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

Ashish K Marwaha,Anne M Pesenacker,Clara Domingo-Vila,Kirsten A Ward-Hartstonge,Jennie H M Yang,Khalif Halani,Laura Cook,Annika Sun,Megan K Levings,Evangelia Williams,Jan P Dutz,Rusung Tan,Kristina M Harris,Samuel Chow,Thomas Elliott,Timothy I M Tree,S Alice Long

doi:10.1093/immadv/ltab022

Abstract

SummaryObjectivesWe 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.MethodsWe 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.ResultsAlthough 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.ConclusionUstekinumab 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.

Highlights

Type 1 diabetes (T1D) is an autoimmune disease that arises from the T cell-mediated destruction of pancreatic β-cells
Data generated from people with recent-onset T1D,1 indicate that functional insulin-secreting β-cells are present at time of disease presentation
Peripheral blood mononuclear cells (PBMC) from children with s recent-onset T1D3 have a higher proportion of CD4+ and CD8+ T cells that secrete IL-17A.4

Summary

Introduction

Type 1 diabetes (T1D) is an autoimmune disease that arises from the T cell-mediated destruction of pancreatic β-cells. Data generated from people (individuals) with recent-onset T1D,1 indicate that functional insulin-secreting β-cells are present at time of disease presentation. Long-term interruption of T cell-mediated, autoimmune β-cell destruction at the time of clinical T1D presentation could preserve sufficient β-cells to maintain insulin secretion. Peripheral blood mononuclear cells (PBMC) from children with s recent-onset T1D3 have a higher proportion of CD4+ and CD8+ T cells that secrete IL-17A (known as nu Th17 and Tc17 cells, respectively).[4] Dysregulated IL-17A production acts in concert with IFN-γ, an a inflammatory and cytotoxic cytokine produced by Th1 cells. A subset of Th17 cells, termed Th17.1 cells, simultaneously produces IFN-γ, and IL-17A, and are defined as 'non-classical' Th1 cells.[5]

Objectives

Methods

Results