A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis

Kris V Kowdley, Raj Vuppalanchi, Cynthia Levy, Annarosa Floreani, Pietro Andreone, Nicholas F LaRusso, Roshan Shrestha, James Trotter, David Goldberg, Simon Rushbrook, Gideon M Hirschfield, Thomas Schiano, Yuying Jin, Richard Pencek, Leigh MacConell, David Shapiro, Christopher L Bowlus, AESOP Study Investigators, Kris V Kowdley, Raj Vuppalanchi, Cynthia Levy, Annarosa Floreani, Pietro Andreone, Nicholas F LaRusso, Roshan Shrestha, James Trotter, David Goldberg, Simon Rushbrook, Gideon M Hirschfield, Thomas Schiano, Yuying Jin, Richard Pencek, Leigh MacConell, David Shapiro, Christopher L Bowlus, AESOP Study Investigators

Abstract

Background & aims: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.

Methods: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.

Results: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.

Conclusions: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.

Registration: ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.

Lay summary: Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.

Keywords: Cholestasis; Farnesoid X receptor; Ursodeoxycholic acid.

Conflict of interest statement

Conflict of interest Dr. Kowdley reports grants from Intercept during the conduct of the study; grants and personal fees from Gilead, Genfit, HighTide, Intercept, NGM Biopharma and CymaBay; personal fees from Assembly, Blade, Conatus, Abbvie and Roche and royalties from Up-To-Date (educational website), outside the submitted work. Dr. Vuppalanchi reports financial support to his institution from Gilead Sciences, Zydus Cadilla, LaJolla Pharmaceuticals for conduct of clinical trials during the conduct of the current study. He received financial support for consulting on the matters of drug safety from LabCorp/Covance. Dr. Levy reports grants from Intercept, grants from Gilead, grants from CymaBay, grants from Novartis, grants from Enanta, grants from Genkyotex, grants from NGM, grants from Lilly, grants and personal fees from GSK, personal fees from Pliant, grants from Genfit, personal fees from TARGET PharmaSolutions, personal fees from Shire, personal fees from Cara Therapeutics, outside the submitted work. Dr. Floreani reports no conflict of interest. Dr. Andreone reports personal fees from Intercept Pharmaceuticals, Inc., outside the submitted work. Dr. LaRusso has nothing to disclose. Dr. Shrestha has nothing to disclose. Dr. Trotter reports no conflict of interest. Dr. Goldberg reports grants from Merck, grants from Gilead, grants from Zydus, outside the submitted work. Dr. Rushbrook reports no conflict of interest. Dr. Hirschfield reports personal fees from Intercept Pharmaceuticals, Inc., personal fees from Cymabay, personal fees from GSK, grants from Gilead, grants from Falk Pharma, outside the submitted work. Dr. Schiano reports being a consultant for Alexion; and his institution received a grant for research from Progenity. Dr. Jin reports no conflict of interest. Dr. Pencek reports personal fees and is a shareholder and former employee of Intercept Pharmaceuticals, Inc., outside the submitted work. Dr. MacConell is an employee and shareholder of Intercept Pharmaceuticals, Inc., outside the submitted work. Dr. Shapiro is an employee and shareholder of Intercept Pharmaceuticals, Inc., outside the submitted work. Dr. Bowlus reports grants from Intercept, during the conduct of the study; grants from Gilead, grants and personal fees from Cymabay, grants and personal fees from Intercept, personal fees from Pliant, personal fees from Parvus, personal fees from BiomX, outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details.

Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1.. Study design.
Fig. 1.. Study design.
ALP, alkaline phosphatase; LTSE, long-term safety extension; OCA, obeticholic acid.
Fig. 2.. Mean change from baseline in…
Fig. 2.. Mean change from baseline in ALP over time by treatment group.
(A) LS mean (SE) change from baseline in serum ALP (U/L) in the DB phase (ITT population). Line at week 12 indicates dose titration. Mean baseline ALP (U/L) (SEM): 562.8 (60.0) (placebo), 422.5 (24.6) (OCA 1.5–3.0 mg), 428.5 (35.0) (OCA 5–10 mg). (B) Mean (SD) change from baseline in serum ALP in the LTSE (pooled data). Mean baseline ALP (U/L) (SD): 456.6 (224.6). ANCOVA was used for these analyses. *p <0.05; OCA dose vs. placebo. ALP, alkaline phosphatase: ANCOVA, analysis of covariance; DB, double-blind; ITT, intent-to-treat; LS, least-square; LTSE, long-term safety extension; OCA, obeticholic acid.
Fig. 3.. Mean change from baseline in…
Fig. 3.. Mean change from baseline in ALP over time by UDCA baseline use.
(A) Percentage or (B) absolute LS mean (SE) change from baseline in serum ALP (U/L) by UDCA baseline use in the DB phase (safety population). Mean baseline ALP (U/L) (SEM) UDCA use: 485.8 (104.0) (placebo), 432.4 (36.5) (OCA 1.5–3.0 mg), 387.1 (33.3) (OCA 5–10 mg); no UDCA use: 642.2 (66.8) (placebo), 413.4 (34.5) (OCA 15–3.0 mg), 468.6 (54.1) (OCA 5–10 mg). (C) Percentage or (D) absolute mean (SD) change from baseline in serum ALP by UDCA baseline use for all patients in the LTSE (pooled data). Mean baseline ALP (U/L) (SD) UDCA use, 427.5 (249.6); no UDCA use, 482.9 (199.8). ANCOVA was used for these analyses. ALP, alkaline phosphatase; ANCOVA, analysis of covariance; DB, double-blind; LS, least-square; LTSE, long-term safety extension; OCA, obeticholic acid; UDCA, ursodeoxycholic acid.
Fig. 4.. Mean change from baseline in…
Fig. 4.. Mean change from baseline in FGF19 over time by treatment group.
(A) Mean (SD) change from DB baseline in serum FGF19 (pg/ml) in DB phase (ITT population). Une indicates dose titration. Mean baseline FGF19 (pg/ml) (SD): 241.8 (339.1) (placebo), 143.2 (88.7) (OCA 1.5–3.0 mg), 187.7 (171.6) (OCA 5–10 mg). (B) Mean (SD) change from baseline in serum FGF19 in LTSE (pooled data). Mean baseline FGF19 (pg/ml) (SD): 182.0 (225.0). DB, double-blind; FGF19, fibroblast growth factor 19; ITT, intent-to-treat; LTSE, long-term safety extension; OCA, obeticholic add.
Fig. 5.. Mean change from baseline in…
Fig. 5.. Mean change from baseline in C4 over time by treatment group.
(A) Mean (SD) change from DB baseline in serum C4 (ng/ml) in DB phase (ITT population). Line indicates dose titration. Mean baseline C4 (ng/ml) (SD): 11.9 (15.8) (placebo), 13.8 (24.3) (OCA 1.5–3.0 mg), 11.1 (12.6) (OCA 5–10 mg). (B) Mean (SD) change from baseline in serum C4 in LTSE (pooled data). Mean baseline FGF19 (pg/ml) (SD): 13.5 (19.5). C4, 7α-hydroxy-4-cholesten-3-one; DB, double-blind; FGF19, fibroblast growth factor 19; ITT, intent-to-treat; LTSE, long-term safety extension; OCA, obeticholic add.

References

    1. Karlsen TH, Folseraas T, Thorbum D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. J Hepatol 2017;67(6): 1298–1323.
    1. Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med 2016;375(12):1161–1170.
    1. Lindor KD, Kowdley KV, Harrison ME, American College of Gastroenterology. ACG clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol 2015;110(5):646–659. quiz 660.
    1. Goode EC, Clark AB, Mells GF, Srivastava B, Spiess K, Gelson WTH, et al. Factors associated with outcomes of patients with primary sclerosing cholangitis and development and validation of a risk scoring system. Hepatology 2019;69(5):2120–2135.
    1. Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2013;58(2):329–334.
    1. Lindstrom L, Hultcrantz R, Boberg KM, Friis-Uby I, Bergquist A. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2013;11(7):841–846.
    1. Rupp C Rossler A, Halibasic E, Sauer P, Weiss KH, Friedrich K, et al. Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis. Aliment Pharmacol Ther 2014;40(11–12):1292–1301.
    1. Fickert P, Hirschfield GM, Denk G, Marschall HU, Altorjay I, Farkkila M, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 2017;67(3):549–558.
    1. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo primary sclerosing cholangitis-ursodeoxycholic add study group. N Engl J Med 1997;336(10):691–695.
    1. Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 2005;129(5):1464–1472.
    1. Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, et al. High-dose ursodeoxycholic add for the treatment of primary sclerosing cholangitis. Hepatology 2009;50(3):808–814.
    1. Papazyan R, Liu X, Liu J, Dong B, Plummer EM, Lewis RD 2nd, et al. FXR activation by obeticholic acid or nonsteroidal agonists induces a humanlike lipoprotein cholesterol change in mice with humanized chimeric liver. J Lipid Res 2018;59(6):982–993.
    1. Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018;67(5):1890–1902.
    1. Hirschfield GM, Chazouilleres O, Drenth JP, Thorburn D, Harrison SA, Landis CS, et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol 2019;70(3):483–493.
    1. Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C, et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver Injury in patients with primary sclerosing cholangitis. Hepatology 2019;70(3):788–801.
    1. Hirschfield GM, Mason A Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015;148(4):751–761.e8.
    1. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375(7):631–643.
    1. Pate J, Gutierrez JA, Frenette CT, Goel A, Kumar S, Manch RA et al. Practical strategies for pruritus management in the obeticholic acid-treated patient with PBC: proceedings from the 2018 expert panel. BMJ Open Gastroenterol 2019;6(1):e000256.
    1. Ponsioen CY, lindor KD, Mehta R, Dimick-Santos L Design and endpoints for clinical trials in primary sclerosing cholangitis. Hepatology 2018;68(3):1174–1188.
    1. Ponsioen CY, Chapman RW, Chazouilleres O, Hirschfield GM, Karlsen TH, Lohse AW, et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process. Hepatology 2016;63(4):1357–1367.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi