Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
Danijela Tatović, Ashish Marwaha, Peter Taylor, Stephanie Hanna, Kymberley Carter, WY Cheung, Steve Luzio, Gareth Dunseath, Hayley Hutchings, Gail Holland, Steve Hiles, Greg Fegan, Evangelia Williams, Jennie H. M. Yang, Clara Domingo‐Vila, Emily Pollock, Muntaha Wadud, Kirsten A. Ward‐Hartstonge, Susie Marques-Jones, Jane Bowen‐Morris, Rachel Stenson, Megan K. Levings, John W Gregory, Timothy Tree, Colin Dayan, USTEKID Study Group, Evelien Gevers, Shankar Kanumakala, Sunil Nair, Chris Gardner, Michal Ajzensztejn, Christina Wei, Chris Mouditis, Fiona Campbell, James Greening, Emma Webb, Mimi Chen, Rakesh Amin, B. White, Ambika Shetty, Chris Bidder, Nicholas Conway, Amalia Mayo, Eleni Christakou, Kamila Sychowska, Yasaman Shahrabi, Maximilian Robinson, Simi Ahmed, Jan Dutz, Laura Cook
Abstract
Abstract 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).