278-OR: Efficacy and Safety of Anti-interleukin (IL)-21 in Combination with Liraglutide in Adults Recently Diagnosed with Type 1 Diabetes

Herrath, Matthias G. von; Bain, Stephen C.; Bode, Bruce W.; Clausen, Jesper O.; Coppieters, Ken; Gaysina, Leylya; Gumprecht, Janusz; Hansen, Troels Krarup; Mathieu, Chantal; Portillo, Cristóbal Morales; Mosenzon, Ofri; Segel, Stine; Tsoukas, George; Pieber, Thomas R.

doi:10.2337/db20-278-or

Cited by 10 publications

(8 citation statements)

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“…These studies targeted adaptive immune cells (such as anti-B cell therapy with rituximab and anti-T cell therapy with teplizumab, antithymocyte globulin, and alefacept), blocked costimulation pathways (abatacept), and inhibited cytokines (anti-IL-21 and anti-TNF; refs. [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

Greenbaum¹,

Serti

Lambert³

et al. 2021

JCI Insight

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Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients. Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years). Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4 + T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated. Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4 + T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes. Trial Registration ClinicalTrials.gov NCT02293837. Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

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Section: Introductionmentioning

confidence: 99%

IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

Greenbaum¹,

Serti

Lambert³

et al. 2021

JCI Insight

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“…Uncertainties in translation of mechanistic and therapeutic results from NOD mice to human disease continue to impede progress in clinical development of candidate DMTs alone (9,10,(17)(18)(19)(20)(21)(22)(23)(24). These uncertainties motivate earlier clinical evaluation of candidate therapies once preclinical safety has been established.…”

Section: Combination Therapiesmentioning

confidence: 99%

“…Even with these fundamental design features having been well addressed, durable modification of T1D will likely require combination therapies (3,5,(7)(8)(9)(10)(11). However, three concerns have limited trials of combination therapies for T1D: 1) the safety of combination therapies, 2) the presumed large study sizes required to test combinations, and 3) limited information from monotherapy studies.…”

mentioning

confidence: 99%

Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes

et al. 2022

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It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further “de-risk” development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.

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“…In the nonobese diabetic (NOD) mouse model of type 1 diabetes, IL-21 has key role in initiating islet autoimmunity by promoting the expansion of Th17 cells 19,20 . A phase II clinical trial in adults with newly diagnosed type 1 diabetes of monoclonal antibody blockade of IL-21, together with liraglutide (a glucagon-like peptide-1 receptor agonist that promotes insulin secretion), found that the combination of agents, but not anti-IL-21 antibody alone, sustained endogenous insulin production and improved glucose metabolism 21 . Our finding lends support to the evidence that IL-21 is involved in the pathogenesis of islet autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes

Harrison

Bandala‐Sanchez

Oakey

et al. 2023

J of Diabetes Invest

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Aims/IntroductionAutoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at‐risk for type 1 diabetes followed from birth who had developed islet autoantibodies (“seroconverted”), by measuring mucosa‐associated cytokines in their sera.Materials and MethodsSera were collected 3 monthly from birth from children with a first‐degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines.ResultsOf eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa‐associated cytokines IL‐21, IL‐22, IL‐25, and IL‐10, the Th17‐related cytokines IL‐17F and IL‐23, as well as IL‐33, IFN‐γ, and IL‐4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex‐ and age‐matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children.ConclusionsIn a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa‐associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

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278-OR: Efficacy and Safety of Anti-interleukin (IL)-21 in Combination with Liraglutide in Adults Recently Diagnosed with Type 1 Diabetes

Cited by 10 publications

References 0 publications

IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes

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