Advancing PBC Care Through Timely Referral and Treatment: From Diagnosis to Long-Term Management

Co-Chair & Presenter, Stuart C. Gordon, MD, FACP, FACG, AGAF, FAASLD, and Marlyn J. Mayo, MD, discuss primary biliary cholangitis in this CME/NCPD/CPE/AAPA activity titled “Advancing PBC Care Through Timely Referral and Treatment: From Diagnosis to Long-Term Management.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE/AAPA information, and to apply for credit, please visit us at https://bit.ly/4maXtAZ. CME/NCPD/CPE/AAPA credit will be available until October 21, 2026.

1. Advancing PBC Care Through Timely
Referral and Treatment

From Diagnosis to Long-Term Management

Stuart C. Gordon, MD, FACP, FACG, AGAF, FAASLD Marlyn J. Mayo, MD

Professor of Medicine Professor of Intemal Medicine
Michigan State University College of Medicine Division of Digestive & Liver Diseases
East Lansing, Michigan University of Texas Southwestern
Division of Hepatology Henry Ford Health System Dallas, Texas

Professor of Medicine

Wayne State University School of Medicine

Detroit, Michigan

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2. Our Goals for Today

Augment your knowledge of symptoms and life
impact experienced by patients living with PBC

Provide guidance on how to optimize current and
emerging treatment options for PBC

Equip you with strategies to implement
evidence-based treatment plans and empathetic
communication techniques

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3. PBC Overview

Epidemiology, Disease Burden, and
Clinical Recognition

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4. PBC: Burden of Disease and Impacts on Quality of Life!*

Overview

+ Slow, progressive, immune-mediated injury of the bile ducts leading to progressive fibrosis and cirrhosis
+ Predominantly affects women aged 40-70 years old
+ United States adjusted prevalence was 40.9/100,000 adults in 2021

Symptoms/clinical burden

+ Fatigue, pruritus, joint pains, Sicca syndrome, hyperlipidemia, osteoporosis, cirrhosis

+ Significant economic costs related to long-term medical care, hospitalizations, medications, ongoing care,
potentially transplantation

+ Reduced physical, emotional, and social well-being
+ Mental health burden: increased risk of depression and anxiety due to chronic symptoms
+ Chronic fatigue, itching, and disability impact work, relationships, and personal activities

1. Melis GF eta. Hepatology. 2013:58:273-83. 2. Gungabissoon U eta. 844 Open 2022;8.2000087.

Gastroenter Pp
3 Tanai Atta Lancet 2034408 1059-1088.4 Levy Cal Mont Corman. 20280087 €

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5. PBC Etiology: Combina

Environmental Triggers’

Other potential associations

Genetics Environmental o
+ Familial + Bacterial Sus

clustering Autoimmune infections Hormone replacement
+ Twin + Xenobiotics therapy

response F
concordance + Lifestyle Geo i
graphic clustering

+ HLA + Microbiome

Socioeconomic
influences

associations

1. Lindor KO et ai. Hepatology. 2019:68:394-4 16. 2, Tanaka A et al. Lancet. 2024:404:1053-1068. 3. Lieo A et al. Semin Liver Dis. 2020:40:34-48. PeerView
4 Tanaka At a. Exp Bol Med (Maywood). 2018 243:184-189, 5. Tanaka A et al Cin Exp Immunol 2019.10525-34. 8. Probert PM etal. J Hepatol. 2018,80:1123-1195 FE CT V IE

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6. yond the Liver: What Matters To Patients’

Fatigue
“Brain fog”
Pruritus
Dryness (eyes, mouth)
Concurrent autoimmune diseases
Reduced bone density
Lipid abnormalities
Abdominal pain
Cancer risk
Pregnancy
Treatment side effects

From asymptomatic and slowly progressive to symptom:

1. Leo A et a Lancet 2020.306:1915-1920. PeerView

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7. PBC

gnostic Process’?

