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1. A43 LONG-TERM EFFICACY AND SAFETY OF OBETICHOCLIC ACID IN PRIMARY BILIARY CHOLANGITIS: RESPONDER ANALYSIS OF OVER 5 YEARS OF TREATMENT IN THE POISE TRIAL

Author

Hirschfield, G, Jones, D, Carbone, M, Bowlus, CL, Nevens, F, Kremer, AE, Liberman, A, MacConell, L, and Hansen, BE

Abstract

Abstract Background Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is approved as second-line treatment for primary biliary cholangitis (PBC) in patients with an incomplete response or intolerance to ursodeoxycholic acid. Aims We evaluated the effect of OCA in PBC patients enrolled in the POISE trial, comparing those who did or did not achieve the POISE response criteria. Methods The phase 3, randomized, double-blind, 1-year POISE trial evaluated the efficacy and safety of OCA 5 and 10 mg vs placebo in patients with PBC; a 5-year open-label extension followed in which all patients received OCA. This analysis evaluated longer-term efficacy and safety in patients who achieved the POISE primary endpoint of alkaline phosphatase (ALP)

Published
2021

2. Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients

Author

MacConell L, Gurney K, Malloy J, Zhou M, and Kolterman O

Subjects
Specialties of internal medicine, RC581-951
Abstract

Leigh MacConell,1 Kate Gurney,2 Jaret Malloy,1 Ming Zhou,3 Orville Kolterman4 1Clinical Development, Bristol-Myers Squibb, San Diego, CA, USA; 2Medical Writing, Bristol-Myers Squibb, San Diego, CA, USA; 3Biostatistics, Bristol-Myers Squibb, Princeton, NJ, 4Safety, Bristol-Myers Squibb, San Diego, CA, USA Background: Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. Methods: Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure-adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. Results: Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site-related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. Conclusion: The overall safety and tolerability profile of exenatide QW was similar to that of other GLP-1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events. Keywords: glucagon-like peptide-1 receptor agonist, hyperglycemia, adverse events, hypoglycemia

Published
2015

3. Reduction and stabilization of bilirubin with obeticholic acid treatment in patients with primary biliary cholangitis

Author

Pares, A, Shiffman, M, Vargas, V, Invernizzi, P, Malecha, E, Liberman, A, Macconell, L, Hirschfield, G, Pares A., Shiffman M., Vargas V., Invernizzi P., Malecha E. S., Liberman A., MacConell L., Hirschfield G., Pares, A, Shiffman, M, Vargas, V, Invernizzi, P, Malecha, E, Liberman, A, Macconell, L, Hirschfield, G, Pares A., Shiffman M., Vargas V., Invernizzi P., Malecha E. S., Liberman A., MacConell L., and Hirschfield G.

Abstract

Background & Aims: Total bilirubin is a predictor of survival in primary biliary cholangitis, with the main elevated component being direct bilirubin. The purpose of this post hoc analysis was to assess the efficacy and safety of obeticholic acid across quartiles of varying baseline levels of direct bilirubin in the phase 3, randomized, placebo-controlled Primary Biliary Cholangitis Obeticholic Acid International Study of Efficacy. Methods: This analysis assessed patients on the basis of their baseline direct bilirubin level (divided by quartile). Biochemistry and safety outcomes were evaluated within each quartile over time. Results: In the quartile with the highest baseline direct bilirubin (>5.47 µmol/L), there was a significant reduction in both direct and total bilirubin at Month 12 compared with placebo. Least squares mean (standard error) change from baseline in direct bilirubin at Month 12 was 4.17 (1.42) µmol/L for placebo, −3.48 (1.63) µmol/L for obeticholic acid 5-10 mg and −3.66 (1.51) µmol/L for obeticholic acid 10 mg (P <.0001, obeticholic acid vs placebo); the corresponding values for total bilirubin at Month 12 were 4.38 (1.55) µmol/L for placebo, −4.53 (1.83) µmol/L for obeticholic acid 5-10 mg and −5.06 (1.64) µmol/L for obeticholic acid 10 mg (P <.0001, obeticholic acid vs placebo). Conclusions: Obeticholic acid treatment was associated with significant reductions in total and direct bilirubin, particularly in patients with high baseline direct bilirubin. Because raised direct bilirubin levels, even within the normal range, are predictive of survival in primary biliary cholangitis, these results suggest substantial benefits of obeticholic acid in at-risk patients.

