Individualizing the PBC Care Pathway: From Baseline and Beyond

Chair, Gideon M. Hirschfield, MA, MB, BChir, FRCP, PhD, discusses primary biliary cholangitis in this CME/AAPA activity titled “Individualizing the PBC Care Pathway: From Baseline and Beyond.” For the full presentation, downloadable Practice Aids, and complete CME/AAPA information, and to apply for credit, please visit us at https://bit.ly/3ZnNPSA. CME/AAPA credit will be available until March 3, 2026.

1. Individualizing the PBC Care Pathway
From Baseline and Beyond

Gideon M. Hirschfield, MA, MB, BChir, FRCP, PhD

Lily and Terry Homer Chair in Autoimmune Liver Disease Research
The Autoimmune and Rare Liver Disease Programme

Division of Gastroenterology & Hepatology

University Health Network

Toronto General Hospital

Toronto, Ontario, Canada

Copyright © 2000-2025, PeerView

2. Our Goals for Today

Augment your knowledge of PBC diagnosis
and test selection

Equip you with strategies for selecting first-line
and second-line therapy

Provide guidance on long-term monitoring
and follow-up

Copyright © 2000-20;

3. Unlocking PBC Diagnosis
Essential Tests and Diagnostic Tips

Gideon M. Hirschfield, MA, MB, BChir, FRCP, PhD

Lily and Terry Homer Chair in Autoimmune Liver Disease Research
The Autoimmune and Rare Liver Disease Programme

Division of Gastroenterology & Hepatology

University Health Network

Toronto General Hospital

Toronto, Ontario, Canada

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

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4. 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. Reshetryak VI. Weld J Gasboonteral. 20521:683:708. 2. Mpavercundaton orpiver diseaseslaucinmunesSverdsease>pinarybitryshotngteete. PeerView

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5. Blood Tests Imaging Tests

Liver enzymes + Ultrasound
- ALPis elevated in diseases 7
where the bile ducts are Used to rule out other causes of bile
blocked or injured

duct damage (eg, gallstones, strictures)

Autoantibodies (ie, AMA)

+ Lipid panel, thyroid function tests,
celiac disease panel

1. Lindor KO etal. Hopatoogy. 2019,80:304-410. 2. hits aw. nid ni govihealh nformatonlver-<iseaselprimary-bilarycholangisagnosis

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6. PBC

gnostic Process’?

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

2. AMA positive or 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. 2019:8:904-410. 2 Semi © eta. Lancet 2011,977:1800-1600 PeerView

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7. 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 patty. 21940204419. 2. nor KO eta Hepatology 2022751012013 PeerView

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8. Navigating PBC
Key Risk Factors and First-Line
Treatment Strategies

Gideon M. Hirschfield, MA, MB, BChir, FRCP, PhD

Lily and Terry Homer Chair in Autoimmune Liver Disease Research
The Autoimmune and Rare Liver Disease Programme

Division of Gastroenterology & Hepatology

University Health Network

Toronto General Hospital

Toronto, Ontario, Canada

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

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9. PBC Treatment Goals!

Disease Normalize ALP
activity and bilirubin

Improve
symptoms
and liver
Stratty disease risk, biochemistry
start UDCA treatment
and set goals

Reassess patient bloodwork and Reduce fibrosis, increase
qualty of He. Consider early 2. transplant free survival and
‘therapy for high-isk patients normalize quality of life

Short-term targets Intermediate targets JJ Long-term targets

Monitor Adjust and
add-on individualize

1. Cangado GOL et al. Lancet Gest Hep. 2025 [Epub ahead of prin) PeerView

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10. 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 ii 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
den SO stress AR
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1. Cangado GOL et al. Lancet Gastro Hep, 2025 [Epub ahead ol prin).

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11. Beyond the Liver Is as Important to Patients!

Fatigue
“Brain fog”
Pruritus
Dryness

> Concurrent autoimmune
diseases

Reduced bone density
Abdominal pain
Cancer risk
Treatment side effects
Pregnancy

From asymptomatic and slowly progressive to symptomatic and rapidly evolving

1. Uo Act al Lancet 2020.3961915-192. PeerView

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12. 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
UDCA treats PBC but
does not alleviate associated

(eg, diarrhea, nausea, symptoms, such as |

abdominal pain) fatigue or pruritus
1. Lindor KO et al. Hepatology. 2019:68:394-418. 2. Bowlus CL et al. J Manag Care Spec Pharm. 2016:22. Pee rvi ew
HE DE A LE a e

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13. he Lower LP, the Better’

HR for Predicting Liver Transplantation or Death

for Percentage Change of ALP From Baseline to 1 Year

Reduction in ALP, %

No reduction
0-10

10-20

20-30

30-40

40-50

50-60

>60

1. Corpechot © et al. Hepatology. 2024:70:204.

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HR (95% CI)
1
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)

45
36
03
23
.03

.003
.005

UDCA is first-line
treatment for any

patient diag
with PBC

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14. AASLD Guidance Statements on ne 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

1. Undor KD et. Hepatology. 291880394418. 2, Lindo KO ela Hepatology. 2021.76:1012:019. PeerView

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15. Optimizing PBC Care
Monitoring First-Line Treatment and
Exploring Second-Line Therapies

Gideon M. Hirschfield, MA, MB, BChir, FRCP, PhD

Lily and Terry Homer Chair in Autoimmune Liver Disease Research
The Autoimmune and Rare Liver Disease Programme

Division of Gastroenterology & Hepatology

University Health Network

Toronto General Hospital

Toronto, Ontario, Canada

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

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16. 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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17. AASLD

idance Statements on Second-Line Trea

a
+ 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

1. Lindor KO etal. Hepatology. 2019.60:304-419. 2. Lndor KO e al. Hopatoogy. 2021:75:1012-1013, PeerView

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18. Limitations to UDCA Treatment!

Response and Other PBC.

Tolerability

Symptoms

+ Up to 40% of patients will not + From AASLD: “UDCA therapy

achieve a complete biochemical does not improve fatigue, pruritus,
response associated bone disease, or
autoimmune features found

+ 5% to 10% of patients are unable in association with PBC.”
to tolerate UDCA :

— Major adverse effects are
G related (eg, diarrhea, nausea,
abdominal pain)

1 Undor KD eta. Hopaolgy 2019:68:304-419. 2 Bowls CL et a. Manag Care Spec Pham. 201022. i
3 pe ivetoundaton orpverdsenses/oulonrnune-iver-<dseavesfpimarybilary-cholangha be. PeerView

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19. POISE Trial: Obeticholic Acid!

Primary Composite Endpoint
Double-Blind Phase Open-Label Phase
oz! Wi mg | Dose adjustment
oe

I Obeticholic acid, 10 mg
beticholic acid, 5-10 mg
Placebo

80

Patients With Response, %

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1.Nevens Feta N Eng! J Mod, 2016:375:831-643.

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20. 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 Feta. N Engl J Med, 2010:375:631-642.
2 Ocalva (obetihali aid) Preseñbing Information. hüps:mw-accessdata fa goudrugsattda_ doeslabel/2022/207000s0081 pall

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wPruritus

= Discontinued treatment
due to pruritus

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21. RESPONSE Trial: Seladelpar!

Biochemical Response*

and ALP Normalization
bal P<.001
so —
sa 617

Patients, %

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

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

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Mean, Ulliter

os383888388

LSM Change

ALP Serum Levels Through Month 12

2

Fi
$

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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22. ELATIVE Trial: Elafibranor!

