Journal Article

First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes: an exploratory analysis of immune biomarkers

Kindermans, Martin, Carlier, Vincent, Bovy, Nicolas, Parmentier, Frédéric, Boitard, Christian, Vanderelst, Luc, Van Mechelen, Marcelle, Achenbach, Peter, Vandepapelière, Pierre, Van Rampelbergh, Jean, Leslie, Richard David

2024

Overview

Background IMCY-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. Methods We 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. Results The 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. Conclusions Promising preliminary efficacy results support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. Trial registration ClinicalTrials.gov NCT03272269; EudraCT: 2016–003514-27.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Adult / Analysis / Antigens / Artificial intelligence / Beta cells / Biological markers / Biomarkers / Biomedicine / Care and treatment / CD4 antigen / CD8 antigen / Cell activation / Cells / Clinical trials / Data analysis / Development and progression / Diabetes / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 - drug therapy / Diabetes Mellitus, Type 1 - immunology / Diabetes therapy / Diagnosis / Disease / Double-Blind Method / Drug dosages / Effectiveness / Effector cells / Expected values / Exploratory analysis / Female / Flow cytometry / Haplotypes / Health services / Histocompatibility antigen HLA / Histocompatibility antigens / HLA histocompatibility antigens / Humans / Hypotheses / Hypothesis testing / Immune biomarker machine learning / Immune response / Immune system / Immunological memory / Immunological tolerance / Immunotherapy / Immunotherapy - methods / Insulin / Learning algorithms / Lymphocytes / Lymphocytes T / Machine learning / Male / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Memory cells / Methods / Middle Aged / Parameter identification / Patient outcomes / Patients / Peptides / Peptides - administration & dosage / Peptides - therapeutic use / Protective antigen / Research Article / Statistical analysis / T cells / Testing / Treatment Outcome / Type 1 diabetes / Unsupervised learning / Young Adult