PBC diagnosis requires at least two of these three criteria:
1. Elevated ALP

2. AMA positive or specific ANA positive (sp 100 or gp210)
3. Liver biopsy consistent with PBC (eg, florid duct lesions, hepatic granulomas)

Exclude Exclude Consider
ALP} nonliver biliary liver
source obstruction biopsy
Not necessary if ALT or AST are also mildly elevated
1. Lindor KD etal. Hepatology. 2019.60:304-419. 2, Semi © etal. Lancet. 2011.377:1800-1800. PeerView

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8. Staging Patients With PBC13

+ Why staging matters
= Predicts long-term outcomes
— Guides management decisions

+ Histology (Ludwig/Batts-Ludwig)
— Stage 1: portal inflammation
— Stage 2: periportal extension
— Stage 3: bridging fibrosis
= Stage 4: cirrhosis

+ Noninvasive tools
— Fibroscan, APRI, FIB-4, ELF

+ Liver biopsy

Stage 1: portal inflammation, granulomatous destruction of small bile ducts
Stage 2: periportal fibrosis (scarred but intact portal tracts), cholestasis
Stage 3: septal or bridging fibrosis, active inflammation

Stage 4: cirrhosis, regenerative nodules

se
1. Lindr KO etl. Hepatology. 2010.80:304419. 2, Corpschl © el. Hoptoogy. 2012:58:19 208,2. Tv PU eal. Hopatol 2014:80:1249-1258. PeerView

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9. Faculty Discussion

®
A

10. Impact of PBC on Quality of Life

Copyright © 2000

11. CS gm ew

= =

Debilitated

Cm em

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1. Chi Metal MU Hepat! 20241227: PeerView

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12. Quality of Life Burden in People With PBC

Because of Pruritus and Fatigue’?

Cholestatic pruritus

+ Fatigue and pruritus
are two of the most
commonly reported
symptoms in people
living with PBC,
occurring in up to 80%

p quality

Lower sl

p Worse HRQOL

Fatigue

or more of patients

Both occur independent
of disease stage and
biochemical response

to treatment

4. Yagi Met a. Sei Rep. 2018:3-12542. 2. Mell. GF etal. Hepatology. 2013:58:273-3. 3, Kapps L et al. Dl Dis Se. 2020:65:2006-2013. 4. Dyson JK eta. Aliment Pharmacol
‘Ther. 2016;44:1026-1050. 5. Daza Jet al. Dig Dis. 2025:43:170-178. 6, Smith HT etal. Hepatol Commun, 2025860836. 7. Zhao Z e al. Front Mad (Lausanne). PeerView
2024.11:1444473, 8. Gungabissoon U el al BMJ Open Gastroenterol. 2022.9:e000867. 9. Christe M et al. EM) Mopato 2024,12.27:35,

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13. PBC-40: A Disease-Speci
for People With PBC’

+ Tool derived from interviews with 30

people with PBC and validated in national Itch
surveys involving 900 people with PBC
+ PBC-40 consists of 40 questioı CI $
CES

six domains

+ Takes 10-20 minutes to complete

— May not be feasible during a clinic
visit (often used in research settings)

— Can use the PBC-10, a shortened
validated questionnaire?

1. Jacoby Atl, Gut 2006;54:16229.2. Aruba Let a Aliment Pharmacol Tr. 2019.50:1223-1231 PeerView

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14. PBC-10: A Short QOL Screening Tool for People With PBC"

Please answer all the questions to the best of your ability. If a particular ques
particular question, simply write on the questionnaire.

In the last 4 weeks, how often did you experience any of the following?

does not apply to you, or you do not know the answer to a

1. have felt embarrassed because of the itching Never Rarely Occasionally Frequently Alays Doesnotapply
2. If leat or drink a small amount and stil felt bloated Never Rarely Occasionally Frequently Always Does not apply
3. My mouth was very dry Never Rarely Occasionally Frequently Always Doesnotapply
4. Fatigue interfered with my daily routine Never Rarely Occasionally Frequently Always Doesnotapply
5. | had to force myself to do the things I needed to do Never Rarely Occasionally Frequently Always Doesnotapply

6. If was busy one day, | needed at least another day to recover Never Rarely Occasionally Frequently Always Does not apply
7. Because of PBC, | found it difficult to concentrate on anything Never Rarely Occasionally Frequently Always Does not apply
Now some more general statements about how PBC may be affecting you as a person. How much do the following statements apply to you?

8. | feel guilty that | can't do what | used to do because

of having PBC Not at all Alittle Somewhat Quite a bit Very much Not applicable
These statements relate to the possible effects of PBC on your social life and your life overall. Thinking of your own situation, how much do you
agree or disagree with them?

9. My social fe has almost stopped Srongly agree. Acree NETTER Disagree Song dsagree Strongy agree

10,PBC has reduced the quality of my ie Stony agree Agree NEWS! pages Srongy agree Stony agree
4. Alubay Letal. Aliment Pharmacol Ther 2019.50:1223-4231 PeerView

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15. Faculty Discussion

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A

16. PBC-Related Symptom Control and
Unmet Needs

17. Initial Management of Pruritus'?

Skin care
+ Moisturizers

Sleep hygiene
+ Cold showers before bed

+ Melatonin

Cut fingernails to avoid scratch
marks and excoriations

Wear loose-fitting clothes made
of natural fibers such as cotton

Avoid woolen clothing and
tight-fitting clothes

@
©
©

Avoid overly scented detergents

Consider antihistamines

Mindfulness and mind-body
programs?

