Ustekinumab Offers Potential in Protecting Beta-Cells for Adolescents with Type 1 Diabetes, Study Suggests

UK: A multicenter, double-blind, randomized phase 2 trial of Ustekinumab for adolescents with type 1 diabetes was featured in an article in Nature Medicine.

The study found that ustekinumab, a monoclonal antibody approved for psoriasis, psoriatic arthritis, and inflammatory bowel disease, seems to safely preserve pancreatic beta-cell function in children with new-onset type 1 diabetes (T1D) by targeting the interleukin (IL)-12/IL-23 pathway.

Type 1 diabetes results from the autoimmune, T-cell-mediated destruction of insulin-producing β-cells. Unlike other autoimmune diseases where immunomodulatory therapies are well-established, the primary treatment for Type 1 diabetes for over a century has been insulin replacement. However, this approach often fails to achieve optimal glycemic control, particularly in younger patients. Research has shown that even preserving a small amount of endogenous insulin production after diagnosis can significantly reduce both short- and long-term complications. This underscores the importance of targeting immune pathways involved in the Type 1 diabetes pathogenic process.

In the study conducted by Danijela Tatovic, Division of Infection and Immunity, Cardiff University School of Medicine, a report on a phase 2, multicenter, double-blind, randomized, placebo-controlled trial of ustekinumab in children and adolescents within 100 days of T1D diagnosis (the USTEKID study) was conducted.

The findings of the study highlight the crucial role of a small proinflammatory subset of TH17.1 cells in β-cell destruction and demonstrate that targeting this subset through IL-12/IL-23 inhibition helps preserve C-peptide levels.

The key findings of the study are as follows:

• A double-blind, randomized controlled trial was conducted on 72 adolescents aged 12-18 years with recent-onset T1D.
• After 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group, meeting the prespecified primary outcome.
• The preservation of C-peptide was correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ.
• There was a notable reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor.
• A significant decrease in β-cell-targeted IL-17A-secreting T cells was observed.
• These findings suggest that targeting an activated subset of TH17.1 cells in Type 1 diabetes can reduce C-peptide loss with minimal adverse effects, though confirmation in a larger study is needed.
  

The study concluded that ustekinumab showed a high safety profile and effectively preserved β-cells in children and adolescents with recently diagnosed Type 1 diabetes by targeting the IL-12/IL-23 pathway. This trial provides the first prospective, randomized controlled evidence of the pathogenic role of TH17 cells in Type 1 diabetes, confirming the preliminary findings from the earlier pilot study.

Reference

Tatovic, D., Marwaha, A., Taylor, P., Hanna, S. J., Carter, K., Cheung, W. Y., Luzio, S., Dunseath, G., Hutchings, H. A., Holland, G., Hiles, S., Fegan, G., Williams, E., Yang, J. H., Pollock, E., Wadud, M., Stenson, R., Levings, M. K., Gregory, J. W., . . . Dayan, C. (2024). Ustekinumab for type 1 diabetes in adolescents: A multicenter, double-blind, randomized phase 2 trial. Nature Medicine, 1-10. https://doi.org/10.1038/s41591-024-03115-2