Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
Tatovic D., Marwaha A., Taylor P., Hanna SJ., Carter K., Cheung WY., Luzio S., Dunseath G., Hutchings HA., Holland G., Hiles S., Fegan G., Williams E., Yang JHM., Domingo-Vila C., Pollock E., Wadud M., Ward-Hartstonge K., Marques-Jones S., Bowen-Morris J., Stenson R., Levings MK., Gregory JW., Tree TIM., Dayan C., Gevers E., Kanumakala S., Nair S., Gardner C., Ajzensztejn M., Wei C., Mouditis C., Campbell F., Greening J., Webb E., Chen M., Amin R., White B., Shetty A., Bidder C., Conway N., Mayo A., Christakou E., Sychowska K., Shahrabi Y., Robinson M., Ahmed S., Dutz J., Cook L.
AbstractImmunotherapy 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 (TH1 and TH17 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 (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 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 TH17.1 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).