Innovative Approaches to Manage Primary Biliary Cholangitis: Charting New Courses of Care

Chair, David Bernstein, MD, MACG, FAASLD, AGAF, FACP, discusses primary biliary cholangitis in this CME/NCPD/AAPA/IPCE activity titled “Innovative Approaches to Manage Primary Biliary Cholangitis: Charting New Courses of Care.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/4ivyUgS. CME/NCPD/AAPA/IPCE credit will be available until March 9, 2026.

1. Innovative Approaches to Manage
Primary Biliary Cholangitis
Charting New Courses of Care

David Bernstein, MD, MACG, FAASLD, AGAF, FACP
Professor of Medicine

NYU Grossman School of Medicine

Director

Gastroenterology and Hepatology Ambulatory Network-Long Island
NYU-Langone Health

Bethpage, New York

Go online to access full CME/NCPD/AAPA/IPCE information, including faculty disclosures.

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2. Our Goals for Today

Augment your knowledge of the diagnosis of PBC

Equip you with strategies for implementing
patient-specific care plans

Provide guidance on recent efficacy and safety
outcomes from clinical trials of drugs to treat PBC

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3. Utilizing Criteria for Early Diagnosis and
Timely Initiation of PBC Treatment

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4. PBC: Burden of Disease and Impact o

Overview

+ Slow, progressive, autoimmune injury of the bile ducts leading to cirrhosis and liver failure

Clinical burden

+ Fatigue, pruritus, jaundice, cirrhosis

+ Long-term medical care, including monitoring for liver failure and transplantation
+ Significant economic costs related to hospitalizations, medications, ongoing care

+ 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

cer Vi
Mets OF el al Hepetoogy. 2013:58273-83. 2. Gungabissoon U et al BH) Open Gestoentera 2022, 2000857. PeerView

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5. PBC Pathogenesis’

+ Exposure to environmental mimic of modified E2 subunit
of the mitochondrial pyruvate dehydrogenase complex
(PDC-E2) triggers an immune response against biliary
epithelial cells (BECs)

immune system by presenting autoantigens on major
histocompatibility complex (MHC) II, leading to production

of disease-specific antimitochondrial antibodies (AMAs)

+ AMAS target immunodominant PDC-E2 epitopes in the
inner mitochondrial membrane, contributing to BEC
damage and apoptosis

+ Dysfunctional anion exchanger 2 (AE2) sensitizes BECS
to apoptosis, exposing PDC-E2 in apoptotic blebs, forming
antigen-antibody complexes that lead to cellular injury

+ An imbalance between proinflammatory effector T cells
and regulatory T cells dysregulates the immune response,
sustaining biliary damage

+ Inadequate immune suppression leads to progressive
inflammation, cholestasis, biliary fibrosis, and cirrhosis

1. Gulamhusein AF, Hirschfeld GM. Nat Rev Gastroenterol Hepatol. 2020, 1799-110. PeerView

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6. 50-year-old woman with hypothyroidism and dyslipidemia

Chief concern: “I've been feeling very tired and have itching, especially at night.”

6-month history of progressive fatigue and pruritus

— Fatigue is constant, severe, and unrelieved by rest, significantly impacting her ability
to perform daily tasks at work and home

— Describes the pruritus as particularly troublesome at night, disturbing her sleep

No history of abdominal pain or weight loss but reports feeling bloated occasionally

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7. Clinical Presentation of PBC?2

+ Fatigue =
+ Pruritus Risk Factors *
+ “Brain fog”

+ Body aches and pains + Female sex (90% of cases are women)

+ Sicca syndrome + Age of onset (typically 30-60 years of age)

+ Associated autoimmune diseases: thyroid
disease, Sjogren syndrome, rheumatoid

Physical Exam Findings arthritis, celiac disease

|

+ Hepatomegaly
+ Xanthelasmas
+» Splenomegaly

1 Resheinyak V Wo Gastoonoe. 20521:769-7708, 2. ips:tveroundatonergverdiseasesaucinmune ver iscasspimary ciar croangaspre. DE ET View

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8. PBC

gnostic Process’?

