Lynda Charters

home

authors

lynda-charters

Dr Tine Van Bergen reported the preclinical data from a study of THR-687 (Oxurion NV), a selective RGD integrin antagonist, for treating diabetic macular oedema (DMO). The results showed that THR-687 provides protection against retinal vascular permeability, inflammation and reactive gliosis in a diabetic rat model. Dr Van Bergen is a senior scientist with Oxurion NV.

RGD-binding integrins modulate numerous biological processes including cell differentiation, adhesion, shape, migration, motility, invasion, proliferation and survival. Under pathological conditions, integrins may be aberrantly activated. In the eye, integrins have been shown to play an important role vascular leakage, inflammation, angiogenesis and gliosis. Consequently, integrins have emerged as promising targets for therapeutics development.

Dr Van Bergen and co-workers investigated the potential of THR-687 in the streptozotocin (STZ)-induced diabetic rat model to determine the effects on DMO-related hallmarks. They tested 3 intravitreally injected doses (6.7, 16.7, or 75 µg/eye) of THR-687 or vehicle (control) in both eyes of the animals at intervals of 1 week.

The investigators reported, “THR-687 reduced the diabetes-induced increases in retinal permeability versus vehicle in a dose-dependent manner. Furthermore, all doses of THR-687 also significantly reduced the number of inflammatory cells compared to vehicle. The highest dose of THR-687 reduced the diabetes-induced activation of Müller cells.”

Based on the results, they concluded that THR-687 inhibits vascular permeability, inflammation and gliosis in the diabetic is rat model. In addition, because of its multifaceted mechanism of action, THR-687 may have the potential for a broader biologic effect compared to anti-VEGF therapy.

THR-687 is currently in Phase 2 clinical trial (INTEGRAL - NCT05063734), which consists of a two-part study. Part A aims to select the dose level after multiple injections, while Part B will evaluate the efficacy and safety of the selected THR-687 dose versus aflibercept in treatment-naïve and previously treated DMO patients. The data of Part A study is expected to be released within this quarter.

Articles

THR-687 is currently being evaluated in a phase 2 clinical trial in patients with DME. The first data from the dose-optimization study is expected to be released in the first half of 2022.

Diabetic rats protected from macular oedema hallmarks with THR-687 treatment

A recent Phase 1/2a trial of an intravitreal treatment designed to treat diabetic macular ischaemia (DMI), BI-X (Boehringer Ingelheim), found the candidate to be well tolerated with no dose-limiting events and no drug-related adverse events, according to Dr Quan Dong Nguyen, a professor of ophthalmology at Byers Eye Institute at Stanford University School of Medicine in Palo Alto, California, United States.

DMI is defined as any disruption in retinal vascularity within the superficial and/or deep retinal plexus as seen on optical coherence tomography angiography, and it is a complication of diabetic retinopathy (DR). Currently, there is no treatment available that can prevent or stop progression of DMI. Dr Nguyen pointed out that the development of a treatment is important because it is a common complication that can have a profound impact on a patient’s vision.

BI-X works as an anti-ischaemia modulator of the human protein, semaphorin 3A, which blocks revascularisation in ischaemic retinas.

DMI patients enrolled in the Phase 1/2a study had previously been treated with laser for DR. The study has two parts, or ‘phases’, and all subjects treated with BI-X have received one intravitreal dose of the drug.

The non-randomised, open-label section of the study is complete. Three cohorts received 0.5-, 1- or 2.5-mg doses of the therapy; the cohorts included three, three and six subjects, respectively. The primary endpoint was the number of dose-limiting events, and the secondary endpoints were the numbers of drug-related and ocular adverse events.

According to Dr Nguyen, the best-corrected visual acuity (BCVA) improved slightly compared with baseline in the subjects assigned to 1 and 2.5 mg of BI-X. No dose-limiting, drug-related or serious adverse events occurred. Three subjects experienced ocular adverse events: specifically, subconjunctival haemorrhage and ocular hyperaemia, both in the 0.5-mg cohort.

One vitreous detachment occurred in the 2.5-mg cohort. Four procedural-related adverse events occurred: subconjunctival haemorrhage, ocular hyperaemia and temporary intraocular pressure increase in the 0.5-mg group, and mild pain after the procedure in the 2.5-mg group.

The findings in the three cohorts were similar. The main take-aways from the SRD study were that BI-X was well tolerated by subjects with DMI in all three dosing cohorts and that the BCVA showed signs of improvement compared with baseline in the 1- and 2.5-mg cohorts.

In the second, ongoing, single masked and randomised segment of the study, the BI-X cohort (20 subjects) will receive three 2- to 5-mg doses separated by 4-week intervals and 10 subjects are to receive sham injections.

The primary endpoint is the number of drug-related adverse events; the secondary endpoints are the number of ocular adverse events and the changes from baseline in the foveal avascular area size, BCVA and central retinal thickness.

“Discovering a treatment for DMI is a major challenge for many clinician-scientists, as DMI can lead to significant visual loss, even if the diabetic macular oedema is well controlled,” Dr Nguyen concluded. “It is our hope that BI-X can be among the first successful treatments for this devastating complication of diabetic retinopathy.”

This article is adapted from Dr Nguyen’s presentation at the American Academy of Ophthalmology Annual Meeting. Dr Nguyen has received research funding from Boehringer Ingelheim.

