Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature

• Published in: Journal of autoimmunity 2019-07, Vol.101, p.26-34
• Main Authors: Bowlus, Christopher L., Yang, Guo-Xiang, Liu, Chung H., Johnson, Cole R., Dhaliwal, Sandeep S., Frank, Darren, Levy, Cynthia, Peters, Marion G., Vierling, John M., Gershwin, M. Eric
• Format: Article
• Language: English
• Subjects: Autoimmune disease; Biliary; Liver; T cell; Treatment
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2019.04.005

Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (−90.9–96.6) and −0.28% (−21.1–15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4+ but not CD8+ T cell populations, including decreases in CD4+ CCR5+ (p = 0.02) and CD4+ PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4+ CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes. •Primary biliary cholangitis (PBC) is an autoimmune disease with loss of humoral and cellular tolerance to mitochondrial self-antigens.•Abatacept (CLTA-4 Ig) suppressed T cell activation in PBC patients with an incomplete response to first-line therapy.•However, abatacept failed to demonstrate clinical efficacy reflected in liver biochemical profiles.•Biologics, including those targeting T and B cells and IL-12/23, have been unsuccessful in PBC.