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

The current paradigm encompasses autoimmune mechanisms in type 1 diabetes (T1D) and the potential for immunomodulatory therapies.

This phase 2 trial investigates ustekinumab, an approved drug for other autoimmune conditions, as a treatment for T1D in adolescents. The study operates within the existing paradigm of autoimmune pathogenesis in T1D and explores a specific pathway (IL-12/IL-23) known to be involved in other autoimmune diseases. The positive results on C-peptide preservation, a key marker of beta-cell function, support and refine the existing paradigm but do not cause a significant shift. The delayed onset of action and the focus on a specific T-cell subset (TH17.1 cells co-expressing GM-CSF and/or IL-2) suggest a refinement or drift within the current model, prompting further investigation and potential adjustments to our understanding of T1D pathogenesis and treatment. Because ustekinumab's effect, although statistically significant, was small and limited to a subset of immune cells and no changes were observed on clinical measures of T1D during the study timeframe, classifying this work as purely 'Normal Science' may be an overstatement. The additional mechanistic findings, while compelling, remain exploratory and require further validation. Thus, 'Model Drift' also appears relevant, reflecting a potential refinement rather than a complete revolution of the current understanding. Therefore, the study seems to bridge the categories of Normal Science and Model Drift.