{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:37:30Z","timestamp":1792179450132,"version":"4.4.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:00:00Z","timestamp":1696204800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:00:00Z","timestamp":1696204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["UM1AI109565"],"award-info":[{"award-number":["UM1AI109565"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\/hypothesis<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Lactococcus lactis<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Adults (18\u201342 years) and adolescents (12\u201317 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 &gt;0.2 nmol\/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12\u201342 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, HbA\n                      <jats:sub>1c<\/jats:sub>\n                      levels, insulin use, and antigen-specific CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell responses using an activation-induced marker assay and pooled tetramers, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 (HbA\n                      <jats:sub>1c<\/jats:sub>\n                      ) post treatment initiation. In participants treated with AG019\/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells after treatment with monotherapy or combination therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>This study was funded by Precigen ActoBio<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-023-06014-2","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T05:01:55Z","timestamp":1696222915000},"page":"27-41","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["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"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4055-5233","authenticated-orcid":false,"given":"Chantal","family":"Mathieu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7329-7288","authenticated-orcid":false,"given":"Alice","family":"Wiedeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7403-6239","authenticated-orcid":false,"given":"Karen","family":"Cerosaletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0281-1240","authenticated-orcid":false,"given":"S. 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Medical writing support was provided by A. Rombout and F. Baert, Emtex Life Science, Belgium. A. Haegeman, E. Festjens and K. Vandenbroucke from Precigen ActoBio contributed to PK sample and data analysis. C. Acosta-Vega from Benaroya Research Institute Human Immunophenotyping Core contributed to CyTOF panel development and staining. E. Balmas, J. L. Blanchfield and J. Chen from Benaroya Research Institute developed the spectral cytometry panels, performed the activation-induced marker assays and analysed the spectral cytometry data.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are not openly available for reasons of sensitivity. The sponsor may, at its discretion, grant access to the data (or portions thereof) to qualified researchers on reasonable request; however, access may be subject to certain use and\/or privacy obligations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This clinical trial was funded by Intrexon Actobiotics N.V. d\/b\/a Precigen ActoBio. The mechanistic assays and immunological data analysis were sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) under award no. UM1AI109565. This report is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"CM serves or has served on advisory panels for Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, Precigen ActoBio, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz and Vertex. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi and Precigen ActoBio; CM serves or has served on speakers bureaus for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca and Novartis. Financial compensation for these activities has been received by KU Leuven. CM is president of the EASD. All external support of the EASD is to be found on\n                      \n                      . JV, SC, KVH, LS, SB and PR are employed by Precigen ActoBio. KC has received funding from Cour Pharmaceuticals and Gentibio. GTN has consulted for Precigen ActoBio as an advisor to the Precigen ActoBio programme. SAL is a consultant for Provention Bio and Sonoma Bio, a co-inventor on a patent filing (\u2018Methods and compositions for preventing type 1 diabetes\u2019) and a member of the mechanistic study panels for TrialNet and ITN. KCH is a co-inventor on teplizumab patents.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"CM, AW, KC, SAL, ES, LC, JV, SC, KVH, LS, SB, PR, GTN and KCH contributed to the study design; data collection, analysis and interpretation; and drafting and critical revision of the article. All authors approved the final version to be published. PR is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}