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

2. AMA positive or specific ANA positive (sp100 or gp210)

3. Liver biopsy consistent with PBC

Exclude Exclude Consider
ALP} nonliver biliary liver
source obstruction biopsy
1. Lindor KO etal. Hepatology. 2019:80:904-410.2. Semi et a Lancet 2011,977:1800-1600 PeerView

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9. pical PBC Presentation and Clinical Findings'

acteristic Typical of a Patient With PBC
Age >45 years
Sex Woman > man (9:1)
Symptoms Fatigue, pruritus, sicca, abdominal pain, arthralgias
en AMA positive in -95%; disease-specific ANA positive
in -30%-50° ¡SMA may be present
Immunoglobulin IgM typically elevated
Serum liver tests ALP elevated
Imaging Normal bile ducts
Liver histology Lymphocytic infiltrate, inflammatory duct lesion, granuloma possible
inde KO et Hepat, 2188639649. 2, Undo KO eta Hope. 202270121013 PeerView

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10. Navigating PBC Treatments
Efficacy and Safety Insights

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11. Let’s Come Back to Debi

Vitals: BP: 128/82 mmHg, HR: 72 bpm, temp: 98.4°F « Laboratory results:
(36.9°C), RR: 16/min, O, sat: 98% on RA ALP: 420 units/L

General: alert and oriented Total bilirubin: 0.8 mg/dL
AST: 43 units/L; ALT: 44 units/L
Skin: non-icteric, scratch marks on back AMA: 1:1280

Abdomen: soft, nontender; no hepatomegaly or ‘Serum IgM: 550 mg/100 mL.
splenomegaly noted; no ascites or palpable masses Anti-gp210: 50 units/mL
TSH: 2 milliunits/L

Neurological: no focal deficits or signs of neuropathy nern

with rosuvastatin)

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12. PBC Treatment Goals

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13. PBC Treatment Goals!

Disease Normalize ALP
activity and bilirubin

Reassess patient
reported outcomes
‘and liver foros

Improve through elastography
symptoms ‘consider add-on
and liver ‘combination therapies

biochemistry targets not reached

mr

Stratify disease risk,
start UDCA treatment
and set goals

‘Consider 2L therapies.
{or patients with
Incomplete response
to UDCA.

Reassess patient bloodwork and Reduce fibrosis, increase
quality of life. Consider early 21. transplant free survival and
‘therapy for at high-risk patients. normalize quality of life

1. Cangado OGL et al Lancet Gast Hep. 2025 [Epub ahead of pint) PeerView

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14. Risk Stratification in Patients Diagnosed With PBC’

Parameter Moderate to High Risk

Parameter

Lower age at diagnosis

Higher age at diagnosis

Advanced fibrosis

No advanced fibrosis,
at diagnosis at diagnosis
Clinical No overlapping liver disease clinica) AIH or MASLD overlap
‘Adequate response to UDCA Incomplete response to UDCA
Globe score <0.3 Globe score >0.3
Low baseline High baseline
Biochemical ALP/bilrubin/GGT Biochemical ALP/bilrubin/GGT
gp210 negative 9p210 positive
ru <10kPa Ares zu
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1. Canpado GOL et al. Lancet Gastro Hep, 2025 [Epub ahead ol pin.

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15. Beyond the Liver Is as Important to Patients!

Fatigue
“Brain fog”
Pruritus
Dryness

me Concurrent autoimmune
diseases

Reduced bone density
Abdominal pain
Cancer risk
Pregnancy
Treatment side effects

From asymptomatic and slowly progressive to symptomatic and rapidly evolving

1. Uso A et Lancet 2020,396:1015-1928, PeerView

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16. First-Line Therapy for PBC

Copyright © 2000:

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

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

Effective in 50% to 60% of patients | or normalize ALP
| or normalize ALT

40% will not achieve
an adequate
biochemical response

Gl side effects ee, {
(eg, diarrhea, nausea,

UDCA treats PBC but
does not alleviate associated
symptoms, such as |

abdominal pain) fatigue or pruritus
1 Undo Ko et Heat. 201829394418. 2, Born Let a J Manag Care Spe Porm. 20162. PeerVi
3. tips /Aiverfoundation orglver-diseases/autoimmune-lver-diseases/primary-biliary-cholangits-pbe. FeerView

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18. The Lower the ALP, the Bette:

HR for Predicting Liver Transplantation or Death

for Percentage Change of ALP From Baseline to 1 Year

Reduction in ALP, % HR (95% Cl)

