Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

Cheryl Guttman Krader, BS, Pharm

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®, experts in retinal disease discussed the challenges of drug delivery for retinal diseases and investigational strategies for improving patient care and outcomes by overcoming existing issues.

Moderated by Albert J. Augustin, MD, the international panel included Jean-François Korobelnik, MD; Mariya Moosajee, PhD, MBBS, BSc, FRCOphth; and Tunde Peto, MD, PhD.

The challenges of drug delivery for retinal diseases (video series)

After reviewing approaches to diagnosis, which establish the indication for treatment, and patient-specific factors that may factor into therapeutic decision-making, the group reviewed the current therapeutic landscape for exudative age-related macular degeneration (AMD), diabetic macular oedema (DMO), diabetic retinopathy, macular oedema secondary to retinal vein occlusion (RVO) and inherited retinal dystrophies.

The physicians’ summaries highlighted the risks of the available modalities and their burdens for patients, caregivers and providers.

Common types of retinal disorders explored (video)

To provide a foundation for understanding solutions to overcome the drawbacks of existing approaches, the discussion turned to barriers and unmet needs related to achieving effective drug delivery to the retina. Finally, participants shared their perspectives on investigational therapeutics, including novel compounds and delivery systems.

The ability to prolong the treatment interval is a main goal for the development of new therapeutics for retinal diseases.

Discussing brolucizumab, which is approved in both the United States and Europe for treating exudative AMD, Korobelnik noted that clinical trial data suggest that the benefit of this anti-VEGF agent may last longer than previously available VEGF inhibitors.

Evaluating patients for a retinal disorder (video)

However, clinical studies investigating brolucizumab were not designed to fully explore response durability, and inflammatory reactions have emerged as a potential concern in postmarketing experience, said Korobelnik, a professor and chief of ophthalmology at the University Hospital of Bordeaux.

He noted that despite some initial encouraging data, development has stalled for conbercept, designed ankyrin repeat proteins and abicipar pegol because of efficacy and/or safety issues.

Age-related macular degeneration: Treatment overview (video)

New agents still in development include ripasudil (Glanatec), a rho kinase inhibitor being investigated as a treatment for diabetic retinopathy, and CLS-AX, a suspension of axitinib for suprachoroidal injection. Axitinib is a VEGF receptor tyrosine kinase inhibitor that provides pan-VEGF inhibition. This formulation is being studied for its potential to be a long-acting treatment for wet AMD.

Discussing faricimab, a bispecific antibody targeting angiopoietin-2 and VEGF-A, Peto said that it has shown promise for allowing less-frequent injections in clinical trials investigating its use to treat both DMO and wet AMD.

Diabetic macular edema: Treatment overview (video)

“During the first year, about one-half of patients needed repeat injections just every 4 months. We will have to wait to see if this prolonged activity holds up in the real world,” said Peto, a professor of clinical ophthalmology at Queen’s University Belfast.

Korobelnik noted that phase 3 studies have been completed investigating triamcinolone acetonide suprachoroidal injectable suspension to treat macular oedema associated with uveitis and RVO. Compared with intravitreal administration, this approach offers easier administration and reduced risk of intraocular infection.

However, it also carries a concern for causing increased IOP, he said.

Inherited retinal disease: Treatment overview (video)

Peto discussed the refillable port delivery system for ranibizumab (Lucentis). Panel members noted that the agent has a practical limitation of requiring placement by a vitreoretinal surgeon and that more research is needed to understand whether there are downsides from continuous exposure to VEGF blockade.

Sustained-release systems under investigation include a micro­particle depot formulation of sunitinib (Sutent), GB-102. Sunitinib is a pan-VEGF inhibitor, and GB-102 is designed to be administered by intravitreal injection twice per year.

Anti-VEGF therapy for retinal disease (video)

“GB-102 has been evaluated for treatment of macular oedema secondary to RVO in a phase 2A trial, and [appears] promising based on interim results from a phase 2B study,” said Augustin, professor and chairman of the Department of Ophthalmology at Klinikum Karlsruhe in Germany.

Patients with DMO or exudative AMD are being recruited for enrolment in a safety study of an intravitreal implant providing sustained release of AR-13503, an inhibitor of rho kinase and protein kinase C. In addition, a sustained-release intravitreal implant of axitinib (OTX-TKI) is being developed as a treatment for wet AMD, DMO and RVO.

