BackgroundIMCY-0098, a synthetic peptide developed to halt disease progression via elimination of key immune cells in the autoimmune cascade, has shown a promising safety profile for the treatment of type 1 diabetes (T1D) in a recent phase 1b trial. This exploratory analysis of data from that trial aimed to identify the patient biomarkers at baseline associated with a positive response to treatment and examined the associations between immune response parameters and clinical efficacy endpoints (as surrogates for mechanism of action endpoints) using an artificial intelligence-based approach of unsupervised explainable machine learning.MethodsWe conducted an exploratory analysis of data from a phase 1b, dose-escalation, randomized, placebo-controlled study of IMCY-0098 in patients with recent-onset T1D. Here, a panel of markers of T cell activation, memory T cells, and effector T cell response were analyzed via descriptive statistics. Artificial intelligence-based analyses of associations between all variables, including immune responses and clinical responses, were performed using the Knowledge Extraction and Management (KEM®) v 3.6.2 analytical platform.ResultsThe relationship between all available patient data was investigated using unsupervised machine learning implemented in the KEM® environment. Of 15 associations found for the dose C group (450 μg subcutaneously followed by 3 × 225 μg subcutaneously), seven involved human leukocyte antigen (HLA) type, all of which identified improvement/absence of worsening of disease parameters in DR4+ patients and worsening/absence of improvement in DR4− patients. This association with DR4+ and non-DR3 was confirmed using the endpoints normalized area under the curve C-peptide from mixed meal tolerance tests where presence of DR4 HLA haplotype was associated with an improvement in both endpoints. Exploratory immune analysis showed that IMCY-0098 dose B (150 μg subcutaneously followed by 3 × 75 μg subcutaneously) and dose C led to an increase in presumed/potentially protective antigen-specific cytolytic CD4+ T cells and a decrease in pathogenic CD8+ T cells, consistent with the expected mechanism of action of IMCY-0098. The analysis identified significant associations between immune and clinical responses to IMCY-0098.ConclusionsPromising preliminary efficacy results support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D.Trial registrationClinicalTrials.gov NCT03272269; EudraCT: 2016–003514-27.