Published
2020

4. Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years

Author

MacConell L, Pencek R, Li Y, Maggs D, and Porter L

Subjects
Specialties of internal medicine, RC581-951
Abstract

Leigh MacConell, Richard Pencek, Yan Li, David Maggs, Lisa PorterAmylin Pharmaceuticals, LLC, San Diego, CA, USABackground: Type 2 diabetes mellitus is a progressive metabolic disease necessitating therapies with sustained efficacy and safety over time. Exenatide once weekly (ExQW), an extended-release formulation of the glucagon-like peptide-1 receptor agonist exenatide, has demonstrated improvements in glycemic and cardiometabolic measures from 30 weeks to 2 years of treatment. Here, the efficacy and safety of treatment with ExQW for 3 years are described.Methods: Patients were initially randomized to receive either ExQW (2 mg) or exenatide twice daily for 30 weeks. Following the initial 30 weeks, all patients were treated with ExQW in an open-label extension. Analyses of primary glycemic endpoints, beta-cell function, and cardiometabolic measures were assessed for patients who completed 3 years of ExQW treatment and for the intention-to-treat population. Safety and tolerability analyses were provided for the intention-to-treat population.Results: Sixty-six percent of the intention-to-treat population (n = 295) completed 3 years of treatment (n = 194). At 3 years, a significant reduction in hemoglobin A1c (least squares mean ± standard error) of -1.6% ± 0.08% was observed, with 55% and 33% of patients achieving hemoglobin A1c targets of

Published
2013

5. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials

Author

Gurney K, Brown C, MacConell L, and Han J

Subjects
Specialties of internal medicine, RC581-951
Abstract

Leigh MacConell, Carl Brown, Kate Gurney, Jenny HanAmylin Pharmaceuticals, Inc. San Diego, CA, USABackground: Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes.Methods: Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 µg and 10 µg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12–52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated.Results: Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166–171 days). Transient, mild-to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%).Conclusion: Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.Keywords: exenatide, safety, adverse events, risk difference

Published
2012

7. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

Author

Nevens, F, Andreone, P, Mazzella, G, Strasser, S, Bowlus, C, Drenth, J, Pockros, P, Regula, J, Beuers, U, Trauner, M, Jones, D, Floreani, A, Hohenester, S, Luketic, V, Shiffman, M, van Erpecum, K, Vargas, V, Vincent, C, Hirschfield, G, Shah, H, Hansen, B, Lindor, K, Marschall, H, Kowdley, K, Hooshmand Rad, R, Marmon, T, Sheeron, S, Pencek, R, Macconell, L, Pruzanski, M, Shapiro, D. Collaborator: Carbone, INVERNIZZI, PIETRO, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, Gastroenterology & Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Graduate School, Other departments, Nevens, F., Andreone, P., Mazzella, G., Strasser, S.I., Bowlus, C., Invernizzi, P., Drenth, J.P.H., Pockros, P.J., Regula, J., Beuers, U., Trauner, M., Jones, D.E., Floreani, A., Hohenester, S., Luketic, V., Shiffman, M., Van Erpecum, K.J., Vargas, V., Vincent, C., Hirschfield, G.M., Shah, H., Hansen, B., Lindor, K.D., Marschall, H.-U., Kowdley, K.V., Hooshmand-Rad, R., Marmon, T., Sheeron, S., Pencek, R., Macconell, L., Pruzanski, M., Shapiro, D., Nevens, F, Andreone, P, Mazzella, G, Strasser, S, Bowlus, C, Invernizzi, P, Drenth, J, Pockros, P, Regula, J, Beuers, U, Trauner, M, Jones, D, Floreani, A, Hohenester, S, Luketic, V, Shiffman, M, van Erpecum, K, Vargas, V, Vincent, C, Hirschfield, G, Shah, H, Hansen, B, Lindor, K, Marschall, H, Kowdley, K, Hooshmand Rad, R, Marmon, T, Sheeron, S, Pencek, R, Macconell, L, Pruzanski, M, Shapiro, and D., C