Drug delivery challenges in retinal disease (video)

KSI-301, an intravitreal anti-VEGF biopolymer conjugate, was associated with positive results in a phase 2 trial of DMO; a phase 3 study is investigating an injection interval of up to 24 weeks.

“Of course, there is the potential for inflammation and induction of immunogenicity with the devices and compounds used for sustained release, and safety is something that everybody is looking at very carefully,” Korobelnik said.

Numerous trials are investigating gene therapy for hereditary retinal disorders, Moosajee said. Most are using adeno-associated viral (AAV) vectors, but these vectors have a packaging limit. Therefore, ongoing research aims to develop alternative approaches for delivering larger genes that include the use of dual AAV vectors and nonviral vectors.

Addressing drug delivery gaps in retinal disease (video)

Although the latter option has potential safety advantages compared with viral vectors, it may need to be used with microneedles, microelectroporation systems or nanoparticles to achieve adequate transduction into target cells, said Moosajee, a professor of molecular ophthalmology at UCL Institute of Ophthalmology and a consultant ophthalmologist in genetic eye disease at Moorfields Eye Hospital in London.

Investigators in gene therapy are also looking at intravitreal injection using novel AAV capsids that may provide more efficient transduction into target cells. A phase 1 clinical trial is under way using this technology to deliver the CHM gene for choroideremia, Moosajee said. Gene therapy for RPE65 retinopathy with voretigene neparvovec is now an approved treatment worldwide.

Drug delivery methods explored for retinal disease (video)

“The hope is that work being done with delivery systems in AMD and diabetic eye disease can be applied to our field and allow gene delivery through intravitreal injection that would have fewer risks and reach more parts of the retina,” she concluded.

Augustin has no relevant financial interests to disclose.

Korobelnik is a consultant for Allergan-AbbVie, Bayer, Kanghong, Novartis and Roche.

Mariya Moosajee, PhD, MBBS, BSc, FRCOphth

Moosajee has no relevant financial interests to disclose.

Peto received advisory board and lecture fees from Bayer, Heidelberg Pharma, Novartis, Optos, Oxurion and Roche.

Articles

Ophthalmologists face challenges of drug delivery for retinal diseases.

Discussing the state of retina therapeutics with international panel

Non-exudative macular neovascularisation (MNV) is asymptomatic, but it is important to identify MNV lesions because they seem to be a precursor for the development of exudative disease, according to Dr Philip J. Rosenfeld, professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Florida, United States. Treatment-naive MNV is now recognised as a state of age-related macular degeneration (AMD) that can be accurately detected with swept-source optical coherence tomography angiography (SS-OCTA).

Dr Rosenfeld discussed the detection, natural history and management of treatment-naive MNV in a presentation at the 2021 Ohio Ophthalmological Society virtual annual meeting. “A double-layer sign (DLS) or shallow, irregular retinal pigment epithelial elevation (SIRE) on the structural OCT B-scan is a characteristic feature of these lesions,” said Dr Rosenfeld.

“Finding these lesions in eyes with dry AMD is important because they have a high risk of conversion to exudative AMD. So far, we have not been able to predict which eyes are likely to progress to exudation based on anatomic changes. Therefore, close follow-up and at-home monitoring [are] crucial in these patients to prevent vision loss.”

Dr Rosenfeld highlighted his message about monitoring with a case history involving a patient who presented in January 2020 with large drusen and 20/40 visual acuity (VA). Routine SS-OCT showed structural elevation of the retinal pigment epithelium (RPE) consistent with drusen in the right eye, but no evidence of exudation.

Non-exudative MNV was detected with SS-OCTA imaging, where the areas of confluent drusen corresponded to a DLS seen on individual B-scans. Segmentation of RPE-Bruch’s membrane on the SS-OCTA angiographic flow map showed that the patient had three independent neovascular complexes.

The patient was counselled to return for follow-up in March 2020, but because of the COVID-19 pandemic, she cancelled that appointment. A re-scheduled visit in April was also cancelled. In May, 4 months after her January appointment, she presented to the emergency department because of sudden vision loss in the right eye.

