A recent Phase 2 study published in Nature Medicine indicates that ustekinumab (Stelara) may be effective in preserving insulin production in adolescents with recent-onset type 1 diabetes (T1D). The study, conducted in the United Kingdom, found that ustekinumab reduces the levels of Th17.1 cells, a type of immune cell implicated in the destruction of insulin-producing beta cells. This research offers a potential new avenue for early intervention in T1D to slow or halt the autoimmune attack on beta cells.
Targeting Th17.1 Cells in Type 1 Diabetes
Type 1 diabetes, an autoimmune disease affecting approximately 2 million Americans, occurs when the body's immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. Current standard of care involves insulin replacement therapy. Sanofi's Tzield (teplizumab-mzwv), a CD3-directed monoclonal antibody approved in November 2022, has demonstrated the possibility of addressing the immune system response in T1D by delaying disease progression. This has spurred interest in therapies that selectively target T cell subsets involved in beta cell destruction.
Ustekinumab, marketed as Stelara by Janssen (a Johnson & Johnson company), is already approved for plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease. It is a biologic that targets the inflammatory response linked to T1D by inhibiting interleukins IL-12 and IL-23, which stimulate immune responses that damage beta cells. Preserving these cells is critical, as their loss directly causes T1D and complications from poor blood sugar control.
Phase 2 Trial Details and Results
The Phase 2 study, led by Danijela Tatovic, involved 72 adolescents aged 12-18 with recent-onset T1D. Ustekinumab was administered within 100 days of diagnosis. The final analysis included 62 patients (41 in the ustekinumab arm and 21 in the placebo arm). Conducted between December 2018 and September 2022, the study assessed whether ustekinumab's blockade of IL-23 and IL-12 could reduce Th17.1 cells.
After 12 months, researchers observed a 49% increase in C-peptide levels in the ustekinumab group compared to placebo, the primary outcome of the study. C-peptide is a marker of the body's own insulin production. The results also provide clinical trial evidence supporting the role of Th17 cells in T1D. These cells, though representing only 0.1% of circulating CD4 T cells, play a key role in beta cell dysfunction.
Implications and Future Directions
According to the researchers, "The highly selective nature of the T cell modulation produced by ustekinumab reduces its impact on other parts of the immune system and underlies its favorable adverse event safety profile seen in the present study." They suggest that the delayed action of the drug in reducing the target immune population may make it better suited for use at earlier stages of the disease, such as stage 1 or stage 2 T1D.
Stelara generated $10.86 billion in revenue globally in 2023, compared to $6.4 billion the previous year. In the first half of 2024, worldwide sales reached $5.3 billion, up 1.8% from the first half of 2023. Five biosimilars referencing Stelara have been approved and are expected to launch in 2025.
