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

Introduction:

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease. Ursodeoxycholic acid (UDCA) is first-line PBC therapy and slows histologic progression in responders; however, up to 40% of patients do not have an adequate response to UDCA and remain at a high risk of progression. Obeticholic acid (OCA), a selective and potent farnesoid X receptor (FXR) agonist, has been approved for use in patients with PBC and an inadequate response to, or intolerance of, UDCA. Preclinical and clinical evidence suggest that FXR activation with OCA exerts anti-fibrotic effects. Preliminary results from liver biopsies performed as part of the Phase 3 study of OCA (POISE) were presented at the European Association for the Study of the Liver International Liver Conference in 2018.1 This analysis further evaluated the effect of 3 years of OCA therapy on histological progression of PBC in patients with inadequate response to UDCA using more rigorous disease-specific methodologies.

Methods:

Patients enrolled in POISE had the option to participate in a biopsy substudy. Those who chose to participate had biopsies prior to (≤1 year from double-blind baseline) and after ˜3 years of OCA treatment. In the present analysis, slides were masked, randomized (including the order of slides within each paired biopsy), and reviewed simultaneously by 2 blinded pathologists using a dual-headed microscope. A consensus reading was captured for each histologic parameter. Fibrosis stage was the primary objective and was defined using a 6-tier staging system (F0 = no fibrosis, F1 = portal/periportal fibrosis without septa, F2 = portal/periportal with septa, F3 = septal fibrosis, F4 = incomplete cirrhosis, F5 = cirrhosis). Key secondary parameters included the Nakanuma staging for histologic evaluation.

Results:

This analysis included 17 patients with adequate paired biopsies (mean age 59 years, 94% female, 100% received UDCA, precirrhotic fibrosis at baseline [F0-F3] n = 14, cirrhosis at baseline [F4-F5] n = 3, ductopenia at baseline n = 11). After 3 years of OCA treatment 12 (71%) patients showed improvement or no progression in fibrosis stage compared to 5 (29%) patients who worsened. The majority of patients who showed improvement or no progression in fibrosis stage also showed improvement in other histological features of PBC, including ductopenia, ductular reaction, interface hepatitis, and lobular hepatitis. Using the Nakanuma staging criteria, 12 (71%) and 13 (76%) patients had an improvement or no progression of Fibrosis Score and Bile Duct Loss Score, respectively, after OCA treatment. For the Nakanuma Disease Stage, 13 (76%) patients had improvement or no progression after OCA treatment.

Conclusion:

In this analysis of non-responders to UDCA at high risk for histologic disease progression, the majority of patients had improvement or no progression in fibrosis stage after 3 years of OCA treatment.

Reference:

1. Bowlus CL, et al. Presented at EASL, 53 rd International Congress; 2018; Paris, France (Poster LBP-014).