New Management Strategies in Primary Biliary Cholangitis

Cynthia Levy, MD, FAASLDProfessor of Medicine

Arthur Hertz Chair in Liver DiseasesUniversity of Miami

Primary Biliary Cholangitis (PBC)

• Chronic cholestatic liver disease• Autoimmune in nature• Inflammation and destruction of small interlobular bile ducts

• Affects predominantly middle-aged females• Rising incidence and prevalence

Carey E et al. Lancet 2015

Primary Biliary Cholangitis: 2 out of 3 needed

Chronic unexplained cholestasis

Positive anti-mitochondrial antibody or PBC-specific anti-nuclear antibody

Non suppurative destructive cholangitis on histology

Lindor K et al. Hepatology 2019

AMA (+) in general population 1:1000

Prevalence of PBC 0.4:1000

First Line Therapy: UDCA

UDCA 13-15

mg/kg/day

Improves TB, ALP,

GGT, AST and ALT

Improves cholesterol,

IgM

Delays histological progression

Delays development of esophageal

varices

Improves survival free of

liver transplantation

Levy C and Lindor KD. In: Zakimand Boyer's Hepatology: ATextbook of Liver Disease.Elsevier Inc;2011:738-753.

According to FOLD-PBC, of 3488 patients with PBC, only 70% had been prescribed

UDCA.

Primary Biliary Cholangitis: Transplant-Free Survival

Lammers WJ et al. Gastroenterology 2014

5 years 15 years

Chart1

5-year5-year

10-year10-year

15-year15-year

10 years

UDCA-treated

Untreated

90

79

78

59

66

32

Sheet1

UDCA-treatedUntreated

5-year9079

10-year7859

15-year6632

APPROXIMATELY 40% OF PATIENTS WITH PBC WILL NOT HAVE COMPLETE BIOCHEMICAL RESPONSE TO UDCA

EASL clinical practice guidelines J Hepatol 2017; AASLD practice guidance 2019

Risk Stratification

Baseline1-year after treatment is

initiated

Biochemistries; Modeling Liver stiffness

HIGH RISK FOR PROGRESSIONBaseline factors

Younger than 45

Male gender

Elevation total

bilirubin, lower

albumin

Presence of gp-210,

anti-centromere

APRILiver

stiffness > 9.6 kPa

Binary definitions Time (months) Treatment failureRochester1 6 ALP ≥2 ULNBarcelona2 12 Decrease in ALP ≤40% and ALP ≥1x ULNParis-I3 12 ALP ≥3x ULN or AST ≥2x ULN or bilirubin >1 mg/dlRotterdam4 12 Bilirubin ≥1x ULN and/or albumin 1.67x ULNParis-II6 12 ALP ≥1.5x ULN or AST ≥1.5x ULN or bilirubin >1 mg/dlEhime7 6 Decrease in GGT ≤70% and GGT ≥1 ULN

Continuous scoring Time (months) Scoring parameters

UK-PBC8 12 12 months: bilirubin, ALP and AST (or ALT); Baseline: albumin and platelets

GLOBE9 12 12 months: bilirubin, ALP, albumin, and platelet count; Baseline: age

EASL Clinical Practice Guidelines. J Hepatol 2017

GLOBE Score: Online Calculation

At a Minimum…

• Look at serum ALP, TB, albumin after 1 year of therapy with UDCA

• If ALP > 2x ULN or abnormal bilirubin Consider incomplete response to UDCA

There are Options for Non-Responders!!!

• Obeticholic Acid is FDA-Approved– In combination with UDCA for patients with PBC who have

been treated with UDCA for > 1 year and have incomplete response

– As monotherapy for patients with PBC who are intolerant to UDCA

FXR Agonist

Modulates BA

homeostasis

Anti-inflammatory

Anti-fibrotic

Increases hepatic insulin

sensitivity

Decreases portal

pressure

46% of patients on OCA met the primary endpoint compared to 10% of pts on placebo

Significant drop in ALP, AST, ALT, GGT, TB

Significant reduction in inflammatory markers

Reduction in HDL-cholesterol

No change in liver stiffness scores

Obeticholic Acid for PBC: POISE trial

Nevens F, et al. N Engl J Med. 2016;375:631-643.

Cumulative Incidence of Complications of PBC

In patients with inadequate response to UDCA, OCA decreased 15-yr cumulative incidences of:

• Decompensated cirrhosis from 12.2% to 4.5%

• HCC from 9.1% to 4%• OLT from 4.5% to 1.2%• Liver-related deaths from 16.2% to

5.7%

Samur S, et al. Hepatology. 2017.

OCA Dosing RecommendationsOCA Dose Disease Stage

Non-cirrhotic or compensated cirrhosis (Child-Pugh A)

Decompensated cirrhosis, Child B or C (including prior decompensation)

Starting dose – 1st

3 months5 mg/day 5 mg/week

Dose titration at3 months

10 mg/day 5 mg twice a week, at least 3 daysapart

May increase to 10 mg twice a week,at least 3 days apart

Maximum dose 10 mg/day 10 mg twice a week

DOSE TITRATION IS RECOMMENDED TO MINIMIZE ITCHING

Real World Effectiveness of OCA in PBC• 15 pts (24%) discontinued OCA

• Adverse events – 16 (25%) itching, fatigue

(12.7%), abdominal pain (9.5%)

• 63 patients treated with OCA– Median age 56 years, median duration of OCA

treatment 10.7 months– 55.6% with cirrhosis, 48% decompensated– 19% with overlap syndrome

