164-OR: Efficacy of New-Onset Type 1 Diabetes (T1D) Intervention Trials: Variation in 1-Year Outcomes

Abstract

Mean 2-hour area under the curve (AUC) C-peptide levels at 1 year remain the primary endpoint for most intervention trials in subjects with new onset T1D. Comparisons of efficacy across T1D intervention trials with positive outcomes remain limited. We performed a cross-trial comparison of the NIH TrialNet sponsored new-onset rituximab, abatacept, low-dose anti-thymocyte globulin (ATG) (2.5mg/kg), and ATG/GCSF trials and the NIH ITN sponsored high-dose ATG (6.5mg/kg), alefacept, and teplizumab trials. One-year study group mean AUC C-peptides were adjusted for baseline C-peptide and age and compared to their internal control to retain individual study effects. To further compare differences in AUC C-peptide across trials, rituximab was used as a reference and percent increase compared to rituximab effect was calculated. Using this methodology, low-dose ATG (164%) and teplizumab (171%) provided for the largest relative improvements in AUC C-peptide. Percent effects over rituximab of the other studies were: high-dose ATG (-43%), alefacept (33%), abatacept (37%) and ATG/GCSF (45%). Despite the limitations of meta-like analyses and the notable differences in control group AUC C-peptides, these data strongly support the notion that low-dose ATG and teplizumab provide for the greatest relative preservation of AUC C-peptide amongst recently completed new onset T1D interventions. Disclosure M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. M.N. Greco: None. D. Schatz: None. M.A. Atkinson: None. T.M. Brusko: Advisory Panel; Self; Caladrius Biosciences, Inc. Board Member; Self; OneVax, LLC. L.M. Jacobsen: None. K.C. Herold: Consultant; Self; Provention Bio, Roche Pharma. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research & Development. Other Relationship; Self; Novo Nordisk Inc. J. Krischer: None. B.N. Bundy: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust; National Institutes of Health; JDRF; Sanofi; Amgen Inc.; McJunkin Family Charitable Foundation

Recent Advances in Immune-Based Therapies for Type 1 Diabetes

“…Thus, low-dose ATG has demonstrated considerable long-term capacity to preserve beta-cell function. As reported by Haller et al [34], no potential safety signals were seen in low-dose ATGtreated new-onset T1D subjects. Only short-lived and fully reversible side effects such as cytokine release syndrome (CRS) and serum sickness were reported in the study group.…”

“…As T1D is thought to be a T-cell-mediated disease, ATG could preserve beta-cell function through the ability to target multiple T-cell pathways. The efficacy of ATG in T1D has been previously reported in clinical studies where different doses were assessed and where ATG was used as monotherapy as well as in combination therapy [32-34].…”

“…Low-dose ATG resulted in a significantly higher mean AUC C-peptide and glycated haemoglobin A1c (HbA1c) improvement at 12 months. The addition of G-CSF did not result in a further increase of C-peptide levels over low-dose ATG monotherapy [34]. Two-year clinical trial outcome data confirmed a sustained effect of low-dose ATG on C-peptide [38].…”

“…Serum sickness was observed in the majority of participants who received low-dose ATG, but this was predictable and manageable. In addition, none of the participants who received low-dose ATG developed a severe infection, required extended hospitalization or readmission due to CRS or serum sickness, and no cases of grade 4 serum sickness or CRS were reported [34].…”

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

“…Importantly, the most effective immune modulator for T1D prevention to date, Teplizumab, is also associated with an exhausted T cell phenotype (68), and T cell exhaustion has also been linked with response to anti-thymocyte globulin (ATG) treatment in Stage 3 T1D (69,70). Intriguingly, we observed an increase in FoxP3 + PD1 + Tregs in the spleen and PLN in TYK2i-treated RIP-LCMV-GP mice.…”