Examination showed count fingers VA and identified a massive sub-macular haemorrhage along with exudation. “This situation could have been prevented by home monitoring and even better by home OCT monitoring that could have showed exudation developing long before the haemorrhage occurred,” Dr Rosenfeld said.

Dr Rosenfeld credited the ability to detect MNV to Dr Ruikang Wang of the University of Washington in Seattle, United States, who developed an optical microangiography algorithm that enables flow detection in OCT images. Using specific segmentation strategies, clinicians can identify subclinical MNV lesions using a number of different slab configurations with different boundaries.

For the purposes of his study, Dr Rosenfeld used a slab extending from the outer retina (OR) to the choriocapillaris (CC), which is termed the ORCC slab. He noted that the presence of subclinical MNV had been described in the 1990s in eyes that had undergone indocyanine green angiography (ICGA). The ability to identify these lesions equally well using non-invasive SS-OCTA imaging was demonstrated by Dr Rosenfeld and his colleagues in a study of patients with asymptomatic, intermediate AMD in one eye and exudative NV AMD in the fellow eye.

Subsequently, Dr Rosenfeld and his colleagues went on to investigate the prevalence and natural history of non-exudative MNV in dry AMD. For this study, they included patients with dry AMD in one eye and a fellow eye with exudative AMD. In the eyes with dry AMD, they found a 14-fold increased risk of developing exudation within 2 years among eyes with non-exudative MNV compared with eyes that did not have subclinical MNV.

Overall, if the fellow eye had exudative AMD, the prevalence of a non-exudative MNV in an eye with dry AMD was 13%. The prevalence was similar in eyes with either intermediate AMD or geographic atrophy.

Follow-up of eyes with non-exudative MNV showed that the lesions can grow without becoming exudative. Anti-vascular endothelial growth factor (VEGF) treatment was administered when symptomatic fluid developed in association with a decrease in vision; the treatment was effective in resolving the fluid and improving VA, but there were no obvious effects on lesion morphology for type 1 MNV, which comprised 93% of the lesions.

Search for changes that predict exudation

Studies conducted to find possible biomarkers to predict exudative conversion have so far shown no association with size or growth of the MNV prior to exudation or with changes in the volume of pigment epithelial detachments associated with the MNV prior to exudation, choriocapillaris flow deficits or the surrounding choroidal vasculature.

 “Additional potential predictors we are looking at include flow velocity within the MNV or in the choriocapillaris around the MNV and changes in choroidal blood flow,” Dr Rosenfeld noted.

He explained that in the Phase 2 FILLY study investigating pegcetacoplan for the treatment of geographic atrophy, the adverse event analysis showed that new-onset exudation developed in a dose-dependent fashion, occurring in 21% of eyes treated monthly with the investigational agent, in 9% of eyes receiving treatment every other month, and in only one eye (1.2%) in the sham-treated control group.

 A post hoc review of images obtained at baseline showed that the DLS was present in 73% of eyes that developed exudative AMD versus 32% that did not develop exudation.

“These eyes with the DLS had subclinical neovascularisation, but we were not prepared to capture these eyes at baseline,” Dr Rosenfeld explained. “Now, in the Phase 3 trials investigating pegcetacoplan, DLS at baseline is being identified and these eyes are being followed carefully for the development of exudation that will be treated with anti-VEGF therapy.”

However, Dr Rosenfeld added that the take-home message from FILLY “is that the VA outcome was just as good in eyes that developed exudation compared with those that did not because they were treated promptly with, and responded very well to, anti-VEGF therapy.”

This article is based on Dr Rosenfeld’s presentation at the 2021 Ohio Ophthalmological Society virtual annual meeting. Dr Rosenfeld receives research support from and is a consultant to Carl Zeiss Meditec and is chairman of the steering committee of the Advanced Retina Imaging Network, which is a global consortium of clinical researchers and the Zeiss Medical Technology business group.

1. Roisman L, Zhang Q, Wang RK, et al. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration. 

2. Yang J, Zhang Q, Motulsky EH, et al. Two-year risk of exudation in eyes with nonexudative age-related macular degeneration and subclinical neovascularization detected with swept source optical coherence tomography angiography. 