Subjects
Liver Cirrhosis, Male, 0301 basic medicine, Cirrhosis, Fibroblast Growth Factor, medicine.medical_treatment, Clinical Trial, Phase III, Placebo-controlled study, Liver transplantation, Gastroenterology, Pruritu, chemistry.chemical_compound, 0302 clinical medicine, Primary biliary cirrhosis, Bone Density, Chenodeoxycholic acid, Adult, Aged, Alkaline Phosphatase, Bile Acids and Salts, Chenodeoxycholic Acid, Double-Blind Method, Female, Fibroblast Growth Factors, Humans, Liver Cirrhosis, Biliary, Middle Aged, Pruritus, Non-U.S. Gov't, Medicine (all), Research Support, Non-U.S. Gov't, Biliary, Obeticholic acid, General Medicine, Clinical Trial, Bile Acids and Salt, Multicenter Study, Randomized Controlled Trial, 030211 gastroenterology & hepatology, Human, medicine.medical_specialty, Randomization, Liver Cirrhosi, Research Support, Placebo, 03 medical and health sciences, Phase III, Internal medicine, Journal Article, medicine, business.industry, medicine.disease, Surgery, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, chemistry, business
Abstract

none 32 BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P

Published
2016

9. A217 NONINVASIVE ASSESSMENTS TO IDENTIFY PATIENTS WITH ADVANCED FIBROSIS DUE TO NASH: SCREENED POPULATION FROM THE REGENERATE TRIAL

Author

Montano-Loza, A J, primary, Boursier, J, additional, Sanyal, A J, additional, Ratziu, V, additional, Rinella, M, additional, Loomba, R, additional, Dufour, J, additional, Mozaffari, E, additional, Shringarpure, R, additional, MacConell, L, additional, Granston, T, additional, Zhou, H, additional, Trylesinski, A, additional, Harrison, S A, additional, Bedossa, P, additional, Goodman, Z, additional, Younossi, Z, additional, Noureddin, M, additional, Bugianesi, E, additional, and Anstee, Q M, additional

Published
2021
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12. Obeticholic Acid Efficacy in Patients With NASH Monitored Using Noninvasive Tests: Post Hoc Analysis of REGENERATE Trial

Author

Alkhouri, N, additional, Sanyal, A, additional, Ratziu, V, additional, Rinella, M, additional, Loomba, R, additional, Dufour, JF, additional, Mozaffari, E, additional, Granston, T, additional, Zhou, H, additional, Shringarpure, R, additional, MacConell, L, additional, Bedossa, P, additional, Goodman, Z, additional, Younossi, Z, additional, Anstee, Q, additional, von Roenn, N, additional, Harrison, S, additional, and Geier, A, additional

Published
2021
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13. T06.01.12 OBETICHOLIC ACID (OCA) IMPROVES NON-INVASIVE MARKERS OF FIBROSIS IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS (NASH): A SECONDARY ANALYSIS OF THE PHASE 3 REGENERATE STUDY

Author

Anstee, Q.M., primary, Harrison, S., additional, Sanyal, A.J., additional, Ratziu, V., additional, Rinella, M., additional, Younossi, Z.Y., additional, Boursier, J., additional, Francque, S., additional, Geerts, A., additional, Petta, S., additional, Bugianesi, E., additional, Romero-Gomez, M., additional, Schattenberg, J.M., additional, Sarkar, S., additional, Bonacini, M., additional, Yataco, M., additional, Porayko, M., additional, Siddique, A., additional, Dufour, J., additional, Ferro, T., additional, Venugopal, A., additional, Zaru, L., additional, Shringarpure, R., additional, Macconell, L., additional, Goodman, Z., additional, and Loomba, R., additional

Published
2020
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14. OC.05.5 OBETICHOLIC ACID TREATMENT IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS: A SECONDARY ANALYSIS OF THE REGENERATE STUDY ACROSS FIBROSIS STAGES

Author

Sanyal, A.J., primary, Ratziu, V., additional, Loomba, R., additional, Rinella, M., additional, Anstee, Q.M., additional, Goodman, Z., additional, Bedossa, P., additional, Khalili, M., additional, Boursier, J., additional, Stinton, L., additional, Marchesini, G., additional, Allison, M., additional, George, J., additional, Arkkila, P., additional, Bugianesi, E., additional, Zaru, L., additional, Macconell, L., additional, Shringarpure, R., additional, and Younossi, Z., additional

Published
2020
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15. Durable response in the markers of cholestasis through 5 years of open-label extension study of obeticholic acid in primary biliary cholangitis

