IDF21-0113 Design of a precision medicine GAD-alum immunotherapy Phase III clinical trial in Type 1 Diabetes

Abstract

Background: Disease heterogeneity poses challenges for clinical development in Type 1 diabetes (T1D). A precision medicine approach targeting genetically defined subgroups can provide a solution. Aim: Our objectives are to describe the design and rationale of the first precision medicine randomized controlled Phase III trial of an immunotherapy (recombinant GAD65 protein) in the population of T1D patients carrying the HLA DR3-DQ2 haplotype. Method: A meta-analysis of 521 individuals with recent-onset T1D showed that recombinant GAD65 conjugated to aluminium hydroxide (GAD-alum [Diamyd®]) has a significant dose-dependent effect on the preservation of endogenous insulin secretion over 15 months in individuals with T1D carrying HLA DR3-DQ2. An even stronger effect was seen in individuals with HLA DR3-DQ2 lacking HLA DR4-DQ8. These HLA-specific effects were subsequently confirmed in a randomized controlled Phase IIb trial. Results: We describe the rationale and key decision points in the design of the randomized placebo-controlled 24-month Phase III DIAGNODE-3 trial in the population of individuals with recent-onset T1D carrying HLA DR3-DQ2, stratified by the absence of DR4-DQ8, which will start enrolling in the second half of 2021. This is the first precision medicine Phase III trial of a disease-modifying treatment in T1D using a genetic marker to identify patients most likely to benefit. We will summarise results from the meta-analysis and the Phase IIb trial and present details on the genetic precision medicine strategy for GAD-alum immunotherapy. We will also present new results from a post-hoc meta-analysis demonstrating that drug product age (up to 3 years) does not influence clinical efficacy. Discussion: Utilising HLA haplotyping to identify responders to antigen-specific immunotherapy in T1D is a promising strategy currently used in a Phase III trial of intralymphatic GAD-alum.