%-44%
Hyperlipidemia 75%-95%
Vitamin deficiency 8%-33%
Complications related to cirrhosis
Varices associated with portal hypertension
6% (with early-stage disease)1
~31%(with late-stage disease)2
Hepatocellular carcinoma 1%-6% of patients per year1
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Hepatocellular Carcinoma in PBC:Global PBC Study Group
Time (0) is time of diagnosis or initiation of UDCATrivedi P, Lammers W, van Buuren, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2015; 0:1-9
Patients at Risk 4565 2917 1482 577 135
20
15
10
5
00 5 10 15 20
Cum
ulat
ive
HC
C In
cide
nce
(%)
Time (Years)
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Long-term Monitoring of Patients with PBC (AASLD Guidelines)
Liver tests every 3-6 months
Thyroid status (TSH) annually
Bone mineral densitometry every 2-4 years
Vitamins A, D, K annually if bilirubin >2.0
Upper endoscopy every 1-3 years if cirrhotic or Mayo risk score >4.1
Ultrasound ± AFP every 6 months in patients with known or suspected cirrhosis
Lindor KD, et al. Hepatology. 2009;50(1):291-308.
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Ursodeoxycholic Acid (UDCA) Approved in 1997
Orally administered hydrophilic bile acid
Preferred dose of 13-15 mg/kg/day
Is the only currently FDA approved therapy for PBC
Improvement in liver biochemistry (ALP) seen within a few weeks
90% of the improvement usually occurs within 6-9 months
However, up to 40% of PBC patients treated with UDCA have a suboptimal response
Lindor KD, et al. Hepatology. 2009;50(1):291-308Czul F, Levy C. Clin Liver Dis 2016;(1):113-30Lammers WJ, et al. Gastroenterology. 2014 Dec;147(6):1338-1349
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Medical Approaches to PBC: UDCASurvival Free of Transplantation
Combined Data
* For the “Placebo UDCA” group, patients randomized to placebo in 2 of the 3 pooled studies were treated with placebo for 2 years and then given the option to receive UDCA for an additional 2 years.Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined Analysis of Randomized Controlled Trials of Ursodeoxycholic Acid in Primary Biliary Cirrhosis. Gastroenterology. 1997; 113:884-890
UDCAPlacebo UDCA
273 236 116275 220 87
Prob
abili
ty o
f Sur
viva
l %1.0
0.5
0 24 48Months
UDCA
Placebo UDCA
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Survival in PBC: UDCA
Poupon RE, Bonnand AM, Chretien Y, et al. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology1999; 29(6):1668-1671
Surv
ival
Rat
e (%
)
UDCA Treated vs. Untreated
0 5 10 years
40
60
80
100
Untreated patientsMayo model
Treated patients
UDCA Treated vs. Healthy Control
0 5 10 years
40
60
80
100 French control group
Treated patients
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Current (2009) Treatment Guidelines Vary
AASLD = American Association for the Study of Liver Diseases; AP = Alkaline phosphatase; EASL = European Association for the Study of the Liver.1. Lindor KD, et al. Hepatology. 2009;50(1):291-308.2. European Association for the Study of the Liver. J Hepatol. 2009;51(2):237-267.
AASLD Guidelines (2009)1
• No specific definition or guidance of treatment success• “About 20% of patients will have normalization of liver biochemistries after 2 years and a
further 15% or 35% of the total will have normalization by 5 years. The effect of treatment can be based on response of serum alkaline phosphatase activity or Mayo risk score, which is dependent on age, albumin, bilirubin, prothrombin time, and presence or absence of fluid retention”
EASL Guidelines (2009)2
“Recommendations”:• Favorable long-term effects of UDCA are observed in patients with early disease and in
those with good biochemical response (II-2/B1), which should be assessed after one year. A good biochemical response after one year of UDCA treatment is currently defined by a serum bilirubin ≤1 mg/dL (17 µmol/L), alkaline phosphatase ≤3 x ULN and AST ≤2 x ULN (‘‘Paris criteria”) or by a decrease of 40% or normalization of serum alkalinephosphatase (‘‘Barcelona criteria”) (II-2/B1)
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Response Criteria Models
Rotterdam3
(2009)
Barcelona1
(2006)
Paris-I2(2008)
Toronto4
(2010) Early Biochemical Response6
(2013)Paris-II5(2011)
Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. 1. Parés A, et al. Gastroenterology. 2006;130:715-720. 2. Corpechot C, et al. Hepatology. 2008;48:871-877. 3. Kuiper EM, et al. Gastroenterology. 2009;136:1281-1287. 4. Kumagi T, et al. Am J Gastroenterol. 2010;105:2186-2194. 5Corpechot C. J Hepatol. 2011;55:1361-1367. 2. Zhang LN, et al. Hepatology. 2013;58:264-272.
ALP with or without bilirubin
Albumin and bilirubin
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1. Trivedi PJ, et al. J Hepatol. 2014;60:1249-1258. 2. Carbone M, et al. Hepatology. 2016; 63(3): 697-99. 3. Lammers WJ, et al. Gastroenterology. 2015; 149(7):1804-12
Current Response Criteria Models
Biochemical response (Barcelona, Paris-I/II, or Toronto) and APRI ≤0.54 after 1 year UDCA
Biochemical + APRI1(2014)
Prognostic index comprising baseline albumin and platelet count, plus bilirubin, ALT or AST, and ALP after 1 year UDCA
UK-PBC Risk Score2
(2015)
GLOBE Score3
(2015)
Prognostic index comprising baseline age, and bilirubin, ALP, albumin, and platelet count after 1 year UDCA
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Liver Transplantation for PBC:Trends in the United States
Lee J, Belanger A, Doucette JT, et al. Transplantation Trends in Primary Biliary Cirrhosis. ClinGastroenterol Hepatol 2007;5(11):1313-5
2002
Number of Liver Transplants
0
1000
2000
3000
4000
5000
6000
7000
1995 1996 1997 1998 1999 2000 2001 2003 2004 2005 2006
Year
P<0.001
Num
ber o
f Liv
er T
rans
plan
ts
Liver Transplants for PBC
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Year
50
100
150
200
250
300
350
0
P=0.004
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CC-33Webb, Hepatology. 62(1) Suppl. 2015
PBC Liver Transplant Data for the UK
Year
80
60
40
20
0
Num
ber
Liver Transplants for PBC Performed/Year100
Year
80
60
40
20
0Mea
n A
ge ±
S.D
. (Ye
ars)
Age at Transplantation
Although liver transplants for PBC have decreased, the average age of patients with PBC undergoing liver transplant has not changed
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CC-34
Summary and Conclusions PBC is increasing in prevalence
Substantial impact on quality of life
May progress to end-stage liver disease, HCC
Rates of progression are variable
UDCA has been cornerstone of therapy,
A substantial number of patients have a suboptimal response or intolerance to UDCA
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CI-1
Linda Robertson, PhDIntercept Pharmaceuticals, Inc.Vice President, Regulatory Affairs and Quality Assurance
Introduction
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CI-2
Obeticholic Acid for the Treatment of PBC Obeticholic Acid (OCA)
‒ FXR agonist and modified bile acid PBC
‒ Rare, chronic, serious non-viral liver disease‒ Life-threatening, leading to either death or liver transplantation ‒ Limited therapeutic options
• Ursodeoxycholic (UDCA) acid is the only approved therapy • Need for new therapies, particularly second line therapy
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CI-3
