A randomized controlled pilot trial of etanercept and alpha-1 antitrypsin to improve autologous islet engraftment

• Published in: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2023-01, Vol.23 (1), p.57-64
• Main Authors: Abdel-Karim, Tasneem R., Hodges, James S., Pruett, Timothy L., Ramanathan, Karthik V., Hering, Bernhard J., Dunn, Ty B., Kirchner, Varvara A., Beilman, Gregory J., Bellin, Melena D.
• Format: Article
• Language: English
• Subjects: Chronic pancreatitis; Cytokines; Diabetes; Diabetes Mellitus - surgery; Etanercept - pharmacology; Etanercept - therapeutic use; Female; Glucose; Humans; Insulin - therapeutic use; Islet autotransplantation; Islets of Langerhans Transplantation; Male; Pancreatectomy; Pancreatitis, Chronic - surgery; Pilot Projects; Thymalfasin; TPIAT; Transplantation, Autologous; Treatment Outcome
• ISSN: 1424-3903; 1424-3911
• DOI: 10.1016/j.pan.2022.11.006

In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).