A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes

Abstract

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.

Keywords: clinical trial; immunomodulatory; type 1 diabetes; ustekinumab.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology.

Figures

Graphical abstract

Figure 1

CONSORT Diagram showing allocation and disposition of study subjects adapted from Pesenacker et al., 2019 [13].

Figure 2

Summary of clinical endpoint data in young adults with new onset T1D receiving ustekinumab. (A) The mean change from baseline of C-peptide MMTT AUC over time was compared between subjects treated with a maintenance dose (five-dose regimen) of 45 mg or 90 mg (navy and red, respectively; week 52 P = 0.081) and between subjects receiving a 90 mg loading dosing (three doses) or maintenance dosing (five doses) (pink and red, respectively; week 52 P = 0.246). (B) Insulin dose and glycated hemoglobin over time for all subjects (intention-to-treat). Dotted lines indicate the cut off for the pre-defined clinical responder status. Data from subjects 26632 and 26491 were excluded after weeks 16 and 28, respectively, due to protocol deviation.

Figure 3

Ustekinumab at 90 mg dose reduces the proportion of Th17.1 cells. (A) Flow cytometry analyses of cryopreserved PBMCs revealed that subjects treated with the 90 mg dose of ustekinumab had a significant reduction in the proportion of IL-17A+IFN-γ +CD4+ Th17.1 cells at week 16 (Wilcoxon test, n = 9–10). Representative dot plots from weeks 0 and 16 are shown. (B) Flow cytometry analyses of cryopreserved PBMCs revealed that reduction in CD4+IL-17A+ T cells (Th17) and IL-17A+IFN-γ +CD4+ cells (Th17.1) following therapy was more pronounced in subjects defined as C-peptide responders (individuals with a loss of C peptide of less than 0.3 pmo/ml/year) compared to C-peptide non-responders and this reached significance at all weeks. (mixed-effects model with Geisser-Greenhouse correction, individual P-values corrected using Original FDR method of Benjamini and Hochberg; * P ≤ 0.05; ** P ≤ 0.01; *** P ≤ 0.001.). (C) Reduction of cytokine production upon ustekinumab administration reverted to baseline when drug administration was stopped at weeks 48 and 52 in both 45 mg and 90 mg three-dose (induction; dashed) groups. Vertical dashed gray line = discontinued ustekinumab (induction group). Subjects 26632 and 26491 excluded after weeks 16 and 28, respectively, where applicable due to protocol deviation. Horizontal dashed grey line = Baseline (100%).

Figure 4

The 90 mg but not 45 mg, ustekinumab dose reduces the proportion of proinsulin-specific IL-17A and IFN-γ-producing CD4+ T cells in young adults with new onset T1D at week 16. Fluorospot analysis was used to count the proinsulin-specific CD4+ T cells by subtracting proinsulin-stimulated PBMCs from control PBS-stimulated cells to ascertain net spots. There was a significant reduction in proinsulin-specific IFN-γ and IL-17A-producing CD4+ T cells from week 0 to week 16 in the 90 mg dosing cohorts (Wilcoxon test, n = 5).