An ischaemia modulator has demonstrated it is safe and well tolerated in a Phase 1/2a trial in diabetic macular ischaemia patients.

Promising early data with intravitreal diabetic macular ischaemia candidate

A team of Spanish investigators, led by Dr Eva Chamorro, director of clinical research, and colleagues from Indizen Optical Technologies SL, Madrid, are studying the effects of different spectacle lenses that add different levels of defocus to the peripheral retina to control myopia.

In a poster presented at the Association for Research in Vision and Ophthalmology’s 2022 annual meeting in Denver, Colorado, United States, the investigators noted that the axial length (AL) changes over the course of a day (diurnal rhythms) with imposed defocus. This suggested, they pointed out, that these short-term changes in the AL might predict the efficacy of treatments to control myopia.

With this in mind, they conducted a pilot study to evaluate the effects of different types of myopia control spectacle lenses on the diurnal AL changes in young adults who were either emmetropic or wore contact lenses. The Als were measured in 6 subjects who wore glasses with a myopia control lens that had a plano central region and imposed peripheral defocus over the dominant eye; the fellow non-dominant eye had a plano control lens.

Three different myopia control lenses were used to induce the defocus, specifically, the Miyosmart (Hoya, Kuala Lumpur, Malaysia); Stellest (Essilor, Kuala Lumpur), and a non-commercial prototype (IOT, Madrid). All measurements of the AL were obtained at baseline without the lenses and then performed over 4 consecutive days with the lenses. After the measurements were completed, the investigators analysed the differences both between the control and study eyes with each type of myopia control lens and the differences between baseline and the treatment days in the treated eyes, they described.

The investigators observed a significant increase in the AL between the control and treatment eyes with the Stellest and the noncommercial prototype lenses after 2 hours in the treated eyes. With the Miyosmart lens, they observed non-significant differences between the eyes at all times during the lens use.

The comparison of the AL changes in the treatment eye between baseline and the treatment day showed significant differences with the 3 myopia control lenses, which indicated that the use of all 3 resulted in increases in the AL. Minimal daily changes in the AL, they reported, were seen at baseline that day, with variations of less than 0.01 mm across all time intervals.

“Myopia control spectacle lenses affect the diurnal rhythms in the AL in young adult human and produced a small short-term increase in the AL that varies in intensity and time interval for each of the 3 studied lenses,” Dr Chamorro concluded. “Additional studies with a larger sample size and longer follow-up periods are necessary to confirm that short-term variations of diurnal rhythms can be used as predictor of myopia control efficacy.”

Dr Eva Chamorro points out that myopia control spectacle lenses affect the diurnal rhythms in the AL in young adult human and produced a small short-term increase in the AL that varies in intensity and time interval for each of the 3 studied lenses. 

Testing spectacle lenses for myopia control in relation to changes in axial length

Dr Christina Herrspiegel and colleagues from the Karolinska Institutet and St. Erik Eye Hospital, Stockholm, Sweden, reported that they have developed a prognostic test, referred to as serUM, that they believe is a strong predictor of metastasis of uveal melanoma.

The test is based on serum obtained from peripheral blood samples at the time of diagnosis of uveal melanoma in 83 patients (52% women; mean age at diagnosed, 65 years) from 1996 to 2000 at St. Erik Eye Hospital, they explained. All patients were diagnosed with primary melanoma in the choroid or ciliary body.

The investigators performed both proteome profiling of 84 different cancer-related proteins to screen for potential biomarkers and an enzyme-linked immunosorbent assay to evaluate the serum levels of the best protein candidates. Receiver operating characteristics were used to define thresholds for metastatic risk, they explained.

The prognostic test, serUM, was developed in a training cohort and tested in a validation cohort.

In the study patients, the mean tumour diameter and thickness were, respectively, 9.8 mm and 4.9 mm.

The proteome profiling evaluated 5 proteins, Leptin, Osteopontin, Progranulin, Tenascin C, and DLL-1, for further analysis. The prognostic test was based on the Leptin and Osteopontin concentrations developed in the training cohort (n = 17) and then tested in a validation cohort (n = 62) after exclusion of three patients with unreliable total protein fractions, the authors reported.

The results showed that with each increasing metastatic risk category, the patients had gradually shorter cumulative metastasis-free survival (log rank p for trend = 0.01).

Multivariate Cox regression analysis indicated that serUM was an independent predictor of metastasis when entering all of the following as covariates, the tumor diameter, tumour thickness, and patient age at diagnosis (hazard ratio 2.4, 95% confidence interval, 1.0-5.3).

Dr Herrspiegel and coauthors concluded, “serUM, a prognostic test based on serum obtained from a peripheral blood sample at diagnosis of uveal melanoma, is a strong predictor of metastasis.” They emphasized the need for future prospective studies to validate the findings of the current study.

Investigators from the Karolinska Institutet and St. Erik Eye Hospital, Stockholm, Sweden, reported that they have developed a prognostic test, referred to as serUM, that they believe is a strong predictor of metastasis of uveal melanoma.

Author | Lynda Charters

Articles

Promising early data with intravitreal diabetic macular ischaemia candidate

Testing spectacle lenses for myopia control in relation to changes in axial length

Predicting metastasis with novel prognostic liquid biopsy for uveal melanoma

Diabetic rats protected from macular oedema hallmarks with THR-687 treatment