• 22.6% had drop in ALP to < 1.5x ULN

• Mean change in ALP was -21.5% (p < 0.0001; similar rates in cirrhotics and non cirrhotics)

Levy C et al. ILC 2018

Management of Moderate to Severe Itching During OCA Treatment

• If on 10 mg/day, reduce dose to 5 mg/day• If on 5 mg/day and no contra-indication consider adding

rifampin or cholestyramine* • If no improvement, consider alternating days: OCA 5 mg qod,

or even a short drug holiday of a few days or a week, then resuming OCA

* As is the case with UDCA, cholestyramine must be administered 1 hour before or > 3 hours after OCA

Management of Itching in PBC

General:- Skin moisturizer- Wet, cooling, moist wraps- Avoid contact to exacerbating factors- Loose clothing- Trim fingernails- Anti-histamines at bedtime

First-Line Agent:-Cholestyramine 4-16 g/day ***

Second-Line Agents:- Rifampin 150-300 mg bid- Sertraline 75-100 mg/day- Naltrexone 12.5-50 mg/day

Other Treatments- Fibrates- Butorphanol- Nasobiliary drainage- Phototherapy- Plasmapheresis- MARS

Liver Transplantation

Carrion AF et al. Clin Liver Dis 2018; Lindor KD et al. Hepatology 2019

Use of Fibrates in PBC

• Available: Bezafibrate & Fenofibrate• PPAR agonists• Several ongoing clinical trials• Currently off-label use only

- BA detoxification- BA secretion- BA synthesis- Fatty acid oxidation- Down-regulates NF-

KB pathway

100 patients with incomplete response to UDCA

Randomized to BZF 400 mg/day or placebo, for 2 years

Primary endpoint* at 2 years: 30% BZF vs. 0% Placebo

Itch score, LSM and ELF improved in BZF group

BEZURSO: Bezafibrate + UDCA vs. Placebo + UDCA

0%

10%

20%

30%

40%

50%

60%

70%

normalization ALP

67%

2%

BZFPlacebo

Corpechot C et al. N Engl J Med 2018

Change in ALP in 48 Patients Treated with Bezafibrate for a median of 38 months

ALP decreased from 2.4x ULN to 1x ULN (p

Effect of Bezafibrate on Pruritus

• 26/48 had pruritus

• 16 resolved, 7 improved, 3 unchanged

Reig et al. Am J Gastro 2017

o Open-label (n = 20)o ALP levels decreased

significantlyo Rebound in ALP levels occurred

following fenofibrate discontinuation

Fenofibrate + UDCA—Phase II Findings in PBC Patients with Incomplete Response to UDCA

Levy C et al Aliment Pharmacol Ther. 2011

Time interval (weeks)M

ean

Seru

m A

LP

(U/L

)

Chart1

0

6

12

24

36

48

9-12 f/u

ALP

405

186

168

174

171

176

328

Sheet1

ALP

0405

6186

12168

24174

36171

48176

9-12 f/u328

Safety concerns with Fibrates

• Hepatotoxicity– Acute and chronic toxicity described– AIH-like picture possible

• Rise in creatinine– Typically reversible and without decline in GFR

• Rhabdomyolysis if in conjunction with a statin

Livertox.com; Ahmad J et al. Dig Dis Sci 2017; Davidson MH et al. Am J Cardiol 2007; 99(supp):3C-18C

o Randomized, double-blind, placebo-controlled trial (NCT00746486)o 62 patients randomized and treated (ITT population) with 36 months of treatment

with UDCA (12–16 mg/kg BW/day) with or without BUD (3 mg tid*)

Budesonide add-on therapy in PBC patients: Phase 3 trial

Hirschfield G, et al. ILC 2018, #2095 (GS-011)

Improved liver histology†

29.4%

42.5%

0

10

20

30

40

50

60

Placebo(n=22)

BUD(n=40)

% o

f pat

ient

s

p=0.225

Improved liver function

• Pruritus: 15% (6/40) in BUD group and 31.8% in placebo group (7/22)

• SAEs: 10 in BUD group and 7 inplacebo group

ALP < 1.67x ULN and >15% drop in ALP:

43% BUD vs. 23% PBO (p=0.038)

Take Home Message: The New PBC ParadigmsProper

diagnosis

• understanding of autoantibodies and role of biopsy

Risk stratification

• at baseline: young age, stage are the strongest predictors of progression

Assess for biochemical

response at 1 year

• binary criteria vs. scoring systems

Start adjuvant therapy for UDCA non-responders

• OCA - FDA approved• Off label - fibrates,

budesonide

New Management Strategies in Primary Biliary CholangitisPrimary Biliary Cholangitis (PBC)Primary Biliary Cholangitis: 2 out of 3 neededFirst Line Therapy: UDCAPrimary Biliary Cholangitis: Transplant-Free SurvivalApproximately 40% of patients with PBC will not have complete biochemical response to UDCASlide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11At a Minimum…There are Options for Non-Responders!!!Slide Number 14Obeticholic Acid for PBC: POISE trialCumulative Incidence of Complications of PBCOCA Dosing RecommendationsReal World Effectiveness of OCA in PBCManagement of Moderate to Severe Itching During OCA TreatmentManagement of Itching in PBCUse of Fibrates in PBCBEZURSO: Bezafibrate + UDCA vs. Placebo + UDCAChange in ALP in 48 Patients Treated with Bezafibrate for a median of 38 monthsEffect of Bezafibrate on PruritusFenofibrate + UDCA—Phase II Findings in PBC Patients with Incomplete Response to UDCASafety concerns with FibratesBudesonide add-on therapy in PBC patients: Phase 3 trialTake Home Message: The New PBC Paradigms