No reduction
0-10

10-20

20-30

30-40

40-50

50-60

>60

1. Compechot O etal. Hepatology. 2024.70:39-8.

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a
0.88 (0.63-1.23)
0.85 (0.60-1.20)
0.67 (0.48-0.95)
0.84 (0.61-1.15)
0.70 (0.51-0.96)
0.59 (0.42-0.83)
0.62 (0.44-0.86)

UDCA is first-line
treatment for any

patient diagnosed
with PBC

+ Reducing ALP to <1.67 times ULN
is defined in clinical trials as a
“complete response” to therapy

— Accepted by FDA as surrogate

endpoint for accelerated approval

+ Normalization of ALP may be
better (in keeping with intuition)

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19. AASLD Guidance Statements on First-Line Treatment!

+ UDCA dosed at 13-15 mg/kg/day is 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

This guidance was developed before the accelerated FDA
approval of PPAR agonists seladelpar and elafibranor,
which are second-line treatments

Most clinicians assess response at 6 months

+. Lindo KD et a. Hepatology. 2019.90:294418. 2, Lindo KO ela Hopooy.2021:76:1012:019. PeerView

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025, Pi

20. mitations to UDCA Treatment"

Response and [+] Other PBC
Tolerability we Symptoms.

+ Up to 40% of patients will not achieve

ie complete ech aca (spores + From AASLD: “UDCA therapy does not
+ 5% to 10% of patients are unable to improve fatigue, pruritus, associated
tolerate UDCA bone disease, or autoimmune features

found in association with PBC.”
— Major adverse effects are
Gl-related (eg, diarrhea,
nausea, abdominal pain)

iS lS ana a itm Ñ
Le moan PeerView

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21. t’s Come Back to Debi

Q Initiated ursodeoxycholic acid (UDCA) 6 months ago

Q Repeat labs

— ALP 320 units/L
— Total bilirubin 0.9 mg/dL

Q Continues to experience pruritus and fatigue

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22. Second-Line Therapy for PBC

Copyright © 2000

23. ho Needs Second-Line Therapy?

+ Per AASLD guidance, biochemical response should be assessed after 12 months of UDCA treatment

using one of many published criteria’
Group
Rochester |
Barcelona
Paris |
Rotterdam
Toronto
Paris Il
Rochester II

Global

1. Lindor KD etal. Hopatoogy. 2019 80:30 410

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Response Cri

ALP 2x ULN

ALP | 40% from baseline or normalization

ALP 3x ULN, AST 2x ULN, and TB 1 mg/dL

TB <1x ULN and albumin >1x LLN
ALP 1.67x ULN + TB <2x ULN
ALP 1.5x ULN, AST 1.5x ULN, and TB 1 mg/dL

ALP 2x ULN
ALP 2x ULN

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24. Therapies

FXR agonist + Obeticholic acid

« Elafibranor

+ Seladelpar

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

- 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 second-line treatments

Most clinicians assess response after 6 months

|. Lindor KD et a. Hepatology. 2019.20:294418. 2, Lindo KO ell Hepetology. 2021:76:1012:019. PeerView

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26. POISE Trial: Obeticholic Acid!

Primary Composite Endpoint
Double-Blind Phase Open-Label Phase
1

100 4 f

Wl Obeticholic acid, 10 mg

z 80 [Wl Obeticholic acid, 5-10 mg
2 I Placebo
2
E 60
£
3 40
2
E
3
En

0

05 3 6 9 2 3 6 9 42
Time, mo
1. Nevens Ft al N Eng Med 2016:375 631-643. PeerView

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27. Patients, %

Adverse Events!

Treatment-Emergent Pruritus and Treatment Discontinuations Due to Pruritus*

80
70

68
56
38
10
0 1

Placebo OCA 5-10 mg OCA 10 mg

1. Nevens F et al. N Engl J Med, 2016;375:691-649.

2 Ocalva (obeichle aci) Preset

PeerView.com/FEE827

Information, Mtps www accessdat fda govidrugsatida_doca/abe/2016/207990S000m pal

wPruritus

= Discontinued treatment
due to pruritus

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28. Therapies

+ Obeticholic acid

+ Elafibranor
PPAR agonists
+ Seladelpar

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29. eroxisome Proliferator-Activated Receptors (PPARs)'®

PPAR isoforms modulate different biological processes, including:

