Drugs that are already approved for other purposes are showing promise in slowing disease progression in people with new-onset type 1 diabetes (T1D), according to the results of three clinical trials presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.
The MELD-ATG trial looked at using the transplantation drug antithymocyte globulin (ATG); the Ver-A-T1D trial tested the old antihypertensive drug verapamil; and the BANDIT study assessed the impact of the oral JAK inhibitor baricitinib, currently used to treat other autoimmune diseases. Trial results varied, but all therapies demonstrated potential for preserving beta cell function, although insulin treatment is still required.
“We’re seeing increasing numbers of disease-modifying therapies in stage 3 [clinical T1D] that show effectiveness and safety. Therefore, we know that we can control the immune pathway; we can also save the remaining beta cells,” co-session moderator Sanjoy Dutta, PhD, chief scientific officer of Breakthrough T1D (formerly JDRF) told Medscape Medical News.
“We’ll continue to have to treat the glucose, but the hope is that because these medications slow down the immune system or protect the beta cells or both, a person with T1D would need less insulin,” Dutta added.
ATG: Lower Dose Effective, Less Adverse Effect
Chantal Mathieu, MD, an investigator and professor of medicine at KU Leuven, Belgium, and president of EASD, presented the results of the MELD-ATG trial, a phase 2, double-blind, randomized placebo-controlled, multi-arm dose-finding study of rabbit-derived ATG in 117 people aged 5-25 years diagnosed with T1D 3-9 weeks before treatment. All had C-peptide concentrations of 0.2 nmol/L or greater and at least one diabetes-related autoantibody (GADA, IA-2A, or ZnT8).
Participants were initially randomized to one of four ATG doses or placebo given as an intravenous infusion over 2 consecutive days. But as the trial progressed the ATG doses were narrowed down, per protocol, to two doses, 2.5 mg/kg (n = 33) and 0.5 mg/kg (n = 34), with n = 30 in the placebo group.
Both ATG doses significantly preserved beta cell function as assessed by C-peptide compared with placebo (P = .0028 for 2.5 mg/kg and P = .014 for 0.5 mg/kg). The investigators determined that the 0.5 mg/kg dose had an acceptable safety profile, as it was associated with lower rates of serum sickness (32% vs 82%) and of cytokine release syndrome (24% vs 33%). Individuals given the 0.5 mg/kg dose also had lower A1c levels compared with placebo.
Rabbit-derived ATG can’t be re-dosed for safety reasons, but newer formulations could offer the potential for further dosing without increasing adverse effects, Mathieu noted.
The study findings were simultaneously published in the Lancet. In an accompanying editorial, Cate Speake, PhD, scientific director of the Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, wrote, “As with other autoimmune diseases, appropriate treatment of T1D is likely to require a variety of therapies to address patient-specific immune responses, and might require combination therapy as applied in cancers. The results of the MELD-ATG trial suggest that further studies with ATG are warranted, Although there are not yet durable cures for type 1 diabetes, this study firmly maintains ATG as part of the existing list of plausible options.”
Verapamil: Missed Endpoint, Findings Still inform
Thomas R. Pieber, MD, professor of medicine head of the Division of Endocrinology and Metabolism, and chairman of the Department of Internal Medicine at the Medical University of Graz, Austria, presented results of Ver-A-T1D, a multi-center randomized, placebo-controlled trial of verapamil in 136 people aged 18-45 years with recent-onset T1D.
In addition to its calcium channel blocking property, verapamil also reduces the cellular redox regulator TXNIP, which has been linked to beta cell deficiency in rodents. Verapamil has also been shown to preserve beta cell function in previous human studies.
Study participants were randomized to once-daily oral sustained-release verapamil (n = 90), titrated from 120 mg to 360 mg, or placebo (n = 46) for 12 months. The primary outcome, 2-hour mixed-meal tolerance test c-peptide area under the curve, did not differ significantly between the two groups at 3, 6, 9, or 12 months. However, there were trends in benefit in both the primary (P = .06) and secondary endpoints and in the per-protocol analysis (P = .034).
And, Pieber noted, the C-peptide decline in the placebo group was slower than anticipated. “Hence, in retrospect, the trial was underpowered to detect the [minimal clinically important difference] in our study population.”
The study will continue to 24 months, followed by an open-label extension called Ver-A-Long, for 3 years. Pieber’s group will also perform a meta-analysis of randomized controlled trials of verapamil in new-onset T1D and plan to repeat Ver-A-T1D in adults with a longer endpoint and/or a larger sample size.
