studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 525A
634
Elevation of alkaline phosphatase during follow-up is
an early predictor of hyperbilirubinaemia and of clinical
endpoints in primary biliary cirrhosis – an international
study
Willem J. Lammers 1 , Henk R. van Buuren 1 , Cyriel Y. Ponsioen 2 ,
Harry L. Janssen 3 , Annarosa Floreani 4 , Gideon Hirschfield 5 ,
Christophe Corpechot 6 , Marlyn J. Mayo 7 , Pietro Invernizzi 8 ,
Pier Maria Battezzati 9 , Albert Pares 10 , Frederik Nevens 11 , Douglas
Thorburn 12 , Andrew Mason 13 , Kris V. Kowdley 14 , Angela
C. Cheung 3 , Teru Kumagi 15 , Palak J. Trivedi 5 , Raoul Poupon 6 ,
Ana Lleo 8 , Llorenç Caballeria 10 , Keith D. Lindor 16,17 , Maren H.
Harms 1 , Bettina E. Hansen 1 ; 1 Gastroenterology & Hepatology,
Erasmus MC, University Medical Center, Rotterdam, Netherlands;
2 Academic Medical Center, Amsterdam, Netherlands; 3 Toronto
Western & General Hospital, Toronto, ON, Canada; 4 University
of Padua, Padua, Italy; 5 University of Birmingham, Birmingham,
United Kingdom; 6 Hôpital Saint-Antoine, APHP, Paris, France; 7 UT
Southwestern Medical Center, Dallas, TX; 8 Humanitas Clinical and
Research Center, Rozzano, Italy; 9 Università degli Studi di Milano,
Milan, Italy; 10 , University of Barcelona, Barcelona, Spain; 11 University
Hospitals Leuven, KULeuven, Leuven, Belgium; 12 The Royal
Free Hospital, London, United Kingdom; 13 University of Alberta,
Edmonton, AB, Canada; 14 Swedish Medical Center, Seattle, WA;
15 Ehime University graduate School of Medicine, Ehim, Japan;
16 Mayo Clinic, Rochester, MA; 17 Arizona State University, Phoenix,
AZ
Background and aim: Earlier reports have shown that patients
with primary biliary cirrhosis (PBC) and low alkaline phosphatase
(ALP) and bilirubin levels after 1 year of ursodeoxycholic
acid (UDCA) treatment have favourable liver transplant-free survival
. However, ALP and bilirubin may increase later during follow-up.
The aim of the study was to identify patients within this
group at risk of adverse outcome during follow-up. Methods:
Patient data were obtained from the international Global PBC
study group database, comprising long-term follow-up data
of 4845 patients from 15 centers across North America and
Europe. UDCA-treated patients with ALP ≤2.0xULN or bilirubin
≤1.0xULN at 1 year follow-up were included in this analysis.
Time-dependent Cox regressions analysis models was applied.
Results: During a median follow-up of 7.11 years (IQR, 3.34-
11.18) 350/2527 patients underwent liver transplantation or
died. Patients who developed elevation of ALP (>2xULN) during
follow-up had an increased risk of liver transplantation/death
compared with those who remained ≤2.0xULN (HR 2.20, 95%
CI 1.73-2.81, P value 1xULN) during follow-up were also at
higher risk of reaching an endpoint (HR 5.51, IQR, 4.40-6.88,
P value 2xULN, 25% had an
event within 6.4 years; for elevated bilirubin levels this was
1.5 years. Elevated ALP proofed to be an early predictor of
abnormal bilirubin levels during follow-up; of patients with both
normal bilirubin levels and ALP levels ≤2.0xULN 407 developed
elevated bilirubin. Those patients who reached ALP levels
>2.0xULN during follow-up were at higher risk of developing
hyperbilirubinaemia (HR 3.79, 2.95-4.86, P value 2.0xULN) during
follow-up is an early predictor of hyperbilirubinaemia, and an
important early marker of a possible clinical event.
