Journal Article

Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

Dayan, Colin, Pollock, Emily, Yang, Jennie H. M., Taylor, Peter, Gregory, John W., Marwaha, Ashish, Holland, Gail, Williams, Evangelia, Cheung, W. Y., Carter, Kym, Wadud, Muntaha, Hiles, Steve, Domingo-Vila, Clara, Luzio, Steve, Stenson, Rachel, Bowen-Morris, Jane, Levings, Megan K., Dunseath, Gareth, Hutchings, Hayley A., Tree, Timothy I. M., Fegan, Greg, Tatovic, Danijela, Ward-Hartstonge, Kirsten, Hanna, Stephanie J., Marques-Jones, Susie

2024

Overview

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (T H 1 and T H 17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group ( P  = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (T H 17.1 cells, P  = 0.04) and, in particular, with the reduction in a subset of T H 17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2 + GM-CSF + T H 17.1 cells, P  = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen ( P  = 0.0003). Although exploratory, our data suggest a role for an activated subset of T H 17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380). A phase 2 randomized controlled trial of ustekinumab in 72 adolescents with recent-onset type 1 diabetes showed that treatment was well tolerated and β-cell function was 49% higher in the intervention group compared to the placebo arm after 12 months.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/38 / 692/699/2743/137 / Adolescent / Adolescents / Beta cells / Biomedical and Life Sciences / Biomedicine / C-Peptide - metabolism / Cancer Research / Child / Clinical trials / Colony-stimulating factor / Diabetes / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 - drug therapy / Diabetes Mellitus, Type 1 - immunology / Double-Blind Method / Female / Granulocyte-macrophage colony-stimulating factor / Helper cells / Humans / Immunotherapy / Infectious Diseases / Insulin / Insulin-Secreting Cells - drug effects / Interleukin 2 / Interleukin-17 - immunology / International standards / Lymphocytes / Lymphocytes T / Male / Metabolic Diseases / Molecular Medicine / Monoclonal antibodies / Neurosciences / Pathogenesis / Peptides / Side effects / Teenagers / Th17 Cells - drug effects / Th17 Cells - immunology / Treatment Outcome / Ustekinumab - therapeutic use / γ-Interferon