A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

Lois, Noemi; Gardner, Evie; McFarland, Margaret; Armstrong, David; McNally, Christine; Lavery, Nuala Jane; Campbell, Christina; Kirk, Rita I; Bajorunas, Daiva R.; Dunne, Ann; Cerami, Anthony; Brines, Michael

doi:10.3390/jcm9072225

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…Cibinetide has been evaluated in several clinical trials showing a favorable safety profile 31 , 32 , 44 – 46 and clinical benefit in several clinical settings, e.g. ability to reduce neuropathy in sarcoidosis and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation

et al. 2021

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During intra-portal pancreatic islet transplantation (PITx), innate immune reactions such as the instant blood mediated inflammatory reaction (IBMIR) cause an immediate loss of islets. The non-hematopoietic erythropoietin analogue cibinetide has previously shown islet-protective effects in mouse PITx. Herein, we aimed to confirm cibinetide’s efficacy on human islets, and to characterize its effect on IBMIR. We cultured human islets with pro-inflammatory cytokines for 18 hours with or without cibinetide. ATP content and caspase 3/7 activity were measured. Dynamic glucose perfusion assay was used to evaluate islet function. To evaluate cibinetides effect on IBMIR, human islets were incubated in heparinized polyvinyl chloride tubing system with ABO compatible blood and rotated for 60 minutes to mimic the portal vein system. Moreover, human islets were transplanted into athymic mice livers via the portal vein with or without perioperative cibinetide treatment. The mice were sacrificed six days following transplantation and the livers were analyzed for human insulin and serum for human C-peptide levels. Histological examination of recipient livers to evaluate islet graft infiltration by CD11b+ cells was performed. Our results show that cibinetide maintained human islet ATP levels and reduced the caspase 3/7 activity during culture with pro-inflammatory cytokines and improved their insulin secreting capacity. In the PVC loop system, administration of cibinetide reduced the IBMIR-induced platelet consumption. In human islet to athymic mice PITx, cibinetide treatment showed an increased amount of human insulin in the livers and higher serum human C-peptide, while histological examination of the livers showed reduced infiltration of pro-inflammatory CD11b+ cells around islets grafts compared to the controls. In summary, Cibinetide protected isolated human islets in a pro-inflammatory milieu and reduced IBMIR related platelet consumption. It improved engraftment of human islets in athymic mice. The study confirms that cibinetide is a promising agent to be used in clinical PITx.

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Section: Discussionmentioning

confidence: 99%

Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation

et al. 2021

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“…Treatment with an EPO-derived peptide in diabetic rats prevents glial dysfunction, microglial activation, and neuronal damage without altering hematocrit or exacerbating neovascularization ( McVicar et al, 2011 ). A phase II clinical trial in DME (EudraCT 2015-001940-12) demonstrated safety but no improvements in BCVA, retinal sensitivity, or CMT ( Lois et al, 2020 ).…”

Section: Novel Treatment Strategiesmentioning

confidence: 99%

Neuroinflammation and neurodegeneration in diabetic retinopathy

Bianco

Arrigo

Aragona

et al. 2022

Front. Aging Neurosci.

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Diabetic retinopathy (DR) is the most common complication of diabetes and has been historically regarded as a microangiopathic disease. Now, the paradigm is shifting toward a more comprehensive view of diabetic retinal disease (DRD) as a tissue-specific neurovascular complication, in which persistently high glycemia causes not only microvascular damage and ischemia but also intraretinal inflammation and neuronal degeneration. Despite the increasing knowledge on the pathogenic pathways involved in DR, currently approved treatments are focused only on its late-stage vasculopathic complications, and a single molecular target, vascular endothelial growth factor (VEGF), has been extensively studied, leading to drug development and approval. In this review, we discuss the state of the art of research on neuroinflammation and neurodegeneration in diabetes, with a focus on pathophysiological studies on human subjects, in vivo imaging biomarkers, and clinical trials on novel therapeutic options.

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“…As efforts to find new therapies in DMO continue, early-phase trials have included MS metrics as secondary endpoints, notably in a phase I/II trial of oral dextromethorphan [168] and a phase II trial of cibinetide [169]. We are unaware of test-retest values derived from DMO cohorts which may hamper understanding of the minimal change thought to be clinically significant.…”

Section: Diabetic Macular Oedemamentioning

confidence: 99%

Clinical Perspectives and Trends: Microperimetry as a Trial Endpoint in Retinal Disease

Yang

Dunbar

2021

Ophthalmologica

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Endpoint development trials are underway across the spectrum of retinal disease. New validated endpoints are urgently required for the assessment of emerging gene therapies and in preparation for the arrival of novel therapeutics targeting early stages of common sight-threatening conditions such as age-related macular degeneration. Visual function measures are likely to be key candidates in this search. Over the last two decades, microperimetry has been used extensively to characterize functional vision in a wide range of retinal conditions, detecting subtle defects in retinal sensitivity that precede visual acuity loss and tracking disease progression over relatively short periods. Given these appealing features, microperimetry has already been adopted as an endpoint in interventional studies, including multicenter trials, on a modest scale. A review of its use to date shows a concurrent lack of consensus in test strategy and a wealth of innovative disease and treatment-specific metrics which may show promise as clinical trial endpoints. There are practical issues to consider, but these have not held back its popularity and it remains a widely used psychophysical test in research. Endpoint development trials will undoubtedly be key in understanding the validity of microperimetry as a clinical trial endpoint, but existing signs are promising.

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A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

Cited by 10 publications

References 33 publications

Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation

Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation

Neuroinflammation and neurodegeneration in diabetic retinopathy

Clinical Perspectives and Trends: Microperimetry as a Trial Endpoint in Retinal Disease

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