Dataset Information

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

ABSTRACT:

Background & aims

Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions.

Methods

Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed.

Results

We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%).

Conclusions

Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC.

Lay summary

Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.

SUBMITTER: D'Amato D

PROVIDER: S-EPMC7930359 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

D'Amato Daphne D De Vincentis Antonio A Malinverno Federica F Viganò Mauro M Alvaro Domenico D Pompili Maurizio M Picciotto Antonino A Palitti Valeria Pace VP Russello Maurizio M Storato Silvia S Pigozzi Marie Graciella MG Calvaruso Vincenza V De Gasperi Elisabetta E Lleo Ana A Castellaneta Antonino A Pellicelli Adriano A Cazzagon Nora N Floreani Annarosa A Muratori Luigi L Fagiuoli Stefano S Niro Grazia Anna GA Feletti Valentina V Cozzolongo Raffaele R Terreni Natalia N Marzioni Marco M Pellicano Rinaldo R Pozzoni Pietro P Baiocchi Leonardo L Chessa Luchino L Rosina Floriano F Bertino Gaetano G Vinci Maria M Morgando Anna A Vanni Ester E Scifo Gaetano G Sacco Rodolfo R D'Antò Maria M Bellia Valentina V Boldizzoni Roberto R Casella Silvia S Omazzi Barbara B Poggi Guido G Cristoferi Laura L Gerussi Alessio A Ronca Vincenzo V Venere Rosanna R Ponziani Francesca F Cannavò Maria M Mussetto Alessandro A Fontana Rosanna R Losito Francesco F Frazzetto Evelise E Distefano Marco M Colapietro Francesca F Labanca Sara S Marconi Giulia G Grassi Giuseppe G Galati Giovanni G O'Donnell Sarah Elizabeth SE Mancuso Clara C Mulinacci Giacomo G Palermo Andrea A Claar Ernesto E Izzi Antonio A Picardi Antonio A Invernizzi Pietro P Carbone Marco M Vespasiani-Gentilucci Umberto U

JHEP reports : innovation in hepatology 20210127 2

<h4>Background & aims</h4>Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions.<h4>Methods</h4>Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical resp ...[more]

PMID: 33681748

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Project description:Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real-world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA-naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow-up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated-measures models were used to assess changes in biochemistry over time. Sixty-four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 109/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L (P < 0.001), GGT of 138 U/L (P < 0.001), ALT of 11.9 U/L (P < 0.001), AST of 5.7 U/L (P < 0.05), and IgM of 0.70 g/L (P < 0.001) over 12 months; TB remained stable (P = 0.98). Forty-four patients met POISE-inclusion criteria, 39% (n = 17) of whom had 12-month biochemical measurements. In this subset, 18% (n = 3/17) met the 12-month POISE primary endpoint, but considering follow-up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. Conclusion: Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real-world setting.

Project description:Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus.ConclusionOCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).

Project description:BackgroundClinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany.ObjectiveThe aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option.MethodsDiagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated.ResultsOverall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001).ConclusionOur large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.

Dataset Information

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

Background & aims

Methods

Results

Conclusions

Lay summary

Publications

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

Similar Datasets

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