3. Shen M, Zhang Q, Yang J, et al. Swept-source oct angiographic characteristics of treatment-naive nonexudative macular neovascularization in amd prior to exudation. 

4. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. 

5. Wykoff CC, Rosenfeld PJ, Waheed NK, et al. Characterizing new-onset exudation in the randomized phase 2 FILLY trial of complement inhibitor pegcetacoplan for geographic atrophy. 

Swept-source optical coherence tomography angiography can detect eyes at risk of developing exudative disease.

Swept-source OCT angiography aids detection of dry AMD

Results from a laboratory study measuring oxygen kinetics during corneal cross-linking (CXL) indicate that supplementary oxygen has the potential to substantially increase the efficacy of the procedure, according to Dr Theo G. Seiler, Jr, senior physician in the Department of Ophthalmology at the University of Bern in Switzerland. The laboratory study, which was performed using de-epithelialised porcine eyes, measured local oxygen concentrations at varying corneal depths under atmospheric (21% O2) and hyperoxygenic (100% O2) conditions with different levels of ultraviolet (UV) irradiation.

The analyses showed that, compared with the atmospheric oxygen environment, supplementary oxygen increased the amount of oxygen available in the stroma during CXL. Dr Seiler noted that the benefit of the hyperoxygenic environment was particularly seen when using higher UV irradiances that are associated with increased oxygen consumption.

“The mechanism of action for CXL involves UV-induced activation of riboflavin, the photosensitiser, resulting in the generation of reactive oxygen species that induce formation of covalent bonds within the collagen fibrils and crosslink the proteoglycans between the fibrils,” he said. “Many previous studies have investigated the influence of varying the parameters for riboflavin imbibition and UV irradiation on CXL effectiveness.”

Dr Seiler said that the study was motivated by the limited research investigating the role of oxygen, which is the third crucial factor for achieving sufficient CXL. “Our findings show that providing supplementary oxygen is likely to be beneficial by increasing the aerobic reaction and allowing more efficient CXL in deeper corneal layers and at UV irradiance levels less than 3 mW/cm2,” he said.

Measurement of the oxygen concentration at different corneal depths was accomplished by inserting a fibre probe into channels created by a femtosecond laser at depths of 100 μm, 200 μm and 300 μm. Eyes were exposed to 0.1% riboflavin (Vibex Rapid, Avedro/Glaukos) for 10 minutes, and then the oxygen concentration was continually measured during irradiation at 3, 9, 18 and 30 mW/cm2. “In order not to alter the cornea during the measurements, the used fibre probe had a tip that was only around 50 μm in diameter,” Dr Seiler said.

Groups of eight eyes each were evaluated under each of the testing conditions while the oxygen concentration was continually measured. Under atmospheric oxygen and with irradiation at 3 mW/cm2, representing the conventional Dresden protocol, there was a surplus of oxygen available at all measured depths during the entire CXL procedure.

However, when the irradiance was increased to 9 mW/cm2, sufficient oxygen for CXL was available only at 100 μm and 200 μm. At UV irradiance above 9 mW/cm2, all oxygen was consumed within the anterior 100 μm, indicating that there was insufficient oxygen for achieving sufficient cross-linking in the profound cornea, Dr Seiler said.

When the testing was done in the hyperoxygenic environment, there was sufficient oxygen available for cross-linking at all measured depths when using the 3 mW/cm2 and 9 mW/cm2 irradiances. At higher UV irradiances, there was more oxygen available than under atmospheric conditions, although still not enough to provide sufficient oxygen through the entire corneal stroma. Additional analyses determining the consumption of oxygen showed that during the procedure, the half-lives were longer and the depletion rates higher with supplementary oxygen, suggesting a more efficient CXL than under atmospheric oxygen conditions, said Dr Seiler.

This article is based on a presentation given by Dr Seiler at the 2020 ESCRS Virtual Congress. The study was published (Seiler TG, Komninou MA, Nambiar MH, et al. Oxygen kinetics during corneal cross-linking with and without supplementary oxygen. 

. 2020;223:368-376). Dr Seiler has no relevant financial interests to disclose.

Ex vivo experiment identifies potential benefit for supplementary oxygen.

