Final analysis of UST1D: A pilot clinical trial of ustekinumab in recent-onset Type 1 Diabetes Mellitus.

Background:Preclinical studies suggest that blockade of pro-inflammatory IL-17/IFN-γ secreting T cells inhibits the T1D autoinflammatory 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). 

Methods:We enrolled 20 patients within 100 days of T1D diagnosis, aged 18-35 years, and with a peak C-peptide of >0.2nmol/l on MMTT. Subjects were divided into four subcutaneous dosing cohorts: i)45mg-weeks 0/4/16, ii)45mg-weeks 0/4/16/28/40, iii)90mg-weeks 0/4/16 and iv)90mg-weeks 0/4/16/28/40. 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, insulin use/kg and HbA1c at 1 year. We performed flow cytometric analyses before and after study drug administration to assess changes in T helper cell subsets. We also assessed the changes in Proinsulin and GAD65 antigen-specific T cell subsets by flourospot. 

Results:Ustekinumab-treated patients had 13 adverse events (1/13 was possibly attributed to study drug). At 1 year, the highest dosing cohort (correlating to highest drug levels) had the most subjects that met clinical responder status (HbA1c < 6.5% with insulin use/kg/day < of 0.5) and the smallest decline in C-peptide AUC (0.1pmol/mL). In addition, ustekinumab administration significantly reduced the percentage of Th17, Th1 and Th17.1 cells from baseline and this reduction is specific to Proinsulin antigen-specific cells.

Conclusion: Our study suggests that the highest ustekinumab dosing schedule will be safe and optimal to prevent decline in C-peptide AUC, induce clinical response and reduce proinsulin antigen specific Th17/Th1 subsets. This pilot has provided a rationale for several placebo-controlled phase II/III efficacy studies using highest dosing approved in children (USTEKID) and adults (UST1D2).