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

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 included stimulated C-peptide levels during a mixed meal tolerance test, HbA1c levels, insulin use, and antigen-specific CD4+ and CD8+ T cell responses using an activation-induced marker assay and pooled tetramers, respectively. Results Data from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA1c) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8+ T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4+ and CD8+ T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8+ T cells after treatment with monotherapy or combination therapy. Conclusions/interpretation Oral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes. Trial registration ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24 Funding This study was funded by Precigen ActoBio Graphical Abstract

Efficacy of teplizumab for treatment of type 1 diabetes: A meta‐analysis of randomized controlled trials

“…AG019 comprises an oral capsule containing engineered Lactococcus lactis, specially modified to deliver both the autoantigen human proinsulin (hPINS) and the tolerance-enhancing cytokine human interleukin-10 (hIL-10) to the mucosal lining of the gastrointestinal tissues. 46 Teplizumab stands out from prior type 1 diabetes treatments in several key ways. Firstly, it is administered in two distinct intravenous courses, each spanning 12 days, leading to a swifter recovery of circulating immune cells than observed with continuously administered therapies or those causing prolonged cell depletion.…”

“…Notably, at 6 months, there was a significant increase in CD8+ T cells with a partially exhausted phenotype. AG019 comprises an oral capsule containing engineered Lactococcus lactis, specially modified to deliver both the autoantigen human proinsulin (hPINS) and the tolerance‐enhancing cytokine human interleukin‐10 (hIL‐10) to the mucosal lining of the gastrointestinal tissues 46 …”

Assessing the causal relationship between gut microbiota and diabetic nephropathy: insights from two-sample Mendelian randomization

“…Oral delivery of staphylococcal nuclease by Lactococcus lactis showed a beneficial protective effect on T1DM by inhibiting inflammation and regulating the immune system ( 70 ). Lactococcus lactis modified to express human proinsulin and human IL-10 showed an active role in the prevention and treatment of T1DM and has a favorable safety profile ( 71 , 72 ). Previous studies have shown that g_Phascolarctobacterium and g_Coprococcus are less abundant in DN patients and animal models ( 73 , 74 ), while g_Anaerostipes exhibited higher abundance in DN patients ( 18 ).…”

Safety and efficacy of teplizumab in the treatment of type 1 diabetes mellitus: An updated systematic review and meta‐analysis of randomized controlled trials

“…Furthermore, exploring teplizumab in conjunction with other interventions, as suggested by Mathieu et al, 37 holds promise as a treatment option. These efforts would contribute to a more comprehensive understanding of the potential applications and challenges of teplizumab use.…”