PMID- 37226224 OWN - NLM STAT- MEDLINE DCOM- 20230526 LR - 20230528 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 21 IP - 1 DP - 2023 May 24 TI - First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes. PG - 190 LID - 10.1186/s12916-023-02900-z [doi] LID - 190 AB - BACKGROUND: Type 1 diabetes (T1D) is a CD4(+) T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic beta-cells by CD8(+) T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong beta-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. METHODS: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 mug for priming followed by three further administrations of 25/75/225 mug, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. RESULTS: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change - 0.108, - 0.041, - 0.040, and - 0.012, respectively), suggesting no disease progression. CONCLUSIONS: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. TRIAL REGISTRATION: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018-003728-35. CI - (c) 2023. The Author(s). FAU - Van Rampelbergh, Jean AU - Van Rampelbergh J AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. j.vanrampelbergh@imcyse.com. FAU - Achenbach, Peter AU - Achenbach P AD - Institute of Diabetes Research, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Munich-Neuherberg, Germany. AD - Forschergruppe Diabetes, Technical University Munich, Klinikum Rechts Der Isar, Munich, Germany. FAU - Leslie, Richard David AU - Leslie RD AD - Department of Immunobiology, Queen Mary University of London, London, UK. FAU - Ali, Mohammad Alhadj AU - Ali MA AD - Diabetes Research Group, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. FAU - Dayan, Colin AU - Dayan C AD - Diabetes Research Group, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. FAU - Keymeulen, Bart AU - Keymeulen B AD - Member of Belgian Diabetes Registry, Academic Hospital and Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium. FAU - Owen, Katharine R AU - Owen KR AD - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. AD - Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK. FAU - Kindermans, Martin AU - Kindermans M AD - Ariana Pharmaceuticals SA, Paris, France. FAU - Parmentier, Frederic AU - Parmentier F AD - Ariana Pharmaceuticals SA, Paris, France. FAU - Carlier, Vincent AU - Carlier V AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Ahangarani, Roxana R AU - Ahangarani RR AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Gebruers, Evelien AU - Gebruers E AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Bovy, Nicolas AU - Bovy N AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Vanderelst, Luc AU - Vanderelst L AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Van Mechelen, Marcelle AU - Van Mechelen M AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Vandepapeliere, Pierre AU - Vandepapeliere P AD - Imcyse S.A., Avenue Pre-Aily 14, Angleur, 4031, Liege, Belgium. FAU - Boitard, Christian AU - Boitard C AD - Inserm U1016, Cochin Institute, Paris, France. AD - Medical Faculty, Universite de Paris, Paris, France. LA - eng SI - ClinicalTrials.gov/NCT03272269 SI - ClinicalTrials.gov/NCT04190693 SI - EudraCT/2016-003514-27 SI - EudraCT/2018-003728-35 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230524 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 RN - 0 (C-Peptide) SB - IM MH - Adult MH - Humans MH - *Diabetes Mellitus, Type 1/drug therapy MH - CD8-Positive T-Lymphocytes MH - Immunotherapy MH - C-Peptide MH - Autoimmunity MH - Disease Progression PMC - PMC10210318 OTO - NOTNLM OT - Beta-cells OT - Clinical study OT - Immunotherapy OT - Safety OT - T cells OT - Type 1 diabetes COIS- JVR, VC, RRA, EG, NB, LVE, MVM, and PV are employees or contractors of Imcyse S.A., Liege, Belgium, and may hold stock options. RDL's institution received study funding and materials from Imcyse. RDL received an honorarium from DMRR and took part in advisory boards for Diamyd and Provention. MAA's institution received study funding and materials from Imcyse. MAA received medical writing and APC support from Imcyse; received grants from EFSD, Wellcome Trust, Cardiff University, Wales Kidney Research Unit, and INNODIA; received honoraria from Sanofi Diabetes, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, MSD, Novo Nordisk and Bayer; received meeting support from Sanofi Diabetes, Eli Lilly, Takeda, Abbott, Merck, Novo Nordisk, NAPP, Miltenyi Biotec and Servier. CD, BK, and CB's institutions received study funding and materials from Imcyse. CD received consultancy honoraria, medical writing, and APC support from Imcyse. PA and KRO declare no competing interests. EDAT- 2023/05/25 01:07 MHDA- 2023/05/26 06:42 PMCR- 2023/05/24 CRDT- 2023/05/24 23:51 PHST- 2022/01/17 00:00 [received] PHST- 2023/05/10 00:00 [accepted] PHST- 2023/05/26 06:42 [medline] PHST- 2023/05/25 01:07 [pubmed] PHST- 2023/05/24 23:51 [entrez] PHST- 2023/05/24 00:00 [pmc-release] AID - 10.1186/s12916-023-02900-z [pii] AID - 2900 [pii] AID - 10.1186/s12916-023-02900-z [doi] PST - epublish SO - BMC Med. 2023 May 24;21(1):190. doi: 10.1186/s12916-023-02900-z.