Author

Nevens, F., primary, Shiffman, M.L., additional, Drenth, J.P.H., additional, Bowlus, C.L., additional, Vargas, V., additional, Andreone, P., additional, van Erpecum, K., additional, Floreani, A., additional, Liberman, A., additional, Pencek, R., additional, Malecha, E. Smoot, additional, MacConell, L., additional, and Trauner, M., additional

Published
2020
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16. Obeticholic Acid Treatment in Patients with Non-Alcoholic Steatohepatitis: A Secondary Analysis of the Regenerate Study Across Fibrosis Stages

Author

Sanyal, A.J., primary, Ratziu, V., additional, Loomba, R., additional, Rinella, M., additional, Anstee, Q.M., additional, Goodman, Z., additional, Bedossa, P., additional, Khalili, M., additional, Boursier, J., additional, Stinton, L., additional, Marchesini, G., additional, Allison, M., additional, George, J., additional, Arkkila, P., additional, Bugianesi, E., additional, Zaru, L., additional, MacConell, L., additional, and Shringarpure, R., additional

Published
2020
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20. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study

Author

Trauner, M., Nevens, F., Shiffman, M.L., Drenth, J.P.H., Bowlus, C.L., Vargas, V., Andreone, P., Hirschfield, G.M., Pencek, R., Malecha, E.S., MacConell, L., Shapiro, D., Trauner, M., Nevens, F., Shiffman, M.L., Drenth, J.P.H., Bowlus, C.L., Vargas, V., Andreone, P., Hirschfield, G.M., Pencek, R., Malecha, E.S., MacConell, L., and Shapiro, D.

Abstract

Item does not contain fulltext, BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis using 3-year interim data from the 5-year open-label extension of the pivotal phase 3 POISE trial. METHODS: In the double-blind phase of POISE, 217 patients with primary biliary cholangitis with inadequate response to or intolerance to ursodeoxycholic acid were randomised to receive placebo, obeticholic acid 5 to 10 mg, or obeticholic acid 10 mg once daily for 12 months. During the open-label extension phase, patients received variable, adjusted doses of obeticholic acid. Markers of cholestasis and liver injury, alkaline phosphatase (ALP), and total and direct bilirubin were evaluated, and safety was assessed for up to 48 months of treatment with obeticholic acid. All analyses in the open-label extension were done in the safety population, defined as any patient randomised in the double-blind phase who received at least one dose of obeticholic acid during the open-label extension. This trial is registered at ClinicalTrials.gov (NCT01473524) and with EudraCT (2011-004728-36). FINDINGS: 193 patients were treated during the open-label extension. In this 3-year interim analysis, ALP concentrations were significantly reduced compared with baseline at 12 months (mean change -105.2 U/L [SD 87.6]), 24 months (-101.0 U/L [98.5]), 36 months (-108.6 U/L [95.7]), and 48 months (-95.6 U/L [121.1]; p<0.0001 for all yearly time points). Total bilirubin concentrations were stabilised, with significant reductions versus baseline at 12 months (mean change -0.9 mumol/L [SD 4.1]; p=0.0042) and 48 months (-0.8 mumol/L [3.8]; p=0.016). Stabilisation was also noted for direct bilirubin, with a significant change from baseline at 12 months (mean change -0.5 mumol/L [SD 3.0]; p=0.021). However, changes in total and direct bilirubin were not significant at other time points. Obeticholic acid was generally well tolerated, with pruritus (149 [77%

Published
2019

21. Langzeitbehandlung mit Obeticholsäure ist bei Patienten mit Primär Biliärer Cholangitis mit Verbesserungen der Kollagen-Morphometrie assoziiert

Author

Kremer, AE, additional, Bowlus, CL, additional, Bedossa, P, additional, Pares, A, additional, Forman, LM, additional, Drenth, JPH, additional, Ryder, S, additional, Terracciano, L, additional, Jin, Y, additional, Liberman, A, additional, Pencek, R, additional, MacConell, L, additional, and Pockros, PJ, additional

Published
2019
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22. OC.01.4 THREE YEARS OF OBETICHOLIC ACID (OCA) THERAPY RESULTS IN HISTOLOGICAL IMPROVEMENTS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS: FURTHER ANALYSIS OF THE POISE BIOPSY SUBSTUDY

