Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes

Quattrin, Teresa; Haller, Michael J.; Steck, Andrea K.; Felner, Eric I.; Li, Yinglei; Xia, Yichuan; Leu, Jocelyn H; Zoka, Ramineh; Hedrick, Joseph A.; Rigby, Mark R.; Vercruysse, Frank; Investigators, Trigr

doi:10.1056/nejmoa2006136

Cited by 167 publications

(112 citation statements)

References 35 publications

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“…Given the challenges in managing type 1 diabetes, clinical trialists have sought drugs that can safely and effectively block autoimmune-mediated destruction of β cells, and have often tested immunotherapies targeting T cells. Transient effects have been observed with some of these drugs, [3][4][5][6][7][8] prompting the search for new approaches.…”

Section: B Discussionmentioning

confidence: 99%

“…Despite these research efforts, there has not been robust success: a small number of large, placebo-controlled, phase 2 studies met their primary endpoint, but treated patients must usually remain on exogenous insulin, and the effects of immunotherapies wane with time as the therapies are withdrawn. [3][4][5][6][7][8] Therefore, investigators continue to search for novel therapies to stop β-cell destruction, with particular attention on repurposing drugs that are already approved for other indications, thereby accelerating their application to type 1 diabetes. In this search, a focus has been on imatinib mesylate (brand name Gleevec), a first-in-class tyrosine kinase inhibitor that has had notable success as a therapy for chronic myelogenous leukemia, 9 and that might also affect both immunological and metabolic pathways.…”

Section: Introductionmentioning

confidence: 99%

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

Gitelman¹,

Bundy²,

Ferrannini³

et al. 2021

The Lancet Diabetes & Endocrinology

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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...

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Section: B Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Gitelman¹,

Bundy²,

Ferrannini³

et al. 2021

The Lancet Diabetes & Endocrinology

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“…Efforts to prevent or slow the progressive deterioration of beta cell function with early immune interventions in children and young adults with newly diagnosed type 1 diabetes have also been met with success. Individuals who were administered golimumab, an anti-TNF-α monoclonal antibody, demonstrated better preservation of meal-stimulated insulin secretion after 52 weeks of therapy relative to control participants, with maintenance treatment infusions of golimumab being given every 2 weeks [21].…”

Section: Prevention Of Type 1 Diabetes and Preservation Of Beta Cell mentioning

confidence: 99%

Transforming type 1 diabetes: the next wave of innovation

Drucker

2021

Diabetologia

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The discovery of insulin in 1921 enabled pharmaceutical production of animal insulins for the treatment of people with type 1 diabetes by 1922. The last several decades have witnessed enormous scientific progress in the therapy of type 1 diabetes, yet some developments have been incremental, and insulin is not a cure. Herein, I highlight key scientific advances potentially poised to improve the quality of life and treatment outcomes in type 1 diabetes. These innovations range from newer insulin analogues to the development of smart insulins, oral and weekly insulins, glucose sensors and closed-loop insulin-delivery devices, as well as strategies for durable human beta cell replacement coupled with selective immune manipulation to preserve beta cell function. Finally, progress in the prediction and prevention of type 1 diabetes highlights the ongoing challenges and potential for altering the natural history of the disease or eliminating type 1 diabetes altogether.

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“…However, the exact mechanisms of action of teplizumab are still unclear, and this therapeutic antibody also had little effect in some patients (e.g., non-responders) [26]. Similarly, a recent trial using golimumab, a therapeutic monoclonal tumor necrosis factor alpha (TNF-α) antibody, led to increased residual beta cell function and reduced insulin usage in new onset pediatric and young adult patients with T1D as compared with placebo [27]. This study also reported an increased number of hypoglycemic events along with increased frequency of infections in the golimumab patients [27].…”

Section: T1d As a Disease Of The Immune System And Beta Cellsmentioning

confidence: 99%

“…Similarly, a recent trial using golimumab, a therapeutic monoclonal tumor necrosis factor alpha (TNF-α) antibody, led to increased residual beta cell function and reduced insulin usage in new onset pediatric and young adult patients with T1D as compared with placebo [27]. This study also reported an increased number of hypoglycemic events along with increased frequency of infections in the golimumab patients [27]. Thus, while some immunotherapies can delay disease progression during stage two or even after onset in stage three, there are patients who do not respond and there are often unintended consequences of systemic immune modulation.…”

Section: T1d As a Disease Of The Immune System And Beta Cellsmentioning

confidence: 99%

Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside

Brawerman

Thompson

2020

Biomolecules

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Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches.

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Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes

Cited by 167 publications

References 35 publications

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

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

Transforming type 1 diabetes: the next wave of innovation

Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside

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