Energy utilization
Cholestasis Lipids eral Inflammation Fibrosis

PPARa — Ss ——

<= +--+

4, Haczaye Feta Hapatol Commun. 2017:1:663-674. 2. Jones D et al Lancet Gastroenterol Hepatol. 2017:2:716:720. 3. valzako K e al Proc Mat Acad Sci USA.
ONE MOB 1908.2137.4.Durmaky AUX Bowls CL. Gattoertera Hepat (NM 20 ESTOS de Gava NV etal rd Mo! Sc 202122008 PeerVi
6. Choi YJ et al. Atherosclerosis. 2012;220:470-476. eerview

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30. Elafibranor: Dual PPARa and PPARG Agonist!

Approved by the FDA in June 2024 for the treatment of PBC in adults
without cirrhosis or with compensated cirrhosis (80 mg daily)

Decreases bile acid synthesis
Modulates bile acid output

ile toxicity

Anti-inflammatory effects

Promotes bile acid transport

1. Goapato Fell. J ean! Autoimmun, 2023:6:100188 PeerView

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31. ELATIVE Trial: Study Design!

ELATIVE trial was a double-blind, randomized, placebo-controlled phase 3 trial to evaluate the efficacy and
safety of elafibranor 80 mg once daily in patients with PBC with an inadequate response or intolerance to UDCA

Primary Endpoint

Elafibranor 80 mg +

161 Patients With PBC UDCA Biochemical response at week 52:

08) + ALP <1.67 x ULN
Select inclusion criteria: + ALP decrease 215% from baseline
+ 212 months of treatment + Total bilirubin < ULN

with UDCA
Select Secondary Endpoints
+ Aged 18-75 years
+ ALP 21.67 x ULN ALP normalization
Reduction in WI-NRS

+ Total bilirubin <2 x ULN en en

q > == 5-D itch scale
Change in ALP

+ Elafibranor was studied in combination with UDCA: 95% (153/161) of patients were receiving concurrent UDCA

+ ULN for ALP was defined as 104 units/L for women and 129 units/L for men
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1. Kowdley KV et al. N Eng! J Med. 2024.300.795-805,

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32. ELATIVE Trial: Efficacy’

ALP Normalization

100
20 MM Elafibranor (n = 108) P=.002
Biochemical Response* * MM Placebo (n= 53) 15
100 MElafibranor (n = 108) z
Im Placebo (n = 53) =
90 a
*
E Time, wk
5
3 Change in Score on WI-NRS
5 10
4
¿a
E
E
Time, wk 2 Elafibranor
E DE mm TE TO es we 82
ALP <1 67x ULN with a decrease of 215% and total bibi normalization rom week 4 to week 52. mee PeerView

1 Kowalay KV et al. N Engl Y Mod. 2024 300 705-805.

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33. Drug Interactions!

Adverse Drug-Drug
Events Interactions
+ No significant adverse events + Reduces exposure of progestin
when compared with placebo except and ethinyl estradiol which can
lead to contraceptive failure and/or
— 6% fracture rate in elafibranor arm breakthrough bleeding

compared with 0% in placebo arm
+ Coadministration of HMG-CoA

reductase ors (statins)
can increase risk of myopathy

— Periodic monitoring of CPK with
HMG-CoA reductase inhibitor use

+ Coadministration of rifampin may
reduce systemic exposure to elafibranor

4. Kowdley etal. N Engl J Med, 2024;380:785-805, PeerView
2 Igivo [ealibranor)Prescribing Information. hips Jwrwwaccessdala da govidrugsafda. doeslabel2024/218260s0000 pal.

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34. Elafibranor Summary!

Elafibranor

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 — Pruritus improvement
alkaline phosphatase + 6% fracture rate
1. Kou at al N Engl Mad 202420070605 PeerView

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35. Seladelpar: PPARG Agonist"?