“Verapamil is a cheap, non-immunosuppressive beta-cell protecting agent, and easy to combine with immune modulating interventions,” he concluded.
Baricitinib: Benefits Continue at 2 Years
Michaela Waibel, PhD, of St. Vincent's Institute of Medical Research, Melbourne, Australia, presented 2-year results from the BANDIT trial of 91 people aged 10-30 years within 100 days of T1D diagnosis, randomized to 4 mg/day of baricitinib or placebo. Results at 48 weeks were previously reported in the New England Journal of Medicine and covered by Medscape at the time.
The primary outcome, mean C-peptide level determined by area under the curve during a 2-hour mixed meal tolerance test at week 48, was 0.65 nmol/L/min with baricitinib versus 0.43 nmol/L/min with placebo, a significant difference (P = .001).
After cessation of treatment, C-peptide levels decreased to 0.49 in the baricitinib group and 0.36 in the placebo group (P = .015) at 72 weeks, and at 96 weeks to 0.37 for baricitinib and 0.26 for placebo (P = .336). The fall in C-peptide in the baricitinib group after drug cessation was associated with increased insulin requirements and no significant differences between treatment groups at weeks 72 and 96.
Time in range on continuous glucose monitoring also deteriorated after baricitinib was stopped to the point that the significant differences that had been seen at 48 weeks were not statistically significant at weeks 72 and 96, Waibel reported.
No additional safety concerns emerged in the follow-up period.
“Among the agents reported as promising to preserve beta cell function in T1D, baricitinib stands out because it is administered orally, is well tolerated — including by young children — and is clearly efficacious. The current data support our previously reported clinical trial data by showing the loss of therapeutic effect when baricitinib is ceased and justify consideration of further studies in stage 3 T1D as well as prevention in stage 2 [autoantibody positive and dysglycemic but asymptomatic] T1D,” she concluded.
Session co-moderator Jay S. Skyler, MD, professor of medicine, pediatrics, and psychology at the University of Miami Leonard M. Miller School of Medicine, Florida, told Medscape that these new studies show proof of concept for the respective drug mechanisms, and that development is underway for a humanized ATG (rather than the current rabbit-derived) and for an agent that inhibits the same pathway as verapamil but with greater specificity.
“We look forward to newer therapies coming that are going to be better than the ones we have, which are going to preserve beta cells and keep people with T1D healthier for longer, and hopefully by doing that, reducing complications and keeping them going until we can replace their islets, [another approach] that will also be coming along. So, I’m enthusiastic about this space as a whole,” Skyler said.
Breakthrough T1D fully funded the baricitinib trial and contributed funding to both the ATG and verapamil trials as part of the Innodia public-private European research consortium.
Skyler has been an advisor to 4Immune Therapeutics, AbbVie, Abvance Therapeutics, Precigen ActoBio, Adocia, Aerami Therapeutics/Dance Biopharm, AiTA Bio, Applied Therapeutics, Arecor, AstraZeneca, Avotres, Bayer, Biomea Fusion, COUR Pharmaceuticals, Dexcom, Eli Lilly, Elvinix, Kriya Therapeutics, Levicure, Novo Nordisk, Oramed Pharmaceuticals, Provention Bio, PolTREG, Quell Therapeutics, RegCell, Remedy Plan, RespondHealth, Sanofi, Shoreline Biosciences, Signos, Vertex Pharmaceuticals, vTv Therapeutics, and WiNK Therapeutics. He is a member of the board of directors of Applied Therapeutics and of SAB Biotherapeutics. He is chair of the Strategic Advisory Board of the European Union EDENT1FI consortium. J.S.S. has equity in 4Immune, Abvance Therapeutics, AiTA Bio, Applied Therapeutics, Avotres, Dexcom, Elvinix, IM Therapeutics, Oramed Pharmaceuticals, SAB Biotherapeutics, Signos, vTv Therapeutics, and WiNK Therapeutics.
Mathieu reported serving or having served on advisory panels for Abbott, Bayer, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Insulet, Medtronic, Novartis, Novo Nordisk, Roche, SAB Bio, Sanofi, and Vertex (financial compensation paid to institution); receiving research support to institution from ActoBio Therapeutics, Medtronic, Novo Nordisk, and Sanofi; serving or having served on speakers bureau for Abbott, Dexcom, Eli Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Vertex (financial compensation paid to institution).
Pieber has received research support from (paid to university), and/or serves on a board/advisory panel for Arecor, Adocia, AstraZeneca, Eli Lilly, Novo Nordisk, Roche Diagnostics, and Sanofi.
Dutta and Waibel have no disclosures.
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