The MultiPepT1De Study—Examining the Safety of Peptide Immunotherapy Using Multiple Islet Antigens in Recent-Onset Type 1 Diabetes

Background: Peptide immunotherapy (PIT) aims to modulate immune responses to specific antigens in order to restore immune tolerance. Recently, we reported outcomes of a phase 1b study of PIT at type 1 diabetes onset, showing safety, tolerability and changes in immune regulation pathways, following up to 12 doses of 10μg of a single proinsulin peptide that is naturally processed and presented by HLA-DR4 (DRB1*0401). Preclinical PIT studies show that multiple peptides in combination enhance tolerance induction. Aims: To evaluate the safety and clinical effects of PIT using a mix of multiple islet autoantigen peptides in adults with recent-onset type 1 diabetes. Methods: The MultiPepT1De study was a single centre, double-blind placebo-controlled, ascending dose, randomized trial recruiting adults aged 18-45 years within 4 years of diagnosis with HLA-DRB1*0401 genotype, positive islet autoantibodies and stimulated C-peptide >0.2pmol/mL. Study drug comprised of 6 naturally processed and presented, islet-derived peptides (MultiPepT1De). Participants were enrolled into 3 cohorts for monthly intradermal injections for 6 months. In each cohort, subjects were randomized to receive placebo (n=2) or MultiPepT1De (n=6) at 10µg (Cohort 1), 100µg (Cohort 2) or 500µg (Cohort 3) doses. Results: Twenty-seven participants were randomized; 3 participants withdrew for non-clinical reasons and were replaced. There were no episodes of systemic hypersensitivity, anaphylaxis or serious adverse reactions linked to MultiPepT1De administration. Analysis of changes in stimulated C-peptide, HbA1c and insulin dose per kg showed no evidence of disease acceleration following dosing compared with placebo. Mild transient injection site erythema was observed in all cohorts, with no increase on repeated dosing. Conclusions: Intradermal administration of multiple islet-derived peptides up to a cumulative dose of 3000µg, is well tolerated with no safety concerns.