Regulatory Challenges in PBC Inherent challenges with regard to an approvable endpoint Chronic liver disease
‒ Slow and variable rate of disease progression‒ Over 10 year median survival in patients with an inadequate response to UDCA
Symptoms, i.e. pruritus and fatigue do not correlate with clinical outcomes Difficult to determine clinical benefit using conventional clinical outcomes in a timely fashion
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CI-4
Accelerated Approval Serious, life-threatening condition Meaningful advantage over existing therapies Surrogate endpoint “reasonably likely to predict clinical benefit”
‒ Based on the entirety of clinical evidence including correlation with clinical outcomes and relationship to disease pathophysiology Requires confirmatory study underway at the time of filing to confirm clinical benefit
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CI-5
Regulatory History
2006 2007 2008 2009-2013 2014 2015
Orphan Designation
GrantedApr 2008
IND 63,307 Submitted
Jan 2006
Fast Track
GrantedMay 2014
Priority Review GrantedAug 2015
CompletedJun 2015
Rolling NDA
SubmittedDec 2014
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CI-6
Basis of Accelerated Approval One Phase 3 and two Phase 2 safety and efficacy double-blind studies with long-term safety extensions Statistically significant effects on composite biochemical endpoint
‒ ALP change and maintenance of normal bilirubin‒ Shown to be associated with clinical outcomes based on data from independent study groups
Over 1500 subjects exposed to OCA including ~400 patients with PBC for up to 5 years‒ Generally safe and well tolerated
Ongoing Phase 4 confirmatory study‒ Initiated February 2015
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CI-7
Proposed IndicationObeticholic Acid (OCA) is indicated for the treatment of primary biliary cirrhosis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA
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CI-8
Dosing and Administration Recommended starting dose is 5 mg once daily Based on the assessment of efficacy and tolerability after 3 months, the dose should be increased to 10 mg once daily to improve response
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CI-9
AgendaUnmet Need in PBC David Jones, MD FRCP, PhD
Professor of Liver ImmunologyUniversity of NewcastleInstitute of Cellular Medicine Director, UK-PBC Study Group Consortium Program Rationale David Shapiro, MD FRCP
Intercept Pharmaceuticals, Inc.Chief Medical Officer Efficacy of OCA in PBC Leigh MacConell, PhD
Intercept Pharmaceuticals, Inc.Vice President, Clinical DevelopmentSafety of OCA in Patients with PBC Roya Hooshmand-Rad, MD, PhD
Intercept Pharmaceuticals, Inc.Executive Director, Medical Safety and PharmacovigilanceBenefit-Risk John M. Vierling, MD FACP, FAASLD
Baylor College of MedicineProfessor of Medicine and SurgeryChief of Hepatology, Director of Advanced Liver Therapies
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CM-10
David Jones, MD FRCP, PhDProfessor or Liver ImmunologyUniversity of NewcastleInstitute of Cellular Medicine Director, UK-PBC Study Group Consortium
Unmet Need in PBC
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CM-11
Limitations of Current Management UDCA
‒ Up to 40% of patients unresponsive to therapy‒ Additional 5% are intolerant to therapy
Transplantation‒ Cost‒ Morbidity ‒ Poor functional status‒ Limited timely organ availability and differential access
Clinical trials‒ Rare disease – requires large number of centers for studies‒ Relatively slow progression of disease
• Precludes easy evaluation of clinical outcomes as primary endpoint
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CM-12
Biochemical Response to UDCA at 1 Year Predicts Disease Progression
00 5 10 15
Proba
bility
of Tr
ansp
lant-fr
ee Su
rvival
Years
0.10.20.30.40.50.60.70.80.91.0
Corpechot et al. Hepatology. 2008; 48(3):871-77.
RespondersN=179
Non-respondersN=113
(p<0.0001; RR, 0.4; 95% CI, 0.3-0.5)
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CM-13
Global PBC Study Group Global PBC Study Group, an international and multicenter collaboration between 15 liver centers in 8 North American and European countries Combined individual patient data from major long-term follow-up cohorts Clinical data of 6191 PBC patients
Lindor KD, et al. Hepatology. 2009;50:291-308; 2. European Association for the Study of the Liver. J Hepatol. 2009;51:237-267; Lammers, WJ et al. Gastroenterology. 2014 Dec;147(6):1338-1349.
Edmonton
Dallas
Seattle
RochesterToronto
Milan PaduaBarcelona
Birmingham
London
Paris
Rotterdam & Amsterdam
Leuven
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CM-14
UK-PBC Consortium Meta-analysis of individual patient data Long-term follow-up cohorts from 150 National Health Service Trusts or Health Boards 100% of UK hospitals and ~35% of UK patients Clinical data of >6000 PBC patients
www.uk-pbc.com
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CM-15
Unmet Need: Transplant-Free Survival in UDCA Era
88%75%
63%
100
80
60
40
20
00 5 10 15
Survi
val (%
)
Follow-up (Years)Adapted from Lammers et al. Gastroenterology. 2014; 147(6):1338-49
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CM-16
Elevated ALP and Bilirubin Values are Associated With Higher Hazard of Liver Transplantation/Death
Lammers et al. Gastroenterology. 2014; 147(6):1338-49
Alkaline Phosphatase (ALP)
Hazar
d Rati
on fo
r Live
rTra
nspla
ntaion
or De
ath
0 1 2 30
2
45
1
3
4 5
At one year follow-up*
*3710/4635 patients were included for this analysis
Thresholds (xULN) for Alkaline Phosphatase Levels
0 1 2 30
4
810
2
6
4 5
BilirubinAt one year follow-up*
*3681/4635 patients were included for this analysis
Thresholds (xULN) for Bilirubin Levels
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CM-17
100
Dichotomous ALP and Bilirubin Classifiers Predict Survival Alkaline Phosphatase (ALP)
0 5 10 150
40
80100
Follow-Up (Years) Follow-Up (Years)
Bilirubin
20
60
Hazard Ratio*ALP >1.67 vs ≤1.67=2.2 (1.9-2.5)
0 5 10 150
40
80
20
60
Hazard Ratio*Abnormal vs normal bili=5.1 (4.3-5.9)
Survi
val (%
)
Survi
val (%
)
ALP ≤1.67 xULN
ALP >1.67 xULN
Normal bilirubin
Abnormal bilirubin
Courtesy of Global PBC Study Group
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CM-18
ALP Values Have Predictive Significance in Addition to Bilirubin in Patients with PBC
00
Liver-
Trans
planta
tion-F
ree Su
rvival
(%)
20
40
60
80
100
5 10 15Follow-up (Years)
ALP ≤1.67xULN>1.67xULNp=0.00015
Normal Bilirubin
Global PBC GroupN=4845
Follow-up (Years)
UK-PBCN=4022
0 5 10 15
20
40
60
80
100NormalBilirubin
AbnormalBilirubin
0
AbnormalBilirubin
ALP ≤1.67xULN>1.67xULNp=0.00086
Liver transplant-free survival for Global PBC is based on all-cause mortality or liver transplant and the UKPBC is based on liver-related death or liver transplant. Courtesy of Global PBC Study Group and UK-PBC
ALP ≤1.67xULN ALP >1.67xULN ALP ≤1.67xULN ALP >1.67xULN
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CM-19
Greatest Risk of Non-Response Associated With Younger Age at Diagnosis0.90.80.70.60.50.40.30.20.1
<30 31-40 41-50 51-60 61-70 >70
r=0.95, p<0.0001
Propo
rtion o
f UDC
A Non
-Resp
onde
rs
Age at DiagnosisCarbone et al. Gastroenterology. 2013; 144(3): 560-69.
