Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Background Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes. MethodsWe did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recentonset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetesassociated autoantibody, and with a peak stimulated C-peptide of greater than 0•2 nmol L -¹ on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed).Findings Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0•095 (90% CI -0•003 to 0•191; p=0•048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastro intestinal issues (six [13%] partici pants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation du...

DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes

“…For instance, β cells experience unmitigated endoplasmic reticulum (ER) stress and activate the terminal unfolded protein response (UPR) leading to apoptosis during the development of T1D [ 4 ]. Small molecule therapeutics that block terminal UPR have shown promise in clinical trials of new onset T1D patients by slowing the decline in C-peptide production after diagnosis [ 5 , 6 ]. Thus, clinical interventions to target β cell stress responses are emerging as a therapeutic strategy for T1D.…”

Gene Expression Signatures Reveal Common Virus Infection Pathways in Target Tissues of Type 1 Diabetes, Hashimoto’s Thyroiditis, and Celiac Disease

“…Tyrosine kinases are important signaling cascade mediators, playing critical roles in a variety of biological processes such as growth, differentiation, apoptosis, and metabolism in response to internal and external stimuli. It is worth noting that imatinib, a tyrosine kinase inhibitor, was shown in a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial to preserve beta-cell function in patients with recent-onset T1D ( 26 ). Possible mechanisms of imatinib might include, 1) inhibiting ABL-IRE1α interaction and dampening IRE1α RNase hyperactivity, thus resulting in the reduction of pancreatic β cell apoptosis as demonstrated in a non-obese diabetic (NOD) mouse study ( 27 ); 2) preventing the process of T cell and macrophage infiltration into islets ( 28 ).…”

Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis

“…By blunting IRE1a RNase hyperactivity, imatinib reduces beta-cell apoptosis and preserves physiological function. In humans, a clinical trial found imatinib preserved beta-cell function at 12 months in adults with recent-onset T1D (195). Ongoing studies will investigate dose and duration of therapy as well as safety and efficacy for use in children.…”

“…An ongoing clinical trial using imatinib mesylate (brand name Gleevec), a tyrosine kinase inhibitor, shows promising results in targeting beta-cell ER stress (195). The efficacy of imatinib for the treatment of various immune-mediated diseases is currently being tested.…”