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. 2025 Jun 1;81(6):1647-1659.
doi: 10.1097/HEP.0000000000001174. Epub 2025 Jan 3.

Hepatic real-world outcomes with obeticholic acid in primary biliary cholangitis (HEROES): A trial emulation study design

M Alan Brookhart  1   2 , Tracy J Mayne  3 , Charles Coombs  4 , Alexander Breskin  2 , Erik Ness  3 , Leona Bessonova  3 , Yucheng Julia Chu  3 , Jing Li  3 , Michael W Fried  2 , Bettina E Hansen  5   6   7 , Kris V Kowdley  8 , David Jones  9 , George Mells  10   11 , Palak J Trivedi  12 , Shaun Hiu  9 , Dorcas N Kareithi  9 , James Wason  9 , Rachel Smith  10 , John D Seeger  13 , Gideon M Hirschfield  7
Affiliations

Hepatic real-world outcomes with obeticholic acid in primary biliary cholangitis (HEROES): A trial emulation study design

M Alan Brookhart et al. Hepatology. .

Abstract

Background and aims: Primary biliary cholangitis is a rare, progressive liver disease. Obeticholic acid (OCA) received accelerated approval for treating patients with primary biliary cholangitis in whom ursodeoxycholic acid failed, based on a surrogate endpoint of reduction in ALP. Analysis of the long-term safety extension with 2 external control groups demonstrated a significant increase in event-free survival in OCA-treated patients. This fully real-world evidence study assessed the effect of OCA treatment on clinical outcomes.

Approach and results: This trial emulation used data from the Komodo Healthcare Map claims database linked to US national laboratory, transplant, and death databases. Patients with compensated primary biliary cholangitis and intolerance/inadequate response to ursodeoxycholic acid who initiated OCA therapy were compared with patients who were OCA-eligible but not OCA-treated. The primary endpoint was time to the first occurrence of death, liver transplant, or hospitalization for hepatic decompensation, analyzed using a propensity-score weighted Cox proportional hazards model. Baseline prognostic factors were balanced using standardized morbidity ratio weighting. For the primary analysis, 4174 patients contributed 11,246 control index dates, and 403 patients contributed OCA indexes. Weighted groups were well balanced. Median (95% CI) follow-up in the OCA and non-OCA arms was 9.3 (8.4-10.6) months and 17.5 (16.2-18.6) months (weighted population; censored at discontinuation). Eight events occurred in the OCA arm and 32 in the weighted control (HR = 0.37; 95% CI = 0.14-0.75; p < 0.001). Effects were consistent for each component of the composite endpoint.

Conclusions: We identified a 63% reduced risk of hospitalization for hepatic decompensation, liver transplant, or death in OCA-treated versus non-OCA-treated individuals.

Trial registration: HEROES; ClinicalTrials.gov NCT05292872.

Keywords: confirmatory trial; death; hepatic decompensation; liver disease; liver transplant.

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Conflict of interest statement

