Diabetes and other autoimmune endocrine diseases
Preclinical studies suggest that blockade of pro-inflammatory T cells that secrete IL-17/IFN-γ may suppress the T1D auto-inflammatory response. We assessed the safety and optimal dosing of ustekinumab (a monoclonal antibody targeting the IL-17/IFN-γ pathway) for the treatment of adult recent-onset T1D in a phase I/II open-label clinical trial (NCT02117765).
We enrolled 10 patients within 100 days of T1D diagnosis, aged 18-35 years, and with a peak C-peptide of 0.2nmol/l or greater on MMTT. Subjects received either 45mg or 90mg ustekinumab every 3 months. The primary endpoint was safety (rate, frequency and severity of adverse events). We also measured the baseline-adjusted change in 2-h AUC C-peptide response to MMTT at 1 year and performed flow cytometric analyses before and after study drug administration to assess any change in T helper cell subsets.
Ustekinumab-treated patients had a total of 10 adverse events (1/10 was possibly attributed to study drug). At 1 year, the 90mg cohort had a mean reduction in C-peptide AUC of 0.1pmol/mL and after one dose of study drug demonstrated a mean 50% reduction in peripherally circulating Th17.1 cells. The 45mg cohort had a mean C-peptide AUC reduction of 0.26pmol/ml and no changes in Th17.1 cells were observed.
Our study confirms the safety of ustekinumab in the context T1D and indicates that a higher 90mg dosing regime is optimal. This pilot provides a rationale to proceed to a phase II/III study to definitively test the efficacy of ustekinumab in preserving endogenous insulin secretion in children with recent-onset T1D.
University of British Columbia
University of British Columbia
Megan K. Levings, PhD
Professor, Dept of Surgery, University of British Columbia
Head, Childhood Diseases Theme, BC Children’s Hospital Research Institute
Dr. Megan Levings has been in the UBC Department of Surgery since 2003 when she was recruited back to Canada as a Canada Research Chair in Transplantation. In 2011 she joined the BC Children’s Hospital Research Institute where she now heads the Childhood Diseases Theme. Dr. Levings’ scientific career started with summer research positions in a fruit fly genetics lab at Simon Fraser University. She then did her graduate training in the genetics program with Dr. John Schrader at UBC. In 1999 she joined Dr. Maria Grazia Roncarolo's lab in Milan, Italy, undertaking postdoctoral training in the emerging area of immune regulation. She was among the first groups to show that a special kind of white blood cell, known as a T regulatory cell, could be used as a therapy to stop harmful immune responses. She continues this line of research at UBC, and is now internationally recognized in the field of human immunology and chairs the Federation of Clinical Immunology Societies Centres of Excellence. She leads a vibrant group of trainees and staff who are researching how to use T regulatory cells to replace conventional immunosuppression in the context of transplantation and autoimmunity.