Disclosures:
Henk R. van Buuren - Grant/Research Support: Intercept, Zambon Nederland BV
Cyriel Y. Ponsioen - Advisory Committees or Review Panels: Takeda; Consulting:
AbbVIE; Grant/Research Support: AbbVIE, Schering Plough, Dr. Falk Pharma,
Tramedico Netherlands, Takeda
Harry L. Janssen - Consulting: AbbVie, Bristol Myers Squibb, GSK, Gilead Sciences,
Innogenetics, Merck, Medtronic, Novartis, Roche, Janssen, Medimmune,
ISIS Pharmaceuticals, Tekmira; Grant/Research Support: AbbVie, Bristol Myers
Squibb, Gilead Sciences, Innogenetics, Merck, Medtronic, Novartis, Roche,
Janssen, Medimmune
Marlyn J. Mayo - Grant/Research Support: Intercept, Salix, NGM, Lumena,
Gilead
Albert Pares - Consulting: Lumena Pharmaceuticals, Intercept Pharmaceuticals, Inc
Frederik Nevens - Consulting: MSD, CAF, Intercept, Gore, BMS, Abbvie, Novartis,
MSD, Eumedica, Janssen, Promethera Biosciences; Grant/Research Support:
Ferring, Roche, Astellas, Novartis, Janssen-Cilag, Abbvie
Andrew Mason - Advisory Committees or Review Panels: AbbVie, Novartis,
Intercept; Grant/Research Support: Abbvie, Gilead, Astellas
Kris V. Kowdley - Advisory Committees or Review Panels: Achillion, BMS, Evidera,
Gilead, Merck, Novartis, Trio Health, Abbvie; Grant/Research Support:
Evidera, Gilead, Immuron, Intercept, Tobira; Speaking and Teaching: Abbvie,
Gilead
Palak J. Trivedi - Grant/Research Support: Wellcome Trust
The following authors have nothing to disclose: Willem J. Lammers, Annarosa
Floreani, Gideon Hirschfield, Christophe Corpechot, Pietro Invernizzi, Pier Maria
Battezzati, Douglas Thorburn, Angela C. Cheung, Teru Kumagi, Raoul Poupon,
Ana Lleo, Llorenç Caballeria, Keith D. Lindor, Maren H. Harms, Bettina E. Hansen
635
Evaluation of the Posology of Obeticholic Acid (OCA) in
Patients with PBC
Richard Pencek, Karen Lutz, Tonya Marmon, Leigh MacConell;
Intercept Pharmaceuticals, San Diego, CA
Background: Obeticholic acid (OCA) is a potent and selective
FXR agonist developed for treatment of primary biliary cirrhosis
(PBC). 216 patients were enrolled in the Phase 3, double-blind,
placebo-controlled trial and randomized to: Placebo (PBO), 10
mg OCA (maximally efficacious dose in PBC), or 5 mg OCA
titrating to 10 mg after Month (M) 6 based on tolerability and
clinical response. Titration of OCA at M6 mitigated tolerability
(pruritus, the most common AE) without compromising efficacy.
While both 5 mg and 10 mg resulted in clinically meaningful
and significant reductions in ALP compared to PBO, efficacy
was greater at the 10 mg dose. This analysis evaluated the tolerability
and efficacy Phase 3 data to support titration of OCA
earlier than M6 after initiating OCA treatment. Methods: Time
to first onset of treatment-emergent pruritus included the number
of patients with pruritus (first onset), without pruritus (censored),
and the minimum and maximum times in days. Kaplan-Meier
estimates were plotted as a “survival curve” for each treatment
group. Liver biochemistry measures (ALP, total bilirubin, GGT,
ALT, and AST) were evaluated by LS mean change over time
during the 12-month treatment period. Results: A Kaplan-Meier
survival curve demonstrated that median time to first pruritus
event was within the initial month of starting OCA. The median
time to first onset of any pruritus event occurred within 2 weeks
(OCA 10 mg), M1 (OCA 5 mg), and M2 (PBO). Mean BL
ALP (U/L) was 327 (PBO) and 316 (OCA 10 mg). Clinically
meaningful and significant improvements in ALP were achieved
within 3M and maintained through the 12M period (Figure).
Similar trends were observed in other liver biochemistry markers.
Conclusions: The timing of onset of pruritus is early for both
OCA doses. The majority of efficacy is observed within the
first 3M of initiating OCA therapy. Thus, 3M after initiation of
OCA is a reasonable timeframe to assess if a PBC patient may
benefit from uptitration of OCA 5 mg to 10 mg.