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

Abstract

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.

Keywords: Beta cells; Exploratory analysis; Immune biomarker machine learning; Immunotherapy; T cells; Type 1 diabetes.

Fig. 1

Summary of immune response methodology

Fig. 2

Example application of quality measures support, confidence, and lift to association rules

Fig. 3

Formal concept analysis of associations between treatment group, clinical endpoints, immune response data, and subgroups. A Analysis workflow. Among all 32,079 generated rules, 12,638 relevant rules were explored to find associations for clinical response. Associations were selected for support ≥ 4, lift ≥ 1.25, confidence ≥ 0.75, and p ≤ 0.05. B Statistically significant associations involving treatment with IMCY-0098 dose C, improvement of clinical endpoints, and HLA type. C, D HLA-dependent changes in subjects among the dose B and dose C groups for C normalized AUC C-peptide from MMTT and fasting C-peptide/glucose and D insulin dose per kg. E Box plot of quantitative response for AUC C-peptide in untreated vs treated groups. Central lines represent median values, boxes represent interquartile range, and whiskers represent upper and lower 1.5 × interquartile range, respectively. Dose B: 150 μg at week 0 followed by 3 × 75 μg; dose C: 450 μg at week 0 followed by 3 × 225 μg. * Fischer’s p = 0.044. AUC, area under the curve; HLA, human leukocyte antigen; MMTT, mixed meal tolerance test

Fig. 4

Immune response to IMCY-0098 treatment—intent-to-treat population. A Frequencies of different T cell subsets over time: naïve (CD45RA + CCR7 +), central memory (CD45RA-CCR7 +), effector memory (CD45RA-CCR7-), and terminal effector (CD45RA + CCR7 − ; no in vitro stimulation; error bars represent SD). B Change from baseline to week 24 in treatment-specific granzyme B⁺ cells within CD4 + T cell subsets after in vitro stimulation with IMCY0163 (insulin C20-A1). C Distribution of CD4⁺ granzyme B + T cells at week 24. D Change from baseline to week 24 in disease-specific Perforin + CD8⁺ T cells after in vitro stimulation with GAD65 and IGRP peptides. ^aFrequency within total CD4⁺ cell population. ^bFrequency within total CD8⁺ cell population. Box and whisker plots (B, D) show change of cell numbers from baseline to week 24, normalized to baseline value. Central lines represent median values, boxes represent interquartile range, and whiskers represent upper and lower 1.5 × interquartile range, respectively. p-values were obtained using Wilcoxon-Mann–Whitney test; p > 0.05 unless indicated otherwise. Dose A: 50 μg at week 0 followed by 3 × 25 μg; dose B: 150 μg at week 0 followed by 3 × 75 μg; dose C: 450 μg at week 0 followed by 3 × 225 μg. SD, standard deviation

Fig. 5

Immune response to IMCY-0098 treatment. Summary of immune parameters identified during formal concept analysis as associated with treatment (A) and changes in treatment-specific granzyme B⁺ CD4⁺ T cells (B) and disease-specific Perforin⁺ CD8⁺ T cells (C) after in vitro stimulation in all patients versus DR4 subgroup (see also Fig. 3 and Additional File 1: Fig. S2). Box and whisker plots (B, C) show change of cell numbers from baseline to week 24, normalized to baseline values. Central lines represent median values, boxes represent interquartile range, and whiskers represent upper and lower 1.5 × interquartile range, respectively. p-values were obtained using Wilcoxon-Mann–Whitney test; p > 0.05 unless indicated otherwise. Disease-specific CD8⁺ T cells refers to all T cells specific to any the disease-peptide loaded multimers. Dose A: 50 μg at week 0 followed by 3 × 25 μg; dose B: 150 μg at week 0 followed by 3 × 75 μg; dose C: 450 μg at week 0 followed by 3 × 225 μg

Fig. 6

Association between clinical outcomes and immune response markers. Results are shown for week 24 for patients receiving IMCY-0098 dose B or C. Associations were selected for confidence ≥ 0.75, support ≥ 4, and p ≤ 0.05. Data for IMCY-0098 dose B and dose C treatment groups were pooled for this analysis. Dose B: 150 μg at week 0 followed by 3 × 75 μg; dose C: 450 μg at week 0 followed by 3 × 225 μg. GAD, glutamic acid decarboxylase; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; IFN, interferon