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CM-20
Management of PBC in the UDCA Era UDCA universally used Routine assessment after 1 year of treatment Capacity to identify minority of patients in whom death liver transplant risk resides (low risk patients in whom therapy can be stepped down) Capacity to target early in the disease course high efficacy therapies in high risk patients (risk vs stage) Trial measures to assess response to therapy
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CM-21
Vision for the Future of PBC Management Better treatment targeted in better ways Key attributes of new therapies include
1. Targeted for patients with unmet need through appropriate risk stratification2. Proof of benefit in studies of appropriate patient cohorts 3. Manageable and tolerable side effects
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CO-22
David Shapiro, MD FRCPIntercept Pharmaceuticals, Inc.Chief Medical Officer
Program Rationale
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CO-23
Goals for a New PBC Therapeutic Drug with desirable pharmacology
‒ Increase bile flow – “choleresis”‒ Decrease toxic endogenous bile acid concentrations in hepatocytes‒ Lessen hepatobiliary inflammation and injury
Farnesoid X Receptor – good therapeutic target‒ Regulates bile acid homeostasis‒ Pleotropic hepatic properties
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CO-24
FXR Activation
Hinge
N-terminaldomain
Ligand-bindingdomain
C-terminal domain
DNA-binding domain
OCA
Target geneActivation/Repression
OCACo-activator
RXR FXR
Modified from Calkin 2012
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CO-25
CDCAChenodeoxycholic Acid
Pellicciari R. J.Med.Chem 2002
Obeticholic Acid (OCA)6-ethyl chenodeoxycholic acid
FXR EC50(agonist)
UDCAUrsodeoxycholic Acid
No activity 8.66 µM
~100x ↑ FXR agonism
OCA6α-ethyl chenodeoxycholic acid
0.099 µM
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CO-26
OCA – Key Properties Pharmacokinetic properties similar to endogenous CDCA
‒ Selective FXR agonist• No binding to other nuclear receptors
‒ Rapidly absorbed‒ Metabolism: conjugation with glycine and taurine
• Equipotent FXR agonists to parent OCA‒ Extensive enterohepatic re-circulation‒ Steady-state half life: ~4 days‒ Excretion
• Fecal >85%• Urine <3%
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CO-27
FXR-Mediated Pharmacological Actions of OCA
Fibrosis↓ Stellate cell activation (α-SMA)↑ Stellate cell apoptosis (TIMP-1)↓ Fibrogenesis (TGF-β1)↑ Matrix degradation (MMP-2)
↓ NF-kB↓ TNF-α, IL-1β,IL-1, IL-6, IL-12, IL-17, IFN-γ↓ CRP
Inflammation↓ Bile acid synthesis (CYP7A1)↑ Bile Salt Excretory Pump (BSEP)↑ Intrahepatic bile flow
Bile Acid Homeostasis
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CO-28
UDCA and OCA PropertiesOCA
5→10 mgUDCA
~1000 mg
No FXR activationPost-transcriptionalNo change in BA synthesis but BA poolMajor circulating BA & ↑ hydrophilicity of BA poolStimulation of biliary HCO3 biliary epithelium protection
Potent FXR activationTranscription effectsBA synthesis <2% of BA pool↑ choleresis (bile flow)↓ inflammation and fibrosis
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CO-29
Clinical Program Overview: >20 Studies 1500 subjects PBC: ~430 patients, ~675 patient years exposure Biopharmaceutics – 4 studies
‒ Bioavailability and bioequivalence Clinical Pharmacology – 12 studies
‒ Food effect‒ Drug-Drug Interactions – 5 studies, multiple probes‒ Thorough QTc – CV safety
Other potential indications Primary Biliary Cirrhosis/Cholangitis – 3 studies
‒ 2 Phase 2 studies‒ 1 Phase 3 study
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CE-30
Leigh MacConell, PhD Intercept Pharmaceuticals, Inc. Vice PresidentClinical Development
Efficacy of OCA in PBC
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CE-31
Randomized Placebo-controlled Studies With Primary Efficacy Data in Patients with PBCOCA Clinical Efficacy Studies
MonotherapyOCA or PBO
CombinationOCA + UDCA or
PBO + UDCA
Phase 3
PBC Clinical Outcomes Study
OCA ± UDCA vs PBO ± UDCA
Phase 4
Two observational (retrospective and prospective) PBC databases>10,000 Patients
Ongoing Extension
≥5yCompletedExtension
≥1yOngoing
Extension≥2.5y
Phase 2
Mono or ComboOCA ± UDCA or
PBO ± UDCA
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CE-32
Proof of Concept – OCA as Add-On to UDCADouble-Blind Phase 2
Continue UDCA
25 mg QD (n = 48)
Placebo QD (n = 38)
50 mg QD (n = 41)
10 mg QD (n = 38)
Month0 31 20.5
Entry Criteria• Diagnosis of PBC• ALP 1.5x to 10x ULN• Conjugated Bili 2x ULN• No prior history of
hepatic decompensation• Stable UDCA 6 Months
3-Month Double-Blind Treatment Period(ITT Population, N = 165)
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CE-33
OCA Effective in PBC Patients Treated With UDCADouble-Blind Phase 2 – Add on to UDCA
Mean ALP (U/L) Over Time
1.67x ULN
150
200
250
300
350
0 1 2 3Month-40
-35-30-25-20-15-10
-505
10
p<0.0001p<0.0001p<0.0001
Primary EndpointPercent Change in ALP (U/L) From
Baseline to Month 3
The primary efficacy endpoint was analyzed using the 2-sided Wilcoxon-Mann-Whitney test.
Placebo (N=38) 10 mg (N=38) 50 mg (N=41)25 mg (N=48)
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CE-34
Proof of Concept – OCA MonotherapyDouble-Blind Phase 2
0.5Month
0 31 2
Placebo QD (n=23)
50 mg QD (n=16)
10 mg QD (n=20)
3-Month Double-Blind Treatment Period(ITT Population, N = 59)
Key Entry Criteria• Diagnosis of PBC• ALP 1.5x to 10x ULN• Conjugated Bili 2x ULN• No prior history of
hepatic decompensation• No UDCA 3 Months
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CE-35
OCA Effective as MonotherapyDouble-Blind Phase 2 – Monotherapy
The primary efficacy endpoint was analyzed using the 2-sided Wilcoxon-Mann-Whitney test.
100
200
300
400
500
0 1 2 3Month
Mean ALP (U/L) Over Time
1.67x ULN-60-50-40-30-20-10
010
p<0.0001p<0.0001
Percent Change in ALP (U/L) FromBaseline to Month 3
Primary Endpoint
Placebo (N=23) 10 mg (N=20) 50 mg (N=16)
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CE-36
Pivotal Trial – OCA Evaluated in High Risk PBC PatientsDouble-Blind Phase 3
In the titration arm, patients were to up-titrate from 5 mg to the 10 mg dose if they had not yet achieved the primary composite endpoint and were tolerating therapy.
If on UDCA: continue UDCA
Month
10 mg (n = 73)
Placebo (n = 73)
Titration (n = 70)
BL 3 6 9 12
12-Month, Double-Blind Treatment Period(ITT Population, N = 216)
Remained on 5 mg (n = 36)
Uptitrated to 10 mg (n = 33)
0.5
• PBC diagnosis• UDCA for at least 12 months (stable dose for ≥3 months)
orUnable to tolerate UDCA(no UDCA for ≥3 months)
• ALP ≥1.67x ULN or Total bilirubin between >ULN and <2x ULN• Presence of hepatic decompensation
Entry Criteria
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CE-37
Primary EndpointDouble-Blind Phase 3
• Proportion of patients achieving ALP <1.67x ULN
and • ALP decrease of ≥15%
and • Total Bilirubin ≤ULN
Endpoints of ALP and Bilirubin: • ALP is a marker of cholestasis used for diagnosis and management of PBC• Bilirubin is an established marker of hepatic excretory function• Both ALP and Bilirubin are established as independent predictors of risk in PBC• Additive predictive utility when used together
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CE-38
Prognostic Utility of Primary EndpointGlobal PBC Database
ALP <1.67xULN with 15% Reduction from Baseline and Normal Bilirubin at 1 Year of Follow-up
Total study populationUDCA treated
UntreatedFemale
MaleAge at diagnosis ≤55 yearsAge at diagnosis ≤60 yearsAge at diagnosis ≤65 years
Diagnosed <1990Diagnosed between 1990-1999Diagnosed between 2000-2010
Biopsy stage 1 or 2Biopsy stage 3 or 4Early disease stage
Moderate disease stageAdvanced disease stage
Double-Blind Phase 3 inclusion criteria0.0 0.5 1.0 1.5
Adjusted HR Increased RiskReduced Risk
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CE-39
Secondary EndpointsDouble-Blind Phase 3
Secondary Endpoints Markers of Disease ProgressionALP and GGT Cholestatic injury
Bilirubin Loss of excretory functionALT and AST Hepatocellular injury
IgM Immunological abnormalitieshs-CRP Systemic inflammation
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CE-40
Patient Analysis PopulationsDouble-Blind Phase 3
Placebon (%)
Titrationn (%)
10 mgn (%)
Totaln (%)
Enrolled/randomized 73 71 73 217ITT population 73 (100) 70 (99) 73 (100) 216 (99.5)Safety population 73 (100) 70 (99) 73 (100) 216 (99.5)Completed DB phase 70 (96) 64 (90) 64 (88) 198 (91)
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CE-41
Demographics Double-Blind Phase 3
PlaceboN=73
Titration N=70
10 mg N=73
TotalN=216
CharacteristicCaucasian, n (%) 66 (90) 67 (96) 70 (96) 203 (94)Female, n (%) 68 (93) 65 (93) 63 (86) 196 (91)Age (years), mean ± SD 56 ± 10 56 ± 11 56 ± 11 56 ± 10≥65 years, n (%) 13 (18) 10 (14) 17 (23) 40 (19)
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CE-42
Baseline Characteristics Reflective of High Risk PBC PopulationDouble-Blind Phase 3Placebo
N=73n (%)
Titration N=70n (%)
10 mg N=73n (%)
TotalN=216n (%)
UDCA use 68 (93) 65 (93) 67 (92) 200 (93)Daily UDCA dose, mg/kg 15 ± 4 17 ± 5 16 ± 5 16 ± 5Age at diagnosis, years 47 ± 9 48 ± 12 47 ± 11 47 ± 11
<50 years 45 (62) 38 (54) 42 (58) 125 (58)ALP, U/L 327 ± 115 326 ± 116 316 ± 104 323 ± 111
ALP >3x ULN 23 (32) 19 (27) 20 (27) 62 (29)Bilirubin, mmol/L 12 ± 7 10 ± 6 11 ± 7 11 ± 7
Bilirubin >ULN 7 (10) 4 (6) 7 (10) 18 (8)Moderately Advanced Disease Stage 13 (18) 12 (17) 11 (15) 36 (17)Cirrhosis 9 (12) 7 (10) 4 (5) 20 (9)
Baseline data are Mean ± SD unless otherwise specified.Cirrhosis defined as PBC Stage Four or fibrosis values of incomplete cirrhosis or cirrhosis on the baseline biopsy report. Moderately advanced as defined per Rotterdam criteria ALP ULN values based on criteria for females (118.3 U/L); Total Bilirubin ULN values based on criteria for females (19.32 μmol/L).
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CE-43
Comparison of Demographics and Baseline CharacteristicsDouble-Blind Phase 3 vs Global PBC Study GroupPBC Patients (Untreated or UDCA-treated)
Double-Blind Phase 3N=216
Global PBC Study GroupaN=4845
Age at entry (years)b 55.8 (10.48) 54.5 (12.0)Duration of PBCc 8.3 (3.1 - 12.1) 7.3 (3.6 - 11.5)Female, n (%) 196 (91) 4348 (90)UDCA-treated patients, n (%) 200 (93) 4119 (85)Baseline ALP
Serum ALP (xULN)c 2.42 (2.01, 3.15) 2.10 (1.31 ,3.72)>3x ULN, n (%) 62 (29) 606 (16)
Baseline Serum BilirubinSerum Bilirubin (xULN)c 0.56 (0.36, 0.66) 0.67 (0.45-1.06)
>ULN, n (%) 18 (8) 740 (20)Biochemical disease stage, n (%)
Early: bilirubin ULN and albumin ≥LLN 174 (80) 2040 (67)Moderately Advanced: abnormal bilirubin or albumin 36 (17) 730 (24)Advanced: abnormal bilirubin and albumin 6 (3) 259 (9)
a Lammers WJ et al. Gastroenterology. 2014 Dec;147 (6):1338-1349.e5. doi: 10.1053/j.gastro.2014.08.029.b Mean (SD)c Median (Q1, Q3)
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CE-44
0102030405060708090
100
Placebo (N=73) 10 mg (N=73)
Primary Endpoint AchievedDouble-Blind Phase 3 – Month 12
Primary Endpoint:Proportion of patients achieving ALP <1.67x ULN with bilirubin ≤ULN and ≥15% reduction in ALP
Perce
nt of
Resp
onde
rs p<0.0001
Missing values were considered a non-response. P-value obtained using CMH test stratified by randomization strata factor.
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CE-45
0102030405060708090
100
Placebo (N=73) 10 mg (N=73) Titration (N=70)
Primary Endpoint AchievedDouble-Blind Phase 3 – Month 12
Primary Endpoint:Proportion of patients achieving ALP <1.67x ULN with bilirubin ≤ULN and ≥15% reduction in ALP
Perce
nt of
Resp
onde
rs
Missing values were considered a non-response. P-value obtained using CMH test stratified by randomization strata factor.
p<0.0001
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CE-46
Parameter Subpopulation N OCA vs Placebo p-value
UDCA use at baselineYes 65 <0.0001
67 <0.0001No 5
6
Age group at PBC diagnosis<50 years 38 0.0006
42 0.0002≥50 years 32 0.0024
31 0.0069
GenderFemale 65 <0.0001
63 <0.0001Male 5
10
Baseline ALP level≤3x ULN 51 <0.0001
53 <0.0001>3x ULN 19
20
Baseline bilirubin level≤ULN 66 <0.0001
66 <0.0001>ULN 4
70.01 0.1 1 10 100
Response by SubpopulationDouble-Blind Phase 3 – Month 12
Favors OCAFavors Placebo*No placebo responders10 mg (N=73) Titration (N=70)
*
*
*
*
Odds Ratio (95%CI)
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CE-47
Efficacy of OCA as MonotherapyDouble-Blind Studies (Pooled) – Month 3
01020304050607080
02468
101214161820
Composite Endpoint ALP Total Bilirubin
050
100150200250300350400450500
37%
3%Placebo 10 mg Placebo 10 mgPlacebo 10 mg
Perce
nt of
Resp
onde
rs
Mean
(SD)
ALP (
U/L)
Mean
(SD)
Total B
ilirub
in (µm
ol/L)
Difference from placebo statistically significant for all 3 parameters.