+ Seladelpar is a selective “delpar’ (PPARS agonist) targeting multiple cell types and processes in PBC

+ Approved by the FDA in August 2024 for the treatment of PBC in adults without cirrhosis or with compensated
cirrhosis (10 mg daily)

Hepatocytes and Macrophages and

Cholangiocytes Kupffer Cells Hepatocytes Hepatocytes
Reduces inflammation Increases lipid metabolism

E E E z Total cholesterol, LDL,
¥ Bile acid synthesis Y, Inflammatory cytokines § Bile acids Y sigycerides
Inflammatory lipid 5 en

Y ar y medistors Y Interleukin (IL)-31 4 Fatty acid oxidation
Y cor Y AT

Seladelpar is a selective PPARS agonist with anticho

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1. Hirschfeld GM etal, Hepatology. 202378-397-415. 2, Kremer AE et al Liver Int 2022:42:112-123,

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36. RESPONSE Trial: Study Design’

RESPONSE trial was a double-blind, randomized, placebo-controlled phase 3 trial to evaluate the efficacy and safety
of seladelpar 10 mg once daily in patients with PBC with an inadequate response or intolerance to UDCA

Month 0 6 EOS 12

Key Inclusion Criteria \
N=193 Open-label

: long-term study*

PBC and inadequate response or SE CO

intolerance to UDCA
or

ALP 21.67x ULN
ALT and AST <3x ULN 2-week safety

Total bilirubin <2x ULN follow-up visit

[+ Can have compensated cirrhosis

Secondary endpoints:

+ ALP normalization at month 12

+ Changes in pruritus NRS at month 6 in patients with
moderate to severe pruritus (NRS 24) at baseline

Primary endpoints:
+ Composite biochemical response at month 12
- ALP <1.67 x ULN
— ALP decrease 215%
— Total bilirubin $1.0 x ULN
‘Misha ota o PeerView

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37. RESPONSE Trial: Efficacy’

Biochemical Response*
and ALP Normalization

bl P<.001

so —

Les 617

Patients, %

Placebo — Seladepar "Placebo Seladepor
NT]
Biochemical Alkaline
Response Phosphatase
Normalization

ALP <1.67% ULNwith a decrease of 215% and total bitrubin normalen at month 12.
1 Hirschfeld GM et al. N Engl J Med. 2024;300:783-704

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Mean, unitsfiter
8888388888

LSM Change

ALP Serum Levels Through Month 12

Re

E
$

Change in Pruritus NRS Scores By Time and Group
in Patients With Baseline Score 24

Seladelpar 92]

Baseine 1 3 y y 2
Time, mo

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38. jal: Safety and

Drug-Drug
Interactions

Adverse

Events

+ OAT3 inhibitors such as probenecid,
rifampin, cabotegravir

+ No significant adverse events
when compared with placebo except
+ Strong CYP2C9 inhibitors such as
fluoxetine and amiodarone (avoid
taking together)

— 4% fracture rate in seladelpar arm
compared with 0% in placebo arm

+ BCRP inhibitors such as rosuvastatin,
glyburide, nitrofurantoin, chlorothiazide,
sulfasalazine

— Monitor closely for adverse effects

+ Mestad Qu ot a. ng J Mad, 2024200783796 i
2. Livdelzi (seladelpar) Prescribing Information. https //www accessdata fda govidrugsatida_docs/label'2024/2178993000Ib1 pdf. PeerV lew

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39. Seladelpar

Selective PPARS agonist |

Dose: 10 mg orally daily, with or without food |

Phase 3 RESPONSE trial
+ 62% met composite endpoint + Statistically significant
+ 25% normalization of alkaline improvement in pruritus
phosphatase + 4% fracture rate
1 Mince GM ot al. Eng J Mad 2024:30002-14, PeerView

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40. Comparing Available PPAR Agonists‘

Elafibranor

+ Dual PPARa and PPARG agonist

+ FDA approved in June 2024

= Approved in patients with PBC with incomplete
response to or intolerant of UDCA

+ Pruritus: numerically reduced itch in phase 3 trial
but was not statistically significant

+ Common AEs: headache, diarrhea, abdominal
pain, nausea; possible elevations in liver enzymes,
particularly in patients with pre-existing liver
disease; fracture

+ Common DDIs: hormonal contraceptives, statins,
rifampin, bile acid sequestrants

1. Ivo (elafbranon) Prescrbing Information. ps: accesedala fda govidrugsatfda_docslabe/2024/2188600000 pa.
2 Lidell (seladelpa) Preseriing Information, hips vr aceessdala fda. govidrugsatida_docs/abel2024/217899s0001 pal.

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Seladelpar

Selective PPARS agonist

FDA approved in August 2024

— Approved in patients with PBC with incomplete
response to or intolerant of UDCA.

Pruritus: met secondary endpoint in phase 3 trial
that itch was statistically significantly reduced

Common AEs: headache, diarrhea, nausea;
potential elevations in liver enzymes (though
typically reversible); pruritus (itching) may worsen
initially, but this is often transient; fracture

Common DDIs: probenecid, rifampin, bile acid
sequestrants

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41. PPAR Agonists vs Obeticholic Acid

Obeticholic acid

Characteristic (5-10 mg, N = 70; Elafibranor
(N = 108)
10 mg,

Baseline ALP, units/L. 326 + 116 (5-10 mg)

(treatment group) 316 + 104 (10 mg) $21.35 121.9
Response rate, % pus 51
Therapeutic response, % Geen 47

ALP normalization, % Not reported 15

ALP reduction, % An) 40.6253

Note: Bezafibrate data not included because it is not approved or available as monotherapy in the US

Seladelpar
(N = 128)

314.6 + 123.0
61.7
41.7
25

42.4

PR
1.Kondy KV el a Eng J Md. 202400708208. 2. Hrs GM eta. M Engl Med. 2024300783704, 3. Nevers Feta. Engl Jen 2orearsesreas, PEETVIEW

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42. Addressing Symptoms and
Complications Associated With PBC

43. C
O... Oi
© Dyslipidemia

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44. PBC-Related Pruritus Assessment
and Treatment

Copyright © 2000

45. Let’s Come Back to Debi

Initiated PPAR agonist after her last visit 6 months ago

ALP and total bilirubin are now WNL

Fatigue has improved

Pruritus continues to interrupt her sleep and affect her activities of daily living

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46. Guideline-Recommended Pruritus Evaluation’?

AASLD 2018
Guideline

AASLD 2017
Guideline

“EASL recommends the evaluation
of all patients for the presence

of symptoms, particularly pruritus, sicca

complex and fatigue. Whilst end-stage

“The symptoms of PBC significantly
impair quality of life and do not typically

improve with UDCA or OCA treatment.
Therefore, they warrant separate
evaluation and treatment.”

liver disease is associated with
progressive symptom burden,
severity of symptoms does
not necessarily correlate with
stage of disease in PBC.”

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1. indo KO tai Hopilogy. 2019.8:304410 2. European Assocation o In Su ol he Liver. J Hepa. 2017.165-172 PeerView

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47. Pruritus Assessment in Clinical Practice’

+ Keep it simple
+ Ask the patient!
+ Consider a 0 to 10 numerical rating scale

— Patients rate their itch at its worst on a scale
from 0 (no itching) to 10 (worst itch imaginable)

— Scores 24 indicate moderate to severe itching

a
a
a
a
a
a
a
a
a
a
a

1. Brekson Set al J invest Derma. 219.139.284 260. 2. Hirshfield GM el. N Engl J Med. 2024990,789-704 PeerView

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48. Initial Management of Pruritus

Skin care
+ Moisturizers

Sleep hygiene
+ Cold showers before bed

+ Melatonin

Cut fingernails to avoid scratch Wear loose-fitting clothes made
marks and excoriations of natural fibers such as cotton

Avoid woolen clothing and

tight-fitting clothes Avoid overly scented detergents

Consider primrose oil,

Consider anti-histamines 2 grams twice a day

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49. Stepwise Approach to Managing Pruritus'

+ Difficult dose finding

Medication Clinical Pearis

+ Bloating
Anion exchange ‘constipation or
diarrhea, nausea administration

Cholestyramine nother medications

mpin + 10% risk of

mg/day) hepatitis usually
‘occurring in the
first 2 months

Drug-drug interaction:

Rifampin May cause discolored
urine or tears

+ Loss of appetite,
iritabilty, GI

+ Somnolence, N
nausea,
dizziness, fatigue

1. Lindr KD, et al Hepatology. 200050-201-308. 2. EASL. J Hep, 201745-172. PeerView

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50. lleal Bile Acid Transport (IBAT) Inhi

Approved for S and PFIC but Not PBC

Medi Dosage Considerations
+ Approved for pruritus in ALGS and PFIC
Odevixibat 40-120 mcg/kg/day
Abdominal pain, diarrhea
+ Approved for pruritus in ALGS and PFIC
Maralixibat 190-380 mcg/kg/day

