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
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