IMCY-0098 (proinsulin Imotope peptide)

Overview

IMCY-0098 is an investigational synthetic peptide immunotherapy developed by Belgian biotech Imcyse using its Imotope™ platform. The molecule combines an HLA-DR4-restricted human proinsulin peptide epitope (C20-A1) with a four-amino-acid thioredoxin oxidoreductase (C-X-X-C) motif flanking the MHC class II binding groove.

When presented on MHC class II molecules by antigen-presenting cells (APCs) in pancreatic lymph nodes, the thioredoxin motif forms a covalent disulfide bridge with redox-sensitive surface proteins on cognate naive CD4+ T cells. Instead of differentiating into conventional helper or Foxp3+ regulatory T cells, those primed T cells differentiate into antigen-specific cytolytic CD4+ T cells (cCD4+ T cells) that trigger granzyme/perforin- and FasL-mediated apoptosis of both the autoantigen-presenting APC and neighboring pathogenic autoreactive CD4+ and CD8+ effector T cells recognizing other islet antigens on the same APC ("bystander elimination"), while sparing systemic immunity.

Key Clinical Evidence

Phase 1b Dose-Escalation (IMCY-T1D-001, NCT03272269) & 48-Week Follow-Up (NCT04190693)

In the first-in-human randomized, double-blind, placebo-controlled Phase 1b study (NCT03272269, published by Van Rampelbergh et al. in BMC Medicine 2023, PMID: 37226224), 41 HLA-DR4+ adults aged 18–30 within 6 months of Stage 3 T1D diagnosis were randomized 3:1 across three ascending subcutaneous alum-adjuvanted dose cohorts (50 µg, 150 µg, and 450 µg prime followed by three biweekly boosts of 25 µg, 75 µg, or 225 µg) versus placebo:

• Safety: IMCY-0098 was well tolerated across all dose levels through Week 24 (NCT03272269) and Week 48 (NCT04190693, n = 30), with zero serious adverse events (0 SAEs) and mild, transient local injection-site reactions as the most common treatment-related event.
• Metabolic Readout: Stimulated 2-hour MMTT C-peptide AUC changes from baseline to Week 24 were -0.108 nmol/L in Cohort 1 (50 µg), -0.041 nmol/L in Cohort 2 (150 µg), -0.040 nmol/L in Cohort 3 (450 µg), and -0.012 nmol/L in the placebo group — showing no statistically significant C-peptide preservation advantage over placebo, while ambient glucose management targeting 70–180 mg/dL (3.9–10.0 mmol/L) remained comparable across groups.
• Exploratory Biomarkers (PMID: 38902652): Multi-parameter immune profiling in the 2024 BMC Medicine companion study identified dose-dependent expansion of proinsulin-specific cCD4+ T cells in the 450 µg cohort that correlated inversely with circulating autoreactive CD8+ effector T cells, motivating a higher-dose evaluation in Phase 2.

Phase 2 IMPACT Trial (IMCY-T1D-003, NCT04524949) — Terminated for Lack of Efficacy

To test whether higher doses and broader HLA-DR3/HLA-DR4 eligibility could preserve beta-cell function, Imcyse launched the adaptive, multicenter, randomized, double-blind, placebo-controlled Phase 2 IMPACT trial (NCT04524949) across Europe, the United Kingdom, the United States, and Australia, backed by JDRF (Breakthrough T1D).

• Enrollment: The trial completed full enrollment of 110 participants aged 12–45 with recent-onset Stage 3 T1D (fasting C-peptide ≥ 0.2 nmol/L).
• Outcome (TERMINATED): In January 2024 (registry update posted June 2024), NCT04524949 was formally terminated. The ClinicalTrials.gov registry records the exact termination reason: "No efficacy at primary analysis after 1 year. Long term follow-up stopped."

Limitations & Why It Is Marked Discontinued

Despite a compelling mechanistic hypothesis and clean Phase 1/2 tolerability, subcutaneous alum-adjuvanted IMCY-0098 failed to slow C-peptide loss in a well-powered 110-patient randomized Phase 2 trial (NCT04524949). Like several prior single-epitope peptide vaccines (GAD-alum in unselected populations, DiaPep277, and oral/intranasal insulin), inducing peripheral peptide-reactive T cells against a single modified proinsulin segment did not translate into durable clinical beta-cell preservation once multi-epitope insulitis is established in Stage 3 T1D.

Summary of Strengths & Limitations

Strengths

• Designed to achieve antigen-specific immune tolerance by inducing cytolytic CD4+ T cells that eliminate pathogenic autoantigen-presenting cells and autoreactive effector T cells without broad systemic immunosuppression
• Subcutaneous alum-adjuvanted peptide injections were well tolerated across both Phase 1b (n = 41) and the multicenter Phase 2 IMPACT trial (n = 110), with zero treatment-related serious adverse events
• Exploratory biomarker analyses from Phase 1b (Van Rampelbergh et al., BMC Medicine 2023 & 2024) confirmed dose-dependent induction of proinsulin-specific cytolytic CD4+ T cells in HLA-DR4+ recipients

Limitations

• The pivotal 110-patient randomized, double-blind, placebo-controlled Phase 2 IMPACT trial (NCT04524949) failed its primary efficacy analysis at 1 year and was formally terminated in 2024 ("No efficacy at primary analysis after 1 year. Long term follow-up stopped")
• Phase 1b (NCT03272269) also showed no statistically significant C-peptide preservation advantage over placebo at 24 or 48 weeks
• Restricted by mechanism to patients carrying specific HLA class II alleles (HLA-DR4 in Phase 1b; HLA-DR3 and/or HLA-DR4 in Phase 2), and clinical development in Type 1 Diabetes has ceased