Chemo drug unlocks new pathway for T1D treatment?

In a phase II trial, imatinib – a first-in-class tyrosine kinase inhibitor (TKI) that has had remarkable success for the treatment of chronic myelogenous leukaemia – preserved β-cell function in individuals with recent-onset type 1 diabetes (T1D), underpinning its potential to alter the course of T1D.

Despite currently available T1D therapies and widely available exogenous insulin, individuals with T1D cannot consistently achieve euglycaemia, leaving them at risk for complications, said the researchers. These challenges have driven the constant quest for novel T1D therapies, particularly those that can effectively and safely block autoimmune-mediated β-cell destruction.

“Missing from the current armamentarium is a therapy that affects metabolism and improves β-cell health … [P]reserving the function of remaining β cells, before or after diagnosis, offers the best means to control the disease process,” they said.

Imatinib acts through various mechanisms, including immunologic and metabolic pathways. [Cell Metab 2017;25:883-897.e8; Trends Endocrinol Metab 2015;26:643-656; Recent Pat Inflamm Allergy Drug Discov 2013;7:259-267; Nat Rev Clin Oncol 2016;13:431-446] “[I]matinib might have broader clinical utility, as it also inhibits other tyrosine kinases, including PDGFR, KIT, CSF-1R, tyrosine-protein kinase ABL2, and tyrosine-protein kinase Lck,” they continued.

Sixty-seven participants were randomized 2:1 to receive imatinib mesylate 400 mg daily (four 100 mg tablets) or matching placebo for 26 weeks. [Lancet Diabetes Endocrinol 2021;9:502-514]

At 12 months, mean estimates in 2-hour C-peptide area under the curve in response to a 4-hour mixed meal tolerance test were 0.583 and 0.489 nmol L^–¹ for imatinib and placebo, respectively. This generated an adjusted mean difference of 0.095 (p=0.048, one-tailed test) and constituted a 19.4-percent treatment effect. However, this effect was not sustained up to 24 months.

The researchers noted an increase in β-cell glucose sensitivity to higher than baseline levels at 3 months, which stabilized up to 6 months. However, the effect waned when participants were off active treatment. “β-cell glucose sensitivity provides a measure of the ability of the β cell to secrete insulin in response to a given glucose concentration, and might thus provide a better overall measure of β-cell function.”

At 24 months, 71 percent of imatinib recipients had a grade ≥2 adverse event (AE), as opposed to 59 percent of placebo-treated patients. Nearly 40 percent of imatinib recipients required temporary dose modification, while 13 percent discontinued imatinib permanently owing to AEs.

Given the relatively young cohort who were otherwise healthy, imatinib might be better tolerated than in oncology settings despite its safety issues, noted the researchers. “In general, imatinib was well-tolerated … [I]f participants did develop AEs, they tended to occur early in the course of drug administration, to be milder than that described in oncology literature, and usually resolved in the ensuing days and weeks with ongoing therapy.”

Despite several limitations (eg, small sample size, adult cohort, short treatment period) and lack of sustained effect, imatinib might have unique benefits in this setting. “[T]he 19.4-percent effect size we found with imatinib at 12 months compares favourably with several other drugs, including rituximab, alefacept, and abatacept,” said the researchers.

Further studies should ascertain the ideal dose, duration, and timing of imatinib therapy, as well as its safety and efficacy in children and adolescents. Other factors that should be taken into context in future trials are its potential to deliver a synergistic response when combined with a complimentary drug, ability to delay or prevent progression to diabetes in an at-risk population, and toxicities that may necessitate dose modification.

“The list of approved TKIs with varied specificities continues to increase steadily … [A]s more is learnt about the most crucial pathways to target in T1D, a better drug might be identified in this class to consider for [T1D] treatment,” they added.