Jean-Francois Korobelnik, MD

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Dr Moosajee, can you talk more in depth about gene therapy in retinal disease? I would also like you to address virus and nonvirus approaches; vectors and nonvectors.

Mariya Moosajee, MBBS, BSc, PhD, FRCOphth:

 Absolutely. The gene therapy field for hereditary retinal disorders is vast. There are hundreds of trials underway for this, and now the most common vector system that we use is the adeno-associated virus [AAV]. There are gene therapy trials for achromatopsia: 

 is the main genetic cause there. Choroideremia has reached phase 3 and we’re waiting to hear the results of that. These adeno-associated viral vectors have a size limit of the gene that it can accommodate. It can accommodate genes that are essentially less than 4000 bases in size. The smaller genes are fine, but you start to get in trouble with genes that are bigger than that, that are also common causes of these retinal degenerations. For example, 

, which is the most common cause for Usher syndrome type 2, but also one of the most common causes of nonsyndromic retinitis pigmentosa, and that gene is something in the region of 18,000 bases in size. How do we then package these genes to deliver it back into the retina so that we can potentially apply this to more people? There are now a lot of studies going into developing dual AAV vectors whereby we split the gene into components and put them into individual AAV vectors with a linker so that, when it’s translated, you end up forming the complete cDNA [complementary DNA] that can be translated into a protein.

They are now in the development of these nonviral gene therapy vectors. One is a DNA plasmid that has a component called a scaffold matrix attachment region; it essentially will allow any sized gene to be carried, even portions of chromosomes, but this can easily accommodate the 

 gene. These viral vectors are still in preclinical development and have gotten into nonhuman primates as well. However, they are showing relatively long expression—up to a year in mouse studies—and good expression of the protein in the retinas following subretinal injection. There are pros and cons to these new types of vectors. The con is that it doesn’t have the infective capability of a virus. We may need to start to use some of the devices that you talked about, like the microneedles or micro-electroporation systems that you’re developing for AMD [age-related macular degeneration], etc, to help these vectors enter into photoreceptors. The pros are that it can carry a gene of any size. They don’t have any viral components, so you’re going to reduce your chance of an immune response. They don’t integrate into the genome, so you reduce your chances of incisional mutagenesis. These specific components, like these S/MARs [scaffold/matrix attachment regions], which are naturally found within our own chromatin that help it to bind, prevent these vectors from being silenced and allow them to replicate extra chromosomally. These are coming into the future that may be the next generation of gene delivery vehicles as we go forward.

Thank you. This was very interesting. The nonviral vectors have a better safety profile and larger cargo capacity, and they have the potential for repeated administration. Sooner or later, if we can overcome the major drawbacks, maybe nonviral vectors will be available, at least for retinal diseases. Do you have experience with the first retinal gene therapy, the Luxturna from Spark Therapeutics? 

 Yes. This is the adeno-associated viral vector that has now been approved by the FDA and the European Medicines Agency. It is approved by our NHS [National Health Service] and is available to patients, and there are sites all over the world offering this. So far, we have seen positive results. This viral vector was approved on the multi-luminance mobility maze test, where we classically see the patient at baseline. Then a year after treatment, where they’re able to navigate through the maze at 1 lux level successfully in a short period of time. In the UK [United Kingdom], my experience with pediatric patients and adults who have now had this, we are seeing a stability, if not improvement, in the children with their visual acuity and their vision in dim light, and also in improving navigational vision for older patients. The hope is that if we can also potentially deliver these genes through intravitreal, we might reach more parts of the retina because, at the moment, we’re just going for the area where we apply the bleb, and there are still islands of retina in the periphery that would be beneficial if we could treat these with the gene therapy. There is still a lot of work to do and a lot of progress to be made in general in trying to optimize the results of these gene therapies.

Videos

Dr Mariya Moosajee comments on the next generation of gene therapy for inherited retinal disease and highlights various systems under investigation.

Future Gene Therapy for Inherited Retinal Disease

By Prof. Robert P. Finger, Prof. Vincent Daien, Mr James S. Talks, Prof. Taiji Sakamoto, Prof. Bora M. Eldem, Dr Monica Lövestam-Adrian and Prof. Jean-François Korobelnik

It is well accepted that randomised controlled trials (RCTs) are the gold standard in establishing the efficacy of a clinical intervention. However, since such studies often have strict inclusion criteria and stringent requirements for patient follow-up, they often have greater patient adherence than that seen in the clinic and can exclude some of the types of patients routinely seen in day-to-day practice.

In addition, RCTs can be extremely expensive to conduct and study enrolment can be relatively slow compared with non-randomised studies.

 This is where data collected from routine clinical practice comes in. Such data enable the generation of real-world evidence (RWE), which can complement information from RCTs by providing insights regarding the safety and effectiveness of an intervention in broader patient populations under routine care conditions.

This evidence can be derived from real-world data from various sources, including electronic health or medical records (also referred to as EHR or EMR), patient registries, medical claims databases, retrospective or prospective observational studies or clinical audits (Table 1).

 RWE is increasingly being used to support drug approvals

 and in health technology assessments to support reimbursement.

In that respect, it is already guiding clinical practice. With a better understanding as to how to assess the quality of real-world studies, clinicians can use this evidence appropriately to inform their own clinical decision-making at both practice and patient level.

Abbreviations: CRVO, central retinal vein occlusion; DMO, diabetic macular oedema.

In ophthalmology, there is an increasing global evidence base that describes the use of intravitreal anti-vascular endothelial growth factors (anti-VEGF) in routine clinical practice.

 Such studies have shown that, in routine practice compared with RCTs, there is both a lack of adherence to, and undertreatment with, anti-VEGF therapy, including non-persistence, whereby patients do not continue therapy in the medium-to-long term.

This remains a significant barrier to optimising real-world outcomes for patients with chronic, progressive retinal conditions such as neovascular age-related macular degeneration (nAMD). Certainly, more RWE for effective strategies that can be employed at a clinic/ practice