Author

Bowlus, C.L., primary, Pockros, P., additional, Kremer, A., additional, Pares, A., additional, Forman, L.M., additional, Drenth, J.P., additional, Ryder, S., additional, Floreani, A., additional, Terracciano, L., additional, Jin, Y., additional, Lieberman, A., additional, Pencheck, R., additional, Iloeje, U., additional, Macconell, L., additional, and Bedossa, P., additional

Published
2019
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23. Three years of obeticholic Acid (OCA) therapy results in histological improvements in patients with primary biliary cholangitis: further analysis of the POISE Biopsy substudy

Author

Bowlus, C.L., primary, Pockros, P.J., additional, Kremer, A.E., additional, Parés, A., additional, Forman, L.M., additional, Drenth, J.P.H., additional, Ryder, S., additional, Terracciano, L., additional, Floreani, A., additional, Jin, Y., additional, Lieberman, A., additional, Pencek, R., additional, Iloeje, U., additional, MacConell, L., additional, and Bedossa, P., additional

Published
2019
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24. Three years of Obeticholic Acid (OCA) Therapy Results in Histological Improvements in Patients with Primary Biliary Cholangitis: Further Analysis of the POISE Biopsy Substudy

Author

Bowlus, CL, additional, Pockros, PJ, additional, Kremer, AE, additional, Parés, A, additional, Forman, LM, additional, Drenth, JPH, additional, Ryder, S, additional, Terracciano, L, additional, Jin, Y, additional, Liberman, A, additional, Pencek, R, additional, MacConell, L, additional, and Bedossa, P, additional

Published
2019
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25. Clinical application of the GLOBE and United Kingdom-primary biliary cholangitis risk scores in a trial cohort of patients with primary biliary cholangitis

Author

Carbone, M, Harms, M, Lammers, W, Marmon, T, Pencek, R, Macconell, L, Shapiro, D, Jones, D, Mells, G, Hansen, B, Carbone, Marco, Harms, Maren H., Lammers, Willem J., Marmon, Tonya, Pencek, Richard, MacConell, Leigh, Shapiro, David, Jones, David E., Mells, George F., Hansen, Bettina E., Carbone, M, Harms, M, Lammers, W, Marmon, T, Pencek, R, Macconell, L, Shapiro, D, Jones, D, Mells, G, Hansen, B, Carbone, Marco, Harms, Maren H., Lammers, Willem J., Marmon, Tonya, Pencek, Richard, MacConell, Leigh, Shapiro, David, Jones, David E., Mells, George F., and Hansen, Bettina E.

Abstract

The GLOBAL Primary Biliary Cholangitis (PBC) Study Group and United Kingdom-PBC (UK-PBC) Consortium have demonstrated that dichotomous response criteria are not as accurate as continuous equations at predicting mortality or liver transplantation in PBC. The aim of this analysis was to assess the clinical utility of the GLOBE and UK-PBC risk scores using data from POISE, a phase 3 trial investigating obeticholic acid (OCA) in patients with PBC. Data (N = 216) at baseline and month 12 were used to calculate the GLOBE and UK-PBC risk scores to assess the projected change in risk with OCA versus placebo. Additionally, the benefit of OCA was assessed in patients not meeting the POISE primary endpoint. Both the GLOBE and UK-PBC risk scores predicted a significant reduction in long-term risk of death and liver transplantation after OCA treatment (P < 0.0001). The differences in the relative risk reduction from baseline in the 10-year event risk after 1 year for OCA 10 mg versus placebo was 26% (GLOBE) and 37% (UK-PBC). The scores also predicted a significantly decreased risk in patients treated with OCA who did not meet POISE response criteria after 1 year of treatment compared to an increased risk with placebo (P < 0.0001). Conclusion: This analysis demonstrates the use of the GLOBE and UK-PBC risk scores to assess risk reduction of a cohort treated with OCA. While validation of this risk reduction in studies with clinical outcomes is needed, this study highlights the potential use of these scores in individualizing risk prediction in PBC both in clinical practice and therapeutic trials.