Placebo (N=29) 10 mg (N=27)
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CE-48
Efficacy in Moderately Advanced PatientsDouble-Blind Phase 3 – Month 12
0
10
20
30
40
50
60
-5-4-3-2-1012345
Primary Endpoint ALP (U/L) Total Bilirubin (mmol/L)
Perce
nt of
Resp
onde
rs
LS Me
an (S
E) Ch
ange
From
Basel
ine
LS Me
an (S
E) Ch
ange
From
Basel
ine
-225-200-175-150-125-100
-75-50-25
0
Placebo (N=13) Titration (N=12) 10 mg (N=11)
0%
42%
27%
Rotterdam Criteria (moderate): total bilirubin or albumin is abnormal.
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CE-49
Reductions in ALP (U/L) Were Observed Early and SustainedDouble-Blind Phase 3
-150-130-110
-90-70-50-30-10103050
0 6 12
LS Me
an Ch
ange
from
Basel
ine (S
E)
Time (Months)
*
* * **W2
*
* * **
Placebo (N=73) 10 mg (N=73) Titration (N=70)
*p<0.0001
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CE-50
-250
-200
-150
-100
-50
0
50
100
0 6 12
OCA Titration Following Month 6 Resulted in Incremental Improvement in ALPDouble-Blind Phase 3Me
an Ch
ange
from
Basel
ine (S
D)
Time (Months)W2
Placebo (N=73) 10 mg (N=73)Up-titrated to 10 mg (N=33)Remained at 5 mg (N=36)
Titration (N=69)
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CE-51
∆ALP=0% ∆ALP=0% ∆ALP=0%
Majority of OCA-Treated Patients Had Improvement in ALP Double-Blind Phase 3 – Baseline vs Month 12
29% of placebo patients saw at least a 15% ALP improvement - compared with 77% of OCA patients
36% of placebo patients experienced an increase in ALP - compared with only 3% of OCA patients
100 200 300 400 500 600 700 800Baseline ALP (U/L)AL
P Cha
nge f
rom Ba
seline
at Mo
nth 12
100 200 300 400 500 600 700 800Baseline ALP (U/L)
-200
-400
200
0
100 200 300 400 500 600 700 800Baseline ALP (U/L)
10 mgN=73
PlaceboN=73 Titration
N=70
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CE-52
Total Bilirubin Maintained Over Time in OCA-Treated PatientsDouble-Blind Phase 3
-2.5-2.0-1.5-1.0-0.50.00.51.01.52.02.53.0
0 3 6 9 12Time (Months)
LS Me
an (S
E) Ch
ange
fro
m Ba
seline
(mmol/
L)
Placebo (N=73) Titration (N=70) 10 mg (N=73)
*p<0.05, **p<0.01, ***p<0.0001
** ** ***
****
*Pe
rcenta
ge (%
) of P
atien
ts
0102030405060708090
100
Placebo(n=7)
Pooled OCA(n=11)
14%
63%
Patients With Abnormal Bilirubin at Baseline who Normalized at Month 12
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CE-53
OCA Treatment Improves Additional Marker of Cholestasis – GGTDouble-Blind Phase 3 Placebo (N=73) Titration (N=70) 10 mg (N=73)
0
50
100
150
200
250
300
350
0 3 6 9 12Time (Months)
LS Mean Change in GGT (U/L)From Baseline to Month 12 Mean GGT (U/L)
Mean
GGT (
U/L)
LS Me
an (S
E) Ch
ange
in GG
T (U/L
)
-200
-150
-100
-50
0
50
p<0.0001
p<0.0001
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CE-54
OCA Treatment Improves Markers of Hepatobiliary DamageDouble-Blind Phase 3
ALT (U/L) AST (U/L)
-40
-30
-20
-10
0
10
p<0.0001p<0.0001
Mean ALT (U/L)
LS Me
an (S
E) Ch
ange
from
Basel
ine to
Month
12
Placebo (N=73) Titration (N=70) 10 mg (N=73)
-40
-30
-20
-10
0
10
p<0.0001p<0.0001
203040506070
0 3 6 9 12
Mean AST (U/L)
203040506070
0 3 6 9 12Me
an Ch
ange
Time (Month)
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CE-55
Improvement in Immunological and Inflammation MarkersDouble-Blind Phase 3Placebo (N=73) Titration (N=70) 10 mg (N=73)
Media
n (±IQ
R)
Hodges-Lehmann estimates for the median difference (OCA - Placebo).**p<0.01, ***p<0.0001; p-value for comparing OCA treatments to placebo was obtained using the Wilcoxon rank-sum test.
0
2
4
6
8
** ***
Baseline Month 12
IgM (g/L) hsCRP (mg/L)
0
2
4
6
8
** **
Baseline Month 12
ULN
ULN
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CE-56
Clinical OutcomesDouble-Blind Phase 3Randomized Treatmentn (%) Double-Blind Phase
Placebo3 (4)
Upper GI Bleeding 2 events of Esophageal Varices
MELD 15
MELD 15
Pooled OCA3 (2)
Upper GI BleedingHepatic Encephalopathy
Ascites Death
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CE-57
Study DesignLong-Term Safety Extension (LTSE) Phase 3
Titration (n=64)
10 mg (n=63)
Placebo (n=66)
0 3 6 9 12 LTSE Baseline
OCA 5 mg for 3 months with dose adjustments based on response
3 6 9 12
Enrolled into Long-Term Safety Extension (N = 193)Double-Blind PhaseRandomized Treatment
Open-Label PhaseAll Receive OCA
Month
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CE-58
5 mg Titration
Open-label PhaseAll Receive OCA
OCA Treatment Durable – ALPLong-Term Safety Extension (LTSE) Phase 3
Data are summarized by randomized treatment and by weighted average daily OCA dose ≤10 mg.