Maximising corneal cross-linking effectiveness

Findings of a retrospective, comparative cohort study demonstrate the benefits of integrating spectral-domain optical coherence tomography (SD-OCT) with ultra-widefield (UWF) imaging in a diabetic retinopathy (DR) telemedicine screening programme.

Dr Aiello, a professor of ophthalmology at Harvard Medical School and director of the Beetham Eye Institute of Joslin Diabetes Center, Massachusetts, United States, presented study data from 422 eyes of 211 patients with diabetes who were consecutively imaged between 8 January and 16 March 2020, using the commercially available platform Monaco (Optos), which allows SD-OCT and UWF imaging in a single sitting. Participants were seen in a UWF image-based DR teleophthalmology programme at the Joslin Diabetes Center.

The results showed that the dual imaging substantially increased detection and reduced false positive assessments of diabetic macular oedema (DMO) and epiretinal membrane (ERM). “Given the reduced effort, compact footprint and reduced overall cost of integrated SD-OCT/UWF devices, their use in large DR screening programmes could substantially improve disease identification and reduce unnecessary referrals,” said Dr Aiello.

“However, it should be noted that this study only evaluated 422 eyes and all images were evaluated in a centralised reading centre using standardised protocols,” he said. “Thus, the applicability of the findings in other settings is unknown.”

Because US Food and Drug Administration (FDA) approval of normative OCT measurements for the Monaco instrument is pending, the OCT images were evaluated qualitatively using a standardised template. Each scan was evaluated for macular pathology, including looking at the foveal contour and looking for macular oedema, ERM, signs of macular degeneration and other macular diseases. The UWF graders were masked to the OCT images and OCT findings, and graders evaluating the SD-OCT images were masked to the UWF images.

The 211 patients included in the study had a mean age of 53.5 years. Based on UWF grading, DR was absent in 58% of eyes and 93% of eyes had no DMO. Eyes with DR spanned the spectrum of severity, but the distribution was weighted towards less severe disease, with most eyes having mild non-proliferative DR. Sixty eyes (14.2%) were graded as having referrable DR, which was defined as moderate non-proliferative DR or worse or any level of macular oedema.

With UWF imaging, less than 1% of eyes were ungradable for determining DR severity and less than 1% were ungradable for determining DMO presence. For both modalities, less than 1% were ungradable for overall macular pathology.

Macular pathology was identified by UWF in 8.1% of eyes and by OCT imaging in 13% of eyes. DMO was the most commonly identified pathology on UWF imaging (75%) but accounted for only 36% of macular disease identified by OCT. ERM accounted for 29% of macular pathology on UWF imaging but 52.7% of macular disease by OCT.

Comparisons between the UWF and SD-OCT gradings showed good agreement when the determination was that DMO was not present; when UWF imaging alone found that DMO was not present, SD-OCT found DMO in only 1.5% of those eyes. When the UWF image grading identified DMO present, however, the determination was not confirmed by SD-OCT in 75% of those cases.

“Overall, UWF image grading suggested that DMO was present in 4.7% of eyes, [whereas] grading by SD-OCT determined DMO was present in only 2.1% of the cohort,” Dr Aiello explained. “Thus, UWF alone had low sensitivity and low positive predictive value for DMO detection, but high specificity and high negative predictive value compared [with] SD-OCT.”

The results were similar in considering detection of clinically significant macular oedema (CSMO), although the sensitivity of UWF was even lower for this diagnosis. Approximately 27% of eyes with CSMO present on SD-OCT were identified by UWF imaging alone.

ERM was detected by UWF image grading in 2.4% of eyes and by SD-OCT in 6.8% of eyes. Only 3.4% of ERMs detected on SD-OCT images were identified on UWF imaging alone. When UWF imaging alone found that ERM was absent, SD-OCT found an ERM in 6.8% of eyes. When UWF grading showed that ERM was present, however, only 10% of those cases were confirmed by SD-OCT.

This article is based on a presentation made at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. Dr Aiello is a consultant to Optos but is not paid for his services.

Integration of spectral domain optical coherence tomography with ultra-wide field imaging can increase accurate detection of diabetic macular oedema and epiretinal membrane.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Swept-source OCT angiography aids detection of dry AMD

Maximising corneal cross-linking effectiveness

Dual imaging in telemedicine screening improving macular pathology detection

Discussing the state of retina therapeutics with international panel