Published
2018

27. Long-Term Obeticholic Acid (OCA) treatment associated with reversal or stabilization of fibrosis/cirrhosis in patients with Primary Biliary Cholangitis (PBC)

Author

Bowlus, C., primary, Pockros, P., additional, Kremer, A.E., additional, Pares, A., additional, Forman, L., additional, Drenth, J.P., additional, Ryder, S., additional, Malecha, E.S., additional, Pencek, R., additional, Iloeje, U., additional, Macconell, L., additional, Shapiro, D., additional, and Pierre, B., additional

Published
2018
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32. PC.01.8 THE AESOP TRIAL: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY OF OBETICHOLIC ACID IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS

Author

Larusso, N.F., primary, Bowlus, C.L., additional, Levy, C., additional, Vuppalanchi, R., additional, Floreani, A., additional, Andreone, P., additional, Srestha, R., additional, Trotter, J., additional, Goldberg, D., additional, Rushbrook, S., additional, Hirschfield, G.M., additional, Van Biene, C., additional, Penceck, R., additional, Macconell, L., additional, and David, S., additional

Published
2018
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35. Obeticholic acid (OCA) improves non-invasive markers of fibrosis in patients with non-alcoholic steatohepatitis (NASH): a secondary analysis of the phase 3 Regenerate study

Author

Anstee, Q.M., Harrison, S., Sanyal, Arun J., Ratziu, V., Rinella, M., Younossi, Z.Y., Boursier, J., Francque, S., Geerts, A., Petta, S., Bugianesi, E, Romero-Gomez, M., Schattenberg, J.M., Sarkar, S., Bonacini, M., Yataco, M., Porayko, M., Siddique, A., Dufour, J., Ferro, T., A.Venugopal, Zaru, L., Shringarpure, R., MacConell, L., Goodman, Z., and Loomba, R.

Published
2020
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43. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

Author

Nevens, F., Andreone, P., Mazzella, G., Strasser, S.I., Bowlus, C., Invernizzi, P., Drenth, J.P.H., Pockros, P.J., Regula, J., Beuers, U., Trauner, M., Jones, D.E., Floreani, A., Hohenester, S., Luketic, V., Shiffman, M., Erpecum, K.J. van, Vargas, V., Vincent, C., Hirschfield, G.M., Shah, H., Hansen, B., Lindor, K.D., Marschall, H.U., Kowdley, K.V., Hooshmand-Rad, R., Marmon, T., Sheeron, S., Pencek, R., MacConell, L., Pruzanski, M., Shapiro, D., Nevens, F., Andreone, P., Mazzella, G., Strasser, S.I., Bowlus, C., Invernizzi, P., Drenth, J.P.H., Pockros, P.J., Regula, J., Beuers, U., Trauner, M., Jones, D.E., Floreani, A., Hohenester, S., Luketic, V., Shiffman, M., Erpecum, K.J. van, Vargas, V., Vincent, C., Hirschfield, G.M., Shah, H., Hansen, B., Lindor, K.D., Marschall, H.U., Kowdley, K.V., Hooshmand-Rad, R., Marmon, T., Sheeron, S., Pencek, R., MacConell, L., Pruzanski, M., and Shapiro, D.

Abstract

Item does not contain fulltext, BACKGROUND: Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS: In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS: Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 mumol per liter], respectively, vs. 0.12 mg per deciliter [2.0 mumol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 3

Published
2016

44. Durable response in the markers of cholestasis through 18 months of open-label extension with obeticholic acid in primary biliary cholangitis

Author

Trauner, M., primary, Nevens, F., additional, Andreone, P., additional, Mazzella, G., additional, Strasser, S., additional, Bowlus, C., additional, Invernizzi, P., additional, Drenth, J., additional, Pockros, P., additional, Regula, J., additional, Floreani, A., additional, Hohenester, S., additional, Luketic, V., additional, Shiffman, M., additional, van Erpecum, K., additional, Vargas, V., additional, Vincent, C., additional, Hansen, B., additional, MacConell, L., additional, Marmon, T., additional, and Shapiro, D., additional

Published
2016
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50. A Multicenter, Randomized, Open Label, Single- and Multiple-Dose, Dose Finding Study and Open-Label Extension to Assess the Effects of Obeticholic Acid in Pediatric Patients with Biliary Atresia

Author

Karpen, S., primary, Eliot, L., additional, Scholz, B., additional, Joshi, M.M., additional, Merrigan, M.M., additional, Sciacca, C., additional, Marmon, T., additional, Hooshmand-Rad, R., additional, MacConell, L., additional, and Shapiro, D., additional

Published
2016
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