M. Alan Brookhart advises and owns stock in Target RWE. He advises Amgen, Astellas/Seagen, Atara Biotherapeutics, Brigham and Women’s Hospital, Kite, Gilead, NIDDK, Vertex, AccompanyHealth, Target RWE, and Vertex. He advises and was employed by Intercept at the time they study was conducted. He owns stock in Accompany Health. Tracy J. Mayne was employed by Intercept at the time the study was conducted. Charles Coombs owns stock in and is employed by Syneos Health and Walmart. Alexander Breskin owns stock in and is employed by Regeneron Pharmaceuticals and Target RWE. Erik Ness was employed by Intercept at the time the study was conducted. He is employed by Madrigal. Leona Bessonova is employed by Intercept. Yucheng Julia Chu consults for and is employed by Intercept. Jing Li is employed by Intercept. Michael W. Fried is employed by and owns stock in Target RWE. Bettina E. Hansen consults for, is on the speakers’ bureau, and received grants from Mirum. She consults for, advises, and received grants from Cymabay, Intercept, and Ipsen. She consults for and advises Pliant. She consults for and received grants from Albireo, Calliditas, and Eiger. She consults for Enyo. She received grants from Gilead. Kris V. Kowdley has received honoraria, fees, equity, research support, and clinical trial grants from AbbVie, Corcept, CymaBay, Enanta, Genfit, Gilead, GSK, Hanmi, HighTide, Inipharm, Intercept, Madrigal, Mirum, Novo Nordisk, NGM Bio, Pfizer, Pliant, Terns, Viking, and 89bio. He advises and received grants from Boehringer Ingelheim and Ipsen. He advises Arbormed. He received grants from AstraZeneca and Akero. He receives royalties from UpToDate. David Jones consults for, is on the speakers’ bureau for, and received grants from Advanz and Intercept. He consults for and is on the speakers’ bureau for Abbott, Ipsen, and GSK. He consults for and received grants from Intercept. He consults for Cymabay and Umecrine. He is on the speakers’ bureau for Falk. George Mells received grants from Intercept. Palak J. Trivedi receives institutional salary support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC). [This paper presents independent research supported by the Birmingham NIHR BRC based at the University Hospitals Birmingham National Health Service Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.] Palak J. Trivedi has received grant support from Wellcome Trust, Medical Research Foundation, the LifeArc Foundation, Innovate UK, GSK, Guts UK, PSC Support, Intercept, Falk, Gilead, and Bristol Myers Squibb; has received speaker fees from Intercept and Falk; and has been an advisory board member/consultant for Albireo, CymaBay, Intercept, Ipsen, Falk, GSK, and Pliant. He consults for, advises, is on the speakers’ bureau, and received grants from Advanz. Shaun Hiu received grants from Intercept. James Wason received grants from Intercept. Rachel Smith received grants from Advanz. John D. Seeger is employed by Optum and has stock in UnitedHealth Group (Optum’s parent company). Participation in this project was supported through a research contract between Optum and Intercept. Gideon M. Hirschfield consults for Intercept, Advanz, Ipsen, Cymabay, HIghTide, Kowa, Pliant, Mirum, Gilead, GSK, and Escient. The remaining author has no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Design of HEROES study. This real-world outcome study emulated a sequence of trials to assess the effect of OCA treatment on time to hospitalization for hepatic decompensation, liver transplant, or death, in patients with primary biliary cholangitis. Patients were randomly assigned to either no-OCA treatment (control, top row) or OCA treatment (bottom row). At health care visits, eligibility was assessed (ineligible, open diamonds; eligible, solid diamonds). For eligible patients without a history of OCA treatment, the visit contributed a control observation and follow-up (orange arrows) started from the visit date (control index date; orange diamonds) until the first occurrence of a clinical event (study endpoint), censor event, or end of follow-up in the control arm or initiation of OCA in the OCA arm. Similarly, for OCA-treated patients, follow-up (green arrow) started from the date of the first dose (OCA index date; green diamond) until the first occurrence of a clinical event, censor event, or end of follow-up. All eligible patients were required to be enrolled at least 12 months before the control or OCA initiation index date (preindex period) to assess comorbidity exclusions. aControl indexes were censored if a patient initiated OCA therapy, if a patient initiated fibrate therapy, or if UDCA was reinitiated for patients who had discontinued the therapy for >6 months. bOCA-treated indexes were censored 90 days after OCA discontinuation, or if fibrates were initiated. Abbreviations: OCA, obeticholic acid; UDCA, ursodeoxycholic acid.
FIGURE 2
FIGURE 2
Kaplan–Meier curves of time to primary endpoint for OCA-treated versus non–OCA-treated patients. This figure illustrates the survival probabilities and number of OCA-treated and non–OCA-treated patients with PBC who are at risk of death, liver transplant, or hospitalization for hepatic decompensation over time. Curves are shown for unweighted control subjects (A) and SMR-weighted control subjects (B). The median (95% CI) follow-up time in the non–OCA-treated group was 15 (14.7–15.4) months in the unweighted population and 17.5 (16.2–18.6) months in the weighted population. In the OCA-treated group, the median (95% CI) follow-up time was 9.3 (8.3–10.4) months and 9.3 (8.4–10.6) months, respectively. Censored data are indicated by + symbols. Abbreviations: OCA, obeticholic acid; PBC, primary biliary cholangitis; SMR, standardized morbidity ratio.
FIGURE 3
FIGURE 3
Subgroup analysis of time to primary endpoint for OCA-treated versus non–OCA-treated patients. This figure shows adjusted HRs for time to hospitalization for hepatic decompensation, liver transplant, or death in subgroups of OCA-treated versus non–OCA-treated patients. Adjusted HRs were estimated using an SMR-weighted Cox proportional hazards model. The median (95% CI) follow-up time in the non–OCA-treated group was 15 (14.7–15.4) months in the unweighted population and 17.5 (16.2, 18.6) months in the weighted population. In the OCA-treated group, the median (95% CI) follow-up time was 9.3 (8.3–10.4) months and 9.3 (8.4–10.6) months, respectively. Black squares and whiskers indicate HRs and 95% CIs, respectively. Abbreviations: OCA, obeticholic acid; SMR, standardized morbidity ratio.
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