1. Lindor KD etal. Hopaolegy. 2019,80:304-410.2. ndor KO el al. Hepatology. 2021,75:1012-1013. 3. Watt Metal, Hepatal Commun. 20237-00318.

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18. Stepwise Therapeutic Approach to Managing Pruritus??

STEED |: Difficult dose finding Both PPAR agonists
E |: Bloating, (seladelpar and Medication Clinical Pearls

Anion exchange ‘constipation or elafibranor) have
resin diarrhea, nausea favorable effects

on pruritus

Cholestyramine

Rifampin + 10% risk of
ET | hepatitis usually
_PXR agonist ‘occurring in the

Rifampin

TIN | - Loss of appetite,
irritability, GI

side effects

+ Somnolence,
nausea,
dizziness, fatigue

1. Lindr KO etl, Hopatlogy. 2009;50:201-308. 2 EASL. J Hepatol 2047,145:172 PeerView

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19. Faculty Discussion

®
A

20. Complications of PBC: Dryness, Fatigue, and Dyslipidemia‘

Dry eyes and

dry mouth Dyslipidemia

+ Artificial tears and saliva are + Lack of specific therapies; + Typically presents as

often helpful seek and treat associated elevated total cholesterol
and alternate causes
+ Pilocarpine can be used for offatigue SS No as

refractory symptoms A elevated

~ Anemia — LDL-C may be normal

— Hypothyroidism or reduced

- Depression + Presence does not

= Sloan dis necessarily correlate with

sala ala increased CV risk
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1. Lindor KD etal. Hopaology. 2009, 50:201-308, 2, EASL. J Hopatal,2017;145-172,

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21. Complications of PBC: Osteoporos'

Osteoporosis

+ Duration/severity of PBC and jaundice
+ Axial skeleton,

+ Reduced osteoblastic activity

+ DEXA scanning

+ Treatment Compression

+ Calcium 1,200 mg/day y fractures

+ Vitamin D 1,000-2,000 units/day

+ Prescription medication (eg, oral or IV
bisphosphonates) may be necessary

+ Data for treatment is extrapolated from
studies in postmenopausal osteoporosis

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1.Dantord CJ eta. Cin Dons. 2020:23:228-298, 2. Danord A et al. Word J Gastroenterol 201824:3513-3520. Pee

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22. Goals of PBC Care

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23. Goals of PBC Care’

Recognizing and addressing
the heterogeneity
of disease presentation,
progression, and
outcomes is essential
for optimizing care

1. Hirschfeld GM et al. Export Rev Gastroonora! Hopao. 2021:15:920:9,

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Treatment should be
individualized based
‘on each patient's risk profile,
liver disease stage, and
associated symptoms

Effectiveness of therapy
and symptom management
must be regularly assessed

and adjusted over time

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24. Ursodeoxycholic Acid (UDCA): First-Line Treatment for PBC

+ First-line therapy for improving biochemical indices and delaying disease progression

Adequate biochemical response
(ALP <1.67 times the ULN)
achieved in 50% to 60% of patients

40% will not achieve
an adequate
biochemical response

10% ae UDCA treats PBC but

Gl side effects predominate unable to does not alleviate associated
(eg, diarrhea, nausea, tolerate symptoms like
abdominal pain) fatigue or pruritus

1 Undo Ko eta Hoatlogy. 201:6:904-418.2. Bonus CL tl J Manag Caro Spee Pharm. 201622 i
3 po vertcundaton ore lsensesiavicineninafverlesocsfmry tary ang pe PeerView

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25. s on First-Line Treatment!

+ The dose of UDCA is 13-15 mg/kg/day in 2-4 divided doses and recommended
for patients with PBC who have abnormal liver enzyme values

+ Biochemical response to UDCA (eg, ALP, ALT levels) should be evaluated 12 months
after treatment initiation to determine whether second-line therapy is indicated

Biochemical response at 6 months may predict 12-month response

| Lindo KD et a. Malay. 2019.9:394419. 2, Lindo KO ell Hepetology. 2021:76:1012:019. PeerView

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26. Response and Monitoring to First-Line Therapy

Is Often Inadequate!>

Management is no longer as simple as
starting UDCA and hoping it works

Approximately 30%-50% nonresponse
to UDCA

Lack of consensus on optimal timing and
serologic threshold to define UDCA response

