68-OR: Influence of the Type 1 Diabetes Genetic Risk Score on Response to Immunotherapies for Type 1 Diabetes Prevention
Authors: REDONDO MARIA J. , BUNDY BRIAN N. , PARIKH HEMANG M. , YOU LU , TRIOLO TAYLOR M. , FERRAT LAURIC A. , TEMPLEMAN ERIN , TOSUR MUSTAFA , STECK ANDREA , GOTTLIEB PETER , ONENGUT-GUMUSCU SUNA , RICH STEPHEN S. , ORAM RICHARD A. , HEROLD KEVAN C. , KRISCHER JEFFREY 
Published: June 2024

Introduction & Objective: Teplizumab has shown efficacy at delaying the onset of type 1 diabetes (T1D) but markers of response to treatment are needed to evaluate risk-benefit ratio. The T1D genetic risk score-2 (GRS2) combines 67 HLA and non-HLA single nucleotide polymorphisms (SNPs) that increase T1D risk. We tested the hypothesis that the likelihood of response to immunotherapies for T1D prevention increases with higher T1D GRS2.
Methods: We studied autoantibody-positive participants in the TrialNet trials TN10 (n=44 teplizumab, n=32 placebo), TN18 (n=101 abatacept, n=111 placebo) and TN07 (n=283 oral insulin, n=277 placebo). Martingale residual scatterplots (MRS) based on the Cox Model were employed to assess T1D risk. Analyses were adjusted for age.
Results: Except for TN10, MRS smoothing curves demonstrated that GRS2 is directly correlated with T1D risk. Analyzing TN10 by arm, the smoothing curve showed that, with higher GRS2, T1D risk increases for the placebo arm while, for the treated arm, the risk appears to decrease, creating a crossover point at GRS=12.8 near zero (relative risk=1). We then fitted a Cox Model including GRS2 dichotomized at 13, treatment arm and an interaction term. The interaction term was significant (p=0.03) and the hazard ratio of T1D risk (teplizumab to placebo) for GRS2 ≥13 was 0.263 (95%CI=0.123-0.562) but 0.898 (95th% CI=0.295, 2.74) for GRS2&lt;13.
Conclusion: In clinical trials with agents that failed to prevent progression to stage 3 T1D (e.g., abatacept and oral insulin), higher T1D GRS (reflecting higher genetic burden of T1D risk) was associated with higher risk of progression, as expected. However, teplizumab modified the relationship between GRS2 and T1D risk suggesting a greater beneficial therapeutic effect in participants with T1D GRS2 ≥13. In contrast, participants with lower T1D GRS2 had worse response to teplizumab. These results support that genetics can help select individuals who will respond to treatments to prevent T1D.

Disclosure
M.J. Redondo: None. B.N. Bundy: None. H.M. Parikh: None. L. You: None. T.M. Triolo: None. L.A. Ferrat: Consultant; Johnson & Johnson Medical Devices Companies. E. Templeman: None. M. Tosur: None. A. Steck: None. P. Gottlieb: Other Relationship; IM Therapeutics. Research Support; Imcyse. Advisory Panel; Imcyse. Consultant; Juvenile Diabetes Research Foundation (JDRF). Research Support; Hemsley Charitable Trust, Novartis AG, Provention Bio, Inc., Precigen, Inc. Advisory Panel; ViaCyte, Inc. Research Support; Nova Pharmaceuticals. S. Onengut-Gumuscu: None. S.S. Rich: None. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. K.C. Herold: Consultant; Sanofi. J. Krischer: None.

Funding
National Institutes of Health NIDDK 1R01DK121843