ALP Normalization

100
M Eañbranor (n= 108)
Biochemical Response" 1H Placebo (n= 53)
100 MElañibranor (n = 108)
u Placebo (n

Time, wk

Change in Score on WI-NRS

Patients, %

LS Mean Change
From BL

Time, wk Elafibranor
05 8 2 mm 8 a es ES
Time, wk
+ ALP <1. 67x ULN van a derease of 215% and (tl ins nomalzan rom week to week 52. PeerView
Y kway KV etl Eng Med 2026280795905,

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23. PPAR Agonists vs Obeticholic Acid

Obeticholic acid!
Characteristic (5-10 mg, N = 70; ad o 7
10 mg, N = 73) QUE PR) WEL)
Baseline ALP, units/L 326 + 116 (5-10 mg)
(treatment group) 316 + 104 (10 mg) SIE EO Se Ta
46 (5-10 mg)
Response rate, % 47 (10 mg) 61.7 51
3 36 (5-10 mg)
Therapeutic response, % 37 (10 mg) 417 47
ALP normalization, % Not reported 25 15
o 33 (5-10 mg)
ALP reduction, % 39 (10 mg) 42.4 406+53
Risk of new-onset pruritus, 1.43 (1.09-1.88) (5-10 mg)
RR (95% Cl} 179 (1.37-2.33) (10 mg) 0.30 (0.12-0.80) 0.77 (0.43-1.38)
Note: Bezafibrate data not included because it is not approved or available as monotherapy in the United States.
4. Nevens Fetal. Eng! ed, 2016;375:631-643. 2. Hirschfeld GM el aL N Engl Mad, 2021:390789-794. PeerView

3 Kowdley KV et al. N Eng! Med. 2024:300.795:05. 4. Giannini EG el al Liver nt. 2024:45:018222

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24. 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

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

4. lavo (elafranor) Presenting Information, hips haw accessdata (a govidrugeatids_docssabel2024/2 1866020008 pat,

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, diarthea, nausea;
potential elevations in liver enzymes (though typically
reversible); pruritus (itching) may worsen initially, but
this is often transient

Common DDIs: probenecid, rifampin, bile acid
sequestrants

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2 Lidell (seladelpa) Prescribing Information. ps ww accesedata da govldrugsatda_docsabel/2024/21 7890500010 pat

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25. Managing the Journey
Long-Term Outcomes and Monitoring in PBC Care

Gideon M. Hirschfield, MA, MB, BChir, FRCP, PhD

Lily and Terry Homer Chair in Autoimmune Liver Disease Research
The Autoimmune and Rare Liver Disease Programme

Division of Gastroenterology & Hepatology

University Health Network

Toronto General Hospital

Toronto, Ontario, Canada

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

Copyright © 2000-2025, PeerView

26. Guideline-Recommended Pruritus Evaluation’?

AASLD 2018
Guideline

AASLD 2017
Guideline

“EASL recommends the evaluation
of all patients for the presence
“The symptoms of PBC significantly of symptoms, particularly pruritus, sicca
impair quality of life and do not typically complex and fatigue. Whilst end-stage

improve with UDCA or OCA treatment. liver disease is associated with
Therefore, they warrant separate progressive symptom burden,
evaluation and treatment.” severity of symptoms does
not necessarily correlate with
stage of disease in PBC.”

DeerVi
1 indor KO eta Hatley. 2019.0:304-418.2. European Assocation o In Su ol he Liver. J Hepa. 2017 67:15.172. PeerView

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27. Pruritus Assessment in Clinical Practice?

+ Keep it simple

+ Ask the patient!
+ Consider a O 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

60060000000

1.EicksonS ta most Dermata.2019:190:284269. 2. Hirsch GM el. N Engl J Med, 2024390.789-704 PeerView

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25, PeerView

28. Use
of topical
moisturizers

shower
temperature
cool

1. Pate J etal. BMY Open Gastroenterol 20188 2000266.

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Use of
fragrance-free
and dye-free
soaps and
detergents

Avoidance
of irritating
fabrics
(bedding
or clothing)

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29. AASLD Guideline Recommended Treatment Options

for PBC-Related Pruritus!

Medication/Class Dose Clinical Pearls
E Dose depends on product + Must space administration from
SE | pie acidresins chosen but is dosed other medications
Bs in g/day, typically divided + Causes Gl side effects
i$ at least 2x per day + Oral slurry tastes bad
Start with 12.5mg/day .
Naltrexone and increase dose every 3-7 days tanto nes oceunwiin abrupt
until 50 mg/day is reached reament een.
gz + Effect on pruritus is independent of any
32 ae 75-100 mg improvement in depressive symptoms
5 Y + Other SSRIs have not been studied for
& E treatment of pruritus
+ Clinically significant drug-drug interactions
Rifampicin 150-300 mg/day + Implicated in drug-induced liver injury
+ May cause red-colored urine or tears
1. Linder KO et al Hate. 2019:50:304-19. PeerView

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30. Emerging Pruritus Treatment Options: PPAR Agonists‘

+ PPAR agonists like seladelpar and elafibranor have demonstrated an ability to reduce itching in clinical trials (in addition to
biochemical improvements)

Seladelpar significantly improved pruritus in those with an elevated baseline NRS itch score; decrease in NRS correlates
with decrease in IL-31

Change in IL-31 by Decrease in Pruritus NRS Elafibranor (ELATIVE): Secondary Endpoints

Decrease in RS <2
ness 0239 n°43

In patients with moderate to severe pruritus

+ Decreases with elafibranor treatment in PBC Worst Itch.
NRS score through week 52 were not significantly
different from placebo: LS mean -1.93 ELA versus -1.15
placebo; differen % Cl, -1.99 to 0.42; P=.20

Placebo
I Seladelpar 5 ma

Change in 123, pg/mL,

I Treatment with elafibranor resulted in greater

10
E Seladelpar 10 mg reductions in PBC-40 Itch total score: LS mean change
from baseline to week 52 -2.5 ELA ver
NRS Chang NRS Change 22 difference, -2.3; 95% Cl, -4.0 to -0.7; P = .0070 (nominal)
Basolino | m Baseline | montn3 Treatment with elafibranor resulted in greater
Placebo 42664 “os ENT] 35(13) reductions in 5-D Itch total score: LS mean change
from baseline to week 52 -4.2 ELA versus -1.2 plac
Seladelpar 5 2306) 1408 ess 2808)
AE, ° à à ? difference, -3.0; 95% Cl, -5.5 to -0.5; P= .0199 (nominal)
Seladeipar10m9 27/07) 1805 109(24) 250

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1. Hirschfield GM et al. Eng J Med, 2024;300:783-704. 2 Kremer AE et al. Hepatology. 2024,80-27-37. 3. Koweley KV et al. N Engl J ed. 2024;300:705-808.

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31. The Future of PBC Treatment!

Inclusion crteria

‘ALP 1.67 x ULN (75%) ALP 215 x
LN but 51.67 x ULN (25%),

‘ALP 21.67 UN
en
ou

PBC: climbing to the top of a pyramid

UDCA: ~40% insufficient response o
1. Cangado GOL et al Lancet Gesto Hep 2025 Epub ae op] PeerView

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32. lleal Bile Acid Transport (IBAT) Inhi

Approved for ALGS and PFIC?2

Medi sage 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 meg/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

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33. 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 Placebo me — SOmg 180 mg 40 m9 90 mg + ItchRO score (0-10) used to assess pruritus
5 TS once daly once daly once daly tice daly twice daly
i, n=19) 5) n= 16) mi) (n= 19) + Combined volixibat groups achieved a
Ea statistically significant reduction from
Ba baseline in pruritus vs placebo (-3.82 points
Bs vs -1.50 points; P < .0001) at the 16-week
E E interim analysis
> P= Dora - 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 Gastroenterol Hepatol. 2023:21:1802-1912 PeerView

2 bips mn gsk comen gb/media/press-teleasealinerxibatshows-posilve phase-ibresulsin<holestateprurits. 3. Kowdley K el al. AASLD 2023. Abstract 5038

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