Inadequate or absent UDCA response
is a strong predictor of poor outcomes

In one survey, only 30% of hepatologists
and gastroenterologists felt they were
competent to monitor UDCA responses

1. Jepson Let al. Di De Se 2018:63:2547-2564, 2. Srakumar Metal Fonte Gasrentre2021:19:323%. Few
3 Tire J e al Hepatol Commun, 20237-60170. 4 Aguilar MT e al Hopat Med. 2020-1220 77.5, Chazcaa OM, Linder KD. Dig is Se. 20168-2407 2486, PeerView

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27. Faculty Discussion

®
A

28. AASLD Guidance Statements on Second-Line Treatment?

+ Patients who do not satisfactorily respond to UDCA should be considered
for treatment with obeticholic acid (OCA), starting at 5 mg/day

+ Fibrates can be considered as off-label alternatives for patients with PBC
and inadequate response to UDCA

This guidance was developed before the accelerated FDA
approval of PPAR agonists seladelpar and elafibranor,

which are additional second-line treatments,
and the voluntary withdrawal of OCA from the US market

1. Undor KD eta. Hopaoogy. 201950:394-41.2.LindorKD ta. Hepaolgy- 202175.1012-1013. PeerView

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29. Peroxisome Proliferator-Activated Receptors (PPARs)!

Ligands

1. Colaieto F et al J Trans! Autoimmun, 2023:8:100188.

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Isoforms and site of action

Actions

PPARa

Reduction of inflammation
Regulation of lipid metabolism,
including fasting/feeding transition

Hepatocytes Reduced liver fibrosis (rat models)
Regulation of bile acid metabolism
PPARY
— Reduction of inflammation
CBC kuprercels Increase of steatosis

Antifibrotic activity

PPARS e” ER

Hepatocytes,
Kupffer cells,
cholangiocytes

Reduction of inflammation
Decrease of steatosis
Protection from carcinogenesis

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30. Elafibranor Summary!

Dual PPARa and PPARS agonist

Dose: 80 mg orally daily, with or without food

Phase 3 ELATIVE trial
+ 51% met primary endpoint + Numerical improvement in WI-NRS
+ 15% normalization of ALP (pruritus scale)

+ 6% fracture rate vs. O with placebo

Effects on lipids: | TG, | VLDL-C, no effects on LDL-C or HDL-C

Drug-drug interactions with oral contraceptives, statins, and rifampin;
do not use in pregnancy

1. Kowaley et al. N Engl J Mod, 2024300 705-805

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31. Seladelp:

Selective PPAR® agonist

Dose: 10 mg orally daily, with or without food

Phase 3 RESPONSE trial

+ 62% met composite endpoint + Statistically significant improvement in
+ 25% normalization of ALP WI-NRS (pruritus scale)
+ 4% fracture rate vs. O with placebo
Effects on lipids: | TC, | LDL-C, no effects on HDL-C or TG

Drug-drug interactions with OATS inhibitors (eg, rifampin), strong CYP2C9
inhibitors (eg, fluoxetine), BCRP inhibitors (eg, rosuvastatin)

14. Hose GM eta. N Engl Med. 2024;390:789-704 PeerView

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32. Test or Assessment Frequency

Liver enzymes (ALP, ALT, AST,

+ Track response to first-line therapy

Every 3-6 months

+ Re-assess need for second-line therapy total bilirubin)
+ Detect disease progression (fibrosis, Platelets, INR, albumin Every 3-6 months
cirrhosis)
q Fibrosis assessment
+ Screen for complications (portal a Every 1-3 years
hypertension, HCC) (eg, transient elastography)
+ Evaluate treatment-related side effects If cirrhosis present, abdominal
ultrasound and AFP Eyoty month
der KO a Hat 201660304410, 2, apache eta Map 2012568808, 3, Coto Meta Heo. 2016430900 PeerView

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33. Faculty Discussion

®
A

34. at the F

re Holds for Personal

Diagnosis Personalized Care Aspirational Goals

UDCA 13-15 mg/kg/d

Tell patient their risk

Use therapies targeted
at patient profiles Achieve normal
+ Liver tests serum liver tests
At12mo ‘ pits a
: 'esolve ductopenia
Assess UDCA response || 7 errs is

and liver fibrosis

Normal quality of life

2

Treat baseline risk and

on-treatment responses No liver transplantation

ine

2L therapy and symptom Bu
initiated to individual need
management Aspire in future for PBC cure
1. Chit Met a. EM Hepatol, 20281227 3, PeerView

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