A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes. Issue 1 (13th November 2021)

• Record Type: Journal Article
• Authors: Marwaha, Ashish K; Chow, Samuel; Pesenacker, Anne M; Cook, Laura; Sun, Annika; Long, S Alice; Yang, Jennie H M; Ward-Hartstonge, Kirsten A; Williams, Evangelia; Domingo-Vila, Clara; Halani, Khalif; Harris, Kristina M; Tree, Timothy I M; Levings, Megan K; Elliott, Thomas; Tan, Rusung; Dutz, Jan P
• Is Part Of: Immunotherapy advances. Volume 2:Issue 1(2022)
• Publication Date: 2021-11-13
• Subjects: ustekinumab -- type 1 diabetes -- clinical trial -- immunomodulatory; Immunotherapy -- Periodicals; 615.37
• DOI: 10.1093/immadv/ltab022
• Languages: English
• ISSNs: 2732-4303

Abstract

Summary: Objectives: We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia. Methods: We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses. Results: Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A. Conclusion: Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response. Graphical Abstract: