ESPE Yearbook of Paediatric Endocrinology

Nat Med. 2024;30(9):2657-66. PMID: 39079992

Brief summary: In this phase 2, multicentre double-blind, randomized, placebo-controlled trial, the monoclonal antibody Ustekinumab was compared to placebo in 72 adolescents (aged 12–18 years) with recent-onset stage 3 type 1 diabetes (T1D). After 12 months, stimulated C-peptide was 49% higher in the Ustekinumab group compared to placebo. Preservation of C-peptide was associated with a reduction in a subset of T helper 17 cells.

Immunotherapy, aimed at modulating the autoimmune response in T1D, has been shown to delay the loss of β-cell function and remains a focus of intensive clinical and translational research (1).

Ustekinumab is a monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting the development of T helper 1 cells and T helper 17 cells (TH1 and TH17), known to be implicated in the pathogenesis of T1D (2). Ustekinumab (STELARA) has been licensed since 2009 for the treatment of psoriasis, psoriatic arthritis and inflammatory bowel disease, including use in children as young as 12 years for some indications.

In this trial, which was conducted in 16 UK clinical sites, Ustekinumab, administered subcutaneously every 4-8 weeks, for a total of 7 injections, exerted a positive effect on β-cell preservation in adolescents with a recent diagnosis of stage 3 T1D. While there was no difference in the primary outcome (C-peptide area under the curve during a mixed meal tolerance test) at 28 weeks, a significant between-group difference emerged at 56 weeks, when stimulated C-peptide was 49% higher in the Ustekinumab compared to placebo group. Treatment was well tolerated with no increase in adverse events. Exploratory data suggested a role for a subset of T_H17 cells, modulated by Ustekinumab, with benefits on β-cell preservation.

Of note, the delayed effect of Ustekinumab at 52 weeks suggests that this drug might be useful in combination with other treatments, e.g. to prolong the effect of Teplizumab. The safety and effectiveness data from this trial also supports the rationale to use Ustekinumab in a prevention study in presymptomatic T1D as a next step.

Further larger studies are needed to better assess the effectiveness of Ustekinumab on additional key outcomes, such as glycemic outcomes, for which the current study was not sufficiently powered. Expanding the study population to include younger age groups is also necessary.

References: 1. O’Donovan AJ, Gorelik S, Nally LM. Shifting the paradigm of type 1 diabetes: a narrative review of disease modifying therapies. Front Endocrinol (Lausanne) 2024; 15: 1477101.2. Koutruba N, Emer J, Lebwohl M. Review of ustekinumab, an interleukin-12 and interleukin-23 inhibitor used for the treatment of plaque psoriasis. Ther Clin Risk Manag. 2010;6:123-41.