A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab

作者：Chantal Mathieu, Alice Wiedeman, Karen Cerosaletti, S. Alice Long, Elisavet Serti, Laura G. Cooney, Joan Vermeiren, Silvia Caluwaerts, Karolien Van Huynegem, Lothar Steidler, S. Blomme, Pieter Rottiers, Gerald T. Nepom, Kevan C. Herold, on behalf of the AG019-T1D-101 Trial Investigators · 发表于：Diabetologia · 年份：2023 · DOI：10.1007/s00125-023-06014-2 · 被引用次数：60 · 研究领域：Diabetes and associated disorders、Pancreatic function and diabetes、T-cell and B-cell Immunology

Abstract Aims/hypothesis We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab. Methods Adults (18–42 years) and adolescents (12–17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12–42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints includ...