Abdominal pain, diarrhea

+ Have shown efficacy in treating cholestatic pruritus in pediatric diseases like ALGS and PFIC
+» Set the stage for further investigation into IBAT inhibitors for treating PBC-related pruritus

1. Byvay (odevicbat Presrking Infomation. htos:le2hmusedT gwrh coude neVaBéantdl-3ca0-4362 a7 1-dSdetSaeS3HSI7S73eO886 89-907
Sita 1Baa QG 62360-85041 907 AI 160a260_source_V PA, 2 Lumar (mara) Presetng Information. PeerView
ips hw accessdata (da. govidrugsatide_docslabel2024/2 14862501 1 pl. eervie

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51. Investigational IBAT Inhibitors

for Treating PBC-Related Pruritus13

GLIMMER: Phase 2b Trial of Linerixibat!? VANTAGE: Phase 2b Study of Volixibat?
In GLIMMER, linerixibat ameliorated itch compared with placebo following
12 weeks’ treatment; lower doses were better tolerated. + N= 30 patients with PBC randomized 1:1:1
3 Mean Worst Daily Itch Score to volixibat 20 mg twice daily, volixibat 80
É (Patients with moderate to severe pruritus’) mg twice daily, or placebo twice daily
2 pce me 90mg 180 mg 40 mg 90 mg + ItchRO score (0-10) used to assess pruritus
5 TS ance daly once daly once daly toe daly dee day
i, n=19) 5) n= 16) mi) (n= 19) + Combined volixibat groups achieved a
Ea statistically significant reduction from
Ea baseline in pruritus vs placebo (-3.82 points
4 3 vs -1.50 points; P < .0001) at the 16-week
E 2 interim analysis
EL” 0374 - Placebo-adjusted difference:
2 -2.32 points (P = .0026)
+ 24-week data from GLISTEN (phase 3 trial) demonstrate the
primary endpoint was met
- Significant reduction in pruritus vs placebo
4. Levy Cet a. Cin Gastroentorot Hepatol. 2023:21:1802-1912 PeerView

2 Hs gs comen gbímedia/press-teleaseslineribatshows-posiive phase-ibresulsin<holestatepruritus. 3. Kowdley K etal AASLD 2023. Abstract 5038.

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52. Management of Symptoms Associated With PBC

Dry
Eyes

Fatigue

+ Artificial tears and saliva are + Seek and treat associated/and

often helpful alternate causes of fatigue
« Pilocarpine can be used for — Anemia
[reco yey mors) — Hypothyroidism
— Depression
— Sleep disturbance

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53. Complications of PBC: Metabolic Bone Diseas:

Osteoporosis: more common

Duration/severity of PBC and jaundice
Axial skeleton

Reduced osteoblastic activity
DXA scanning

Calcium 1200 mg/day and vitamin D
1,000-2,000 units/day

Bisphosphonates

Osteomalacia: less common

+ Vitamin D deficiency and fat malabsorption
+ Calcium and phosphate levels

+ 25-hydroxyvitamin D level

+ Calcium and vitamin D supplements

serVi
1.Hee Ko Seta. Bone Metab, 201219:199-98 erView

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54. Treatment of Metabolic Bone D

2 PE

+» 1,000-1,500 mg/d

+ 800-1,000 units (normal 25-OH vitamin D level)

+ 50,000 units vitamin D,, 2-3 times weekly if 25-OH vitamin D level is low and
then maintenance

Bisphosphonates

+ Alendronate 70 mg weekly
+ Data lacking regarding efficacy

+ Not first line because of complications

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55. Complications of PBC: Dyslipidel

Xanthomas and

Early disease Late disease SEniokanes Atherosclerosis risk

No increased risk
of ischemia heart

1 HDL, LDL, J in HDL and Cholesterol disease, stroke,
and VLDL 1 in LDL >600 mg/dL or TÍA unless there
is a separate
lipid disorder
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56. Conclusions: Approv urrent Medical Treatments for PBC

First-line
therapy

. . PPAR Inhibitors
Obeticholic Elafibranor Second-line
acid therapy
Seladelpar

Transplantation
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57. Conclusions

+ PBC is achronic, progressive, autoimmune cholestatic disease
+ Simple diagnostic criteria

+ Two-tiered treatment approach
- Liver disease

- Complications and associated conditions (eg, pruritus)
+ End-stage disease treated with liver transplantation

« Early diagnosis and treatment saves lives!

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