Long-term effectiveness, safety, and liver stiffness dynamics of PBC treatment with obeticholic acid in real-world

Abstract Background and Aims A number of studies have assessed short-term effectiveness and safety of obeticholic acid (OCA) in the real-world setting. We aimed to extend the knowledge on real-world OCA treatment effectiveness and safety by expanding sample size and follow-up, and by exploring liver stiffness measurement (LSM) changes over time. Methods The RECAPITULATE project involves centres belonging to the "Italian-PBC-registry" and/or the "Club-Epatologi-Ospedalieri" (CLEO) PBC working group. Effectiveness was evaluated as biochemical response according to PBC-OCA-International-Study-of-Efficacy (POISE) and normal range (NR) criteria (normal ALP/ALT/bilirubin). Safety was assessed as incidence of de novo/worsening pruritus and discontinuation rate/causes. Available LSMs were also captured. Results We included 747 patients from 66 Italian centres [58 years; F/M 88%/14%, median follow-up 24 months (IQR 12-42), 28% with cirrhosis, and 14% with autoimmune hepatitis (AIH)/PBC overlap]. Probabilities of POISE and NR response increased from baseline up to 57% and 20% at the 42nd month, respectively. They were lower in cirrhosis (p=0.02 and p=0.004 for POISE and NR), while not different between AIH/PBC overlap and PBC (p=0.8). Overall, 130 patients (17%) discontinued treatment, mainly due to pruritus (36.9%), while 28.5% did so after developing hepatic events. Discontinuation rate was higher in cirrhosis (p<0.001). LSM was available in 573 patients (∼77%), of whom 255 had multiple measurements. LSM variation over time differed based on the attainment of POISE biochemical response ([expected mean annual variation -0.48 (-0.78, -0.19)] in responders, +0.33 (-0.07, 0.73) in non-responders, respectively, p<0.001]). Conclusions These findings from a comprehensive real-world cohort of PBC patients treated with OCA confirm the drug's effectiveness and safety profiles in the medium/long term and demonstrate that biochemical response impacts the trend of LSM over time. Impact and Implications After the conditional approval of OCA for the treatment of PBC, the main confirmatory study failed to demonstrate OCA's ability to reduce liver-related events, leading EMA to revoke the drug's marketing authorization. The ensuing scientific debate highlights an urgent need for further evidence from real-world practice. In the largest real-world series of patients treated with OCA to date, we confirm that the drug's effectiveness and safety profiles are maintained over a medium-to-long follow-up period. Valuable data for the management of the drug in relevant subgroups of patients, such as those with cirrhosis and autoimmune hepatitis/PBC overlap, are also provided. Our original results on liver stiffness measurement trend over time suggest a favourable impact of OCA on fibrosis progression, particularly in patients achieving a biochemical response to the drug. Overall, these data provide important insights for clinicians managing patients with PBC, and are also highly valuable for the ongoing scientific debate about the effectiveness/safety profile of this drug.