Mean
(SD)
Chan
ge fro
m Ba
seline
in AL
P (U/L
)
Double-Blind PhaseRandomized Treatment
Placebo (N=51) Titration (N=50) 10 mg (N=54) Open-Label OCA
-250-200-150-100
-500
50100
0 3 6 9 12 15 18 21 24 27 3015 18 21 2412/LTSE 0
27 30
Time (Months)
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CE-59
5 mg Titration
OCA Treatment Durable – Total BilirubinLong Term Safety Extension (LTSE) Phase 3
Open-label PhaseAll Receive OCA
Mean
(SD)
∆ in T
otal B
ilirub
in (µm
ol/L)
from
Basel
ine
Double-Blind PhaseRandomized Treatment
Placebo (N=51) Titration (N=50) 10 mg (N=54) Open-Label OCA
Data are summarized by randomized treatment and by weighted average daily OCA dose ≤10 mg.Time (Months)
16.0
0 3 6 9 12 15 18 21 24 27 30-10.0
-8.0-6.0-4.0-2.00.02.04.06.08.0
10.0
0 3 6 9 12 15 18 21 24 27 3012/LTSE 0 15 18 21 24 27 30
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CE-60
OCA Represents Promising Novel Treatment for PBC Significant increase in proportion of patients achieving
primary endpoint Clinically meaningful improvements in markers of
‒ Cholestasis, hepatic function, hepatobiliary damage, and inflammation
Consistent results across high risk subpopulations Durable efficacy with longer-term treatment Starting subjects at 5-mg OCA and titration to 10-mg OCA
is an appropriate dosing strategy
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CS-61
Roya Hooshmand-Rad, MD, PhDIntercept Pharmaceuticals, Inc.Executive DirectorMedical Safety and Pharmacovigilance
Safety of OCA in Patients with PBC
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CS-62
OCA ExposureIntercept Sponsored and Investigator Initiated Studies
Intercept sponsored for other indicationsN=74
Clinical pharmacology studiesN=844
Investigator initiated studiesN=305
N Mean Years Patient Exposure YearsAll PBC Studies 432 1.6 675
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CS-63
OCA Exposure in Patients with PBC432 425 397
300 290 283 267208
155
42 19 14
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CS-64
Patient DispositionDouble-Blind Phase 3
PlaceboN=73 n (%)
TitrationN=71n (%)
10 mgN=73n (%)
All treated population 73 (100) 70 (99) 73 (100)Completed DB phase 70 (96) 64 (90) 64 (88)
Completed DB and entered LTSE 66 (94) 63 (98) 64 (100)Overall discontinuations due to AE 3 (4) 5 (7) 8 (11)
Due to pruritus 0 1 (1) 7 (10)
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CS-65
Overall Summary of Adverse EventsDouble-Blind Phase 3
PlaceboN=73 n (%)
TitrationN=70n (%)
10 mgN=73n (%)
Patients with AE 66 (90) 65 (93) 69 (95)Patients with SAE 3 (4) 11 (16) 8 (11)Death 0 1 (1) 0
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CS-66
Serious Adverse EventsDouble-Blind Phase 3
Preferred TermPlacebo
N=73 n (%)
TitrationN=71n (%)
10 mgN=73n (%)
All SAEs 3 (4) 11 (16) 8 (11)SAEs >1 patient
Varicose vein 0 2 (3) 0Osteoarthritis 0 0 2 (3)
~80% OCA-treated patients with SAE continued long term treatment
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CS-67
Adverse Drug Reactions Double-Blind Phase 3
ADRs CategoryPlacebo
N=73n (%)
TitrationN=70n (%)
10 mgN=73n (%)
Pruritus/skin eruptions 28 (38) 39 (56) 51 (70)
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CS-68
Adverse Drug Reactions Double-Blind Phase 3
ADRs CategoryPlacebo
N=73n (%)
TitrationN=70n (%)
10 mgN=73n (%)
Pruritus 28 (38) 39 (56) 51 (70)Fatigue/tiredness 11 (15) 13 (19) 18 (25)Abdominal pain and discomfort 10 (14) 13 (19) 7 (10)Rash and urticaria 6 (8) 5 (7) 7 (10)Oropharyngeal pain 1 (1) 5 (7) 6 (8)Dizziness 4 (5) 5 (7) 5 (7)Constipation 4 (5) 5 (7) 5 (7)Arthralgia 3 (4) 4 (6) 7 (10)Cough 5 (7) 4 (6) 6 (8)Thyroid function abnormality 2 (3) 4 (6) 3 (4)Eczema 0 4 (6) 2 (3)Procedural pain 1 (1) 4 (6) 1 (1)Edema peripheral 2 (3) 2 (3) 5 (7)Palpitations 1 (1) 2 (3) 5 (7)Pyrexia 1 (1) 0 5 (7)
ADRs=events that occurred in ≥5% in either OCA treatment group and occurring in ≥1% more than in placebo
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CS-69
Pruritus as an Adverse Event Double-Blind Phase 3
Discontinued Due to Pruritus Regardless of Management Efforts
No Pruritus (62%)
PlaceboN=73
TitrationN=70
10 mgN=73
No Pruritus(44%)
No Pruritus (30%)
PruritusNo Treatment
(26%)
Pruritus &Treatment
(19%)
PruritusNo Treatment
(21%)
Pruritus &Treatment
(33%)Pruritus &Treatment
(34%)
10%1%
PruritusNo Treatment
(19%)
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CS-70
0102030405060708090
100
Patient Experience: Visual Analog Scale Double-Blind Phase 3
BLTime (Months)
W2 3 6 9 12
Last observation is carried forward*Reich et al Acta Derm 2012
Placebo (N=73) Titration (N=70) 10 mg (N=73)
Mean
(SD)
VAS S
core
Mild*
Mode
rate
Sever
e
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CS-71
Hepatic Adverse EventsDouble-Blind Phase 3
*Standardized MedDRA query of Hepatic Disorders‡Events reported as AEs by the investigator (not laboratory values)
PlaceboN=73n (%)
TitrationN=70n (%)
10 mgN=73n (%)
All patients with hepatic AEs* 2 (3) 3 (4) 2 (3)Patients with clinical hepatic AEs 1 (1) 2 (3) 1 (1)
Ascites 0 1 (1) 1 (1)Hepatic encephalopathy 0 1 (1) 0Varices esophageal 1 (1) 1 (1) 0
Patient with other hepatic AEs 0 0 2 (3)Hepatic pain 0 0 1 (1)Spider nevus 0 0 1 (1)
Patients with biochemical hepatic AEs‡ 1 (1) 1 (1) 0International normalized ratio increased 0 1 (1) 0Liver function test abnormal 1 (1) 0 0
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CS-72
CTCAE Graded Serum Liver AbnormalitiesDouble-Blind Phase 3
CTCAE=Common Terminology Criteria for Adverse EventsCTCAE grades (version 4.03): 1 ≥ULN - 3.0 x ULN, 2 ≥3.0 - 5.0 x ULN, 3 ≥5.0 - 20.0 x ULN, 4 ≥20.0 x ULN.For females: AST ULN = 25.7 U/L, ALT ULN = 22.9 U/L. For males: AST ULN = 33 U/L, ALT ULN = 33.4 U/L.
*Total bilirubin remained within normal limitsNo Grade 3 or 4 Bilirubin increase in any arm (no elevation >3X ULN)
PlaceboN=73n (%)
TitrationN=70n (%)
10 mgN=73n (%)
ALTCTCAE grade 3 6 (8) 1 (1)* 0CTCAE grade 4 0 0 0
ASTCTCAE grade 3 2 (3) 1 (1)* 0CTCAE grade 4 0 0 0
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CS-73
HDL Over TimeDouble-Blind Phase 3
0.00.51.01.52.02.53.03.5
0 3 6 9 12
Time (Months)
Mean
(SD)
HDL (
mmol/
L)
Placebo (N=73) Titration (N=70) 10 mg (N=73)
LLN=Lower Limit of Normal
LLN
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CS-74
TG, VLDL and LDL Over TimeDouble-Blind Phase 3
0123456
0 3 6 9 12
Mean
(SD)
LDL (
mmol/
L)
ULN
Placebo (N=73)Titration (N=70)10 mg (N=73)
Mean
(SD)
VLDL
(mmo
l/L)
Time (Months)
ULN
0.00.10.20.30.40.50.60.70.80.91.0
0 3 6 9 120.00.51.01.52.02.5
0 3 6 9 12Time (Months)
ULN
Mean
(SD)
Trigly
ceride
s (mm
ol/L)
TG: Triglycerides; VLDL: very low density lipoprotein; LDL: low density lipoprotein
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CS-75
Long Term SafetyLTSE Phase 3 No new category of safety observations with long term use Pruritus: most common AE
‒ Single most common reason for discontinuation (3%) No pattern in SAEs occurring with long term exposure SAEs occurring in 2 or more patients were
‒ Osteoarthritis (3%)‒ Variceal bleeding (2%)
One fatal event Lipid levels remained stable
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CS-76
OCA Generally Well Tolerated in Patients With PBC Pruritus most frequent AE
‒ Tolerable with 1 discontinuation in titration arm Infrequent hepatic events Early changes in HDL
‒ Stabilize within months with continued treatment‒ Overall remain within normal limits
Small transient increase in LDL‒ Comparable to placebo by end of study
AE profile stable with long-term treatment‒ No new signals with longer treatment
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CB-77
John M. Vierling, MD FACP, FAASLDBaylor College of MedicineProfessor of Medicine and SurgeryChief of HepatologyDirector of Advanced Liver Therapies
Benefit-Risk
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CB-78
Status Quo of PBC Treatment: 1997-2016PBC
UDCA
Non-Responders
Progressive disease
Cirrhosis, portal hypertension and/or HCC
Premature death or OLT
Responders
Reduced liver related deaths or OLT
Symptomatic/Asymptomatic
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CB-79
Vision for the Future of PBC Management Key attributes of new therapies include
1. Targeted for patients with unmet need through appropriate risk stratification2. Proof of benefit in studies of appropriate patient cohorts 3. Manageable and tolerable side effects
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CB-80
ALP Values Have Predictive Significance in Addition to Bilirubin in Patients with PBC
00Tra
nspla
nt-fre
e Surv
ival* (
%)
20
40
60
80
100
5 10 15Follow-up (Years)
ALP ≤1.67xULN>1.67xULNp=0.00015
Normal Bilirubin
Global PBC GroupN=4845
AbnormalBilirubin
ALP ≤1.67xULN>1.67xULNp=0.00086
Courtesy of Global PBC Study Group and UK-PBC*Transplant-free survival includes all-cause mortality for Global PBC and liver-related death for UK-PBC.
Double-Blind Phase 3Inclusion Criteria:ALP ≥1.67x ULN
or Bilirubin >ULN and <2x ULN
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CB-81
Vision for the Future of PBC Management Key attributes of new therapies include
1. Targeted for patients with unmet need through appropriate risk stratification2. Proof of benefit in studies of appropriate patient cohorts 3. Manageable and tolerable side effects
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CB-82
Efficacy of OCA in Phase 3
Secondary Endpoints‒ ALP and Bilirubin‒ Markers of hepatobiliary injury: GGT, ALT, AST‒ Immune and inflammatory markers
Primary Composite Endpoint:• ALP <1.67x ULN and • ALP of ≥15% and • Bilirubin ≤ULN
0
10
20
30
40
50
Placebo(N=73)
Titration(N=70)
10 mg(N=73)
%
Month 12* *
*p<0.0001 vs. Placebo
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CB-83
Durability of ResponsePlacebo Titration 10 mg
∆ from
BL
in ALP
(U/L)
∆ from
BL
in T. B
ilirub
in (µm
ol/L)
Time (Months)
Open-label PhaseDouble-Blind Phase
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CB-84
Vision for the Future of PBC Management Key attributes of new therapies include
1. Targeted for patients with unmet need through appropriate risk stratification2. Proof of benefit in studies of appropriate patient cohorts 3. Manageable and tolerable side effects
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CB-85
Pruritus Common and distressing symptom
‒ Can be managed in most patients Pruritus in Double-Blind Phase 3
‒ Generally well tolerated with proposed titration regimen• VAS comparable among treatment groups after 6 months of therapy and generally mild• Substantial group not requiring therapy• Discontinuation: 1 patient in titration group
‒ Responsive to• Interruption/cessation of therapy• Alternative day dosing• Investigator initiated therapies
‒ High voluntary entry into LTSE Overall, well tolerated by patients
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CB-86
Changes in Lipids PBC associated with hypercholesterolemia
‒ Driven by HDL elevation‒ Generally not associated with increased cardiovascular risk
OCA associated with‒ Reduction in HDL
• Soon after initiating OCA• Maintenance of mean levels within the normal range
‒ LDL: transient elevation returning to baseline within 3-6 months
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CB-87
Hepatic Safety Profile Overall, clinical hepatic AEs infrequent in treatment and placebo arms At the proposed clinical doses (5 mg titrating up to 10 mg once daily) treatment emergent changes in ALT, AST
‒ Elevations in OCA treatment arms less frequent than placebo arm‒ Elevations predominantly transient ‒ None accompanied by total bilirubin abnormalities
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CB-88
Conclusion – Favorable Benefit-Risk Ratio Benefits
‒ Addresses unmet need in patients non-responsive to or intolerant of UDCA‒ Efficacy: OCA met primary and secondary endpoints‒ Durability: LTSE confirms durable response
Risks‒ Identifiable and manageable‒ Adverse events
• Pruritus• Mild HDL reductions and transient LDL increases• Infrequent liver related safety observations
‒ Reversible with discontinuation
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CB-89
PBC Treatment: 2016 OnwardPBC
UDCA
Non-Responders
Progressive disease
Cirrhosis, portal hypertension and/or HCC
Premature death or OLT
Responders
Reduced liver related deaths or OLT
Symptomatic/Asymptomatic
OCA
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CB-90
Experts Available for QuestionsDavid Jones, MD FRCP, PhDProfessor of Liver ImmunologyUniversity of NewcastleInstitute of Cellular Medicine Director, UK-PBC Study Group Consortium John Vierling, MD FACP, FAASLDBaylor College of MedicineProfessor of Medicine and Surgery,Chief of HepatologyDirector of Advanced Liver TherapiesGideon Hirschfield, MA, MB BChir, PhD, FRCPSenior Lecturer/Honorary Consultant Transplant HepatologistInstitute of Immunology and ImmunotherapyCollege of Medicine and Dentistry, University of BirminghamUniversity Hospitals BirminghamKris Kowdley MD FACP, FAASLDDirector, Liver Care Network and Organ Care ResearchSwedish Medical CenterBettina Hansen, PhD, MScSenior BiostatisticianDepartment of Gastroenenterology and HepatologyErasmus Medical CenterUniversity Medical Center Rotterdam
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CI-1
Gastrointestinal Drugs Advisory Committee MeetingApril 7, 2016
Backup Slides Shown
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Change in ALP and Total Bilirubin:Primary Endpoint Non-RespondersDouble-Blind Phase 3 – Month 12
P-value for comparing active treatments to placebo is obtained using an ANCOVA model with baseline value as covariate and fixed effects for treatment, double-blind baseline UDCA usage (yes/no) and double-blind baseline total bilirubin (ULN/>ULN).
ALP (U/L) Total Bilirubin (mol/L)
-3
-2
-1
0
1
2
3
4
-180-160-140-120-100
-80-60-40-20
020
LS Me
an (S
E) Ch
ange
from
Basel
ine
Placebo(n=63)
Titration(n=32)
10 mg(n=28)
Placebo(n=63)
Titration(n=32)
10 mg(n=28)
p=0.0004
p=0.0001 p=0.0246p=0.0069
EF-560
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Percentage of Subjects Who Met Criteria for Advanced Disease StageDouble-Blind Phase 3
Criteria For Advanced DiseasePlaceboN=73n (%)
TitrationN=70n (%)10 mgN=73n (%)
TotalN=216n (%)Met criteria for advanced disease 30 (41) 22 (31) 20 (27) 72 (33)Subjects who met criteria 30 22 20 72
Baseline total bilirubin >ULN 7 (23) 4 (18) 7 (35) 18 (25)Baseline total ALP >5x ULN 3 (10) 1 (5) 2 (10) 6 (8)Baseline TE ≥10.7 kPa 17 (57) 13 (59) 10 (50) 40 (56)Cirrhosis 9 (30) 7 (32) 4 (20) 20 (28)Medical history of interesta 7 (23) 6 (27) 4 (20) 17 (24)
EF-488
aIncludes one or more of the following: ascites, hepatic cirrhosis, jaundice, portal hypertension, portal hypertensive gastropathy, and esophageal varices
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1Carbone M, et al. Hepatology. 2016; 63(3): 697-99. 2Lammers WJ, et al. Gastroenterology. 2015; 149(7):1804-12.
Optimized Response Criteria ModelsPrognostic index comprising baseline albumin and platelet count, plus bilirubin, ALT or AST, and ALP after 1 year UDCA
UK-PBC Risk Score1
(2016)
GLOBE Score2(2015)
Prognostic index comprising baseline age, and bilirubin, ALP, albumin, and platelet count after 1 year UDCA
UN-153
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Projected Risk of Liver Transplant or Death Prior to and Following 1 Year of Treatment with OCA or PlaceboUK-PBC
0
5
10
15
20
25
5 10 15
Placebo ± UDCABL: N=73Month 12: N=68
Titration ± UDCABL: N=70Month 12: N=60
10 mg ± UDCABL: N=73Month 12: N=60
Risk is defined as risk of liver transplant or liver-related death*p<0.001 vs placebo using rank ANCOVA model with baseline rank as a covariate
0
5
10
15
20
25
5 10 15
**
**
**Years Years
Baseline Following 1 Year ofOCA/Placebo
Media
n Proj
ected
Risk
(%)
(Q1, Q
3)
Media
n Proj
ected
Risk
(%)
(Q1, Q
3)
UN-129
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Change from Baseline in Total Bilirubin120-Day Safety Update – 2 Year Completer Population
Mean
(SD)
∆ in T
otal B
ilirub
in (µm
ol/L)
from
Basel
ine
Mean baseline total bilirubin 10.631 mol/L. Data are presented based on OCA baseline.Months on OCAMonths on OCA
-10
-5
0
5
10
0 3 6 9 12 15 18 21 24
EF-343
Weighted Average Daily OCA Dose ≤10 mg (N=104)
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Titration From 5 mg to 10 mg Results in Incremental BenefitDouble-Blind Phase 3 (n=33)
01020304050607080
02468
101214161820
Composite Endpoint ALP Total Bilirubin
0
50
100
150
200
250
300
39%
0%
ULN
1.67x ULN
Month 6 (5 mg)
Month 12(10 mg)
Month 6 (5 mg)
Month 12(10 mg)
Month 6 (5 mg)
Month 12(10 mg)
Perce
nt of
Resp
onde
rs
Mean
(SD)
ALP (
U/L)
Mean
(SD)
Total B
ilirub
in (µm
ol/L)
EF-336
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Framingham 10-Year Risk (Assumed Smoker)Double-Blind Phase 3
0
20
40
60
80
100
<10% 10 to<20%
20 to<30% ≥30% <10% 10 to
<20%20 to<30% ≥30%
Placebo (N=73) Titration (N=70) 10 mg (N=73)
Perce
nt of
Patie
nts (%
)
Framingham 10-Year Risk Percentage
Baseline Month 12
SA-1230
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Key Efficacy: Rotterdam Pre-Specified Criteria (Moderately Advanced Patients)Double-Blind Phase 3 – Month 12
0
10
20
30
40
50
60
-5-4-3-2-1012345
Primary Endpoint ALP (U/L) Total Bilirubin (mol/L)
Perce
nt of
Resp
onde
rs
LS Me
an (S
E) Ch
ange
From
Basel
ine
LS Me
an (S
E) Ch
ange
From
Basel
ine
-225-200-175-150-125-100
-75-50-25
0
Placebo (N=13) Titration (N=12) 10 mg (N=11)
0%
42%
27%
Rotterdam Criteria (moderately advanced): total bilirubin or albumin is abnormal. EF-638
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Hazard Ratios for Liver Transplantation or Death for BilirubinGlobal PBC Study Group Log-linear association was observed between bilirubin levels and the risk of liver transplantation and death at baseline and up to 5 years follow-up
* 3681/4635 patients were included for this analysis** 2109/3161 patients were included for this analysisLammers WJ, et al. Gastroenterology. 2014 Dec;147(6):1338-1349.
Bilirubin Values (xULN)
Hazar
d Rati
o for
Liver
Trans
planta
tion o
r Deat
h One Year Follow-up*
0 1 2 3 4 5
Five Years Follow-up**
0 1 2 3 4 5
Baseline*1086420 0 1 2 3 4 5
UN-111
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No Clear Optimal Cut-Off Point for ALP
Lammers et al. Gastroenterology. 2014 Dec;147(6):1338-1349.
1.67xULN
2xULN
1.67 xULN0.80
0.75
0.70
0.65
0.601.0 1.5 2.0 2.5 3.0
C-Stat
istics
ALP (xULN) Values After 1 Year Follow-Up
UN-42
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Hazard Ratios for Liver Transplantation or Death for ALPGlobal PBC Study Group Log-linear association was observed between ALP levels and the risk of liver transplantation and death after 1 year and up to 5 years follow-up** Higher ALP levels were associated with reduced transplant-free survival
*3710/4635 patients were included for this analysis**2203/3161 patients were included for this analysisLammers et al. Gastroenterology. 2014 Dec;147(6):1338-1349.
Alkaline Phosphatase Values (xULN)
Hazar
d Rati
o for
Liver
Trans
planta
tion o
r Deat
h One Year Follow-up*
0 1 2 3 4 5
Five Years Follow-up*
0 1 2 3 4 5
Baseline*543210 0 1 2 3 4 5
UN-110
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Summary of SAEs: Patients with CirrhosisDouble-Blind Phase 3OCA
PlaceboN=9n (%)TitrationN=7n (%)
10 mgN=4n (%)TotalN=11n (%)
Serious AE 0 2 (29%) 1 (25%) 3 (27%)Ascites 0 1 (14%) 0 1 (9%)Erysipelas 0 0 1 (25%) 1 (9%)Hepatic encephalopathy 0 1 (14%) 0 1 (9%)Edema 0 1 (14%) 0 1 (9%)Upper gastrointestinal hemorrhage 0 1 (14%) 0 1 (9%)
SA-283
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Individual Change in ALP Over Time: Patients with CirrhosisDouble-Blind Phase 3Ch
ange
in AL
P (U/L
)
-300
-200
-100
0
100
200
0 100 200 300Visit Day
Placebo (n=9)
-300
-200
-100
0
100
200
0 100 200 300Visit Day
Titration (n=7)
-200
-100
0
100
200
0 100 200 300Visit Day
10 mg (n=4)
-300
EF-295
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Study DesignPhase 4 PBC Clinical Outcomes Trial
Standard of Care
Entry~350 PBC patients
Mean bilirubin >1-3x ULNand/or
Mean ALP >5x ULN
Placebo Control
Historical Control
5 mg OCA titrated to 10 mg**at or after Month 3 (based on tolerability)
02 year recruitment/6 year follow-up
Quarterly visits
Study 747-302 protocol was finalized based on feedback from FDA regarding trial design and analysis plan
EF-225
Primary Composite Endpoint: Death (all cause), Liver Transplant; or Events related to End-Stage Liver Disease
121 Events (both groups combined) Provides 80% power to demonstrate statistical significancePlacebo survival estimate of 0.5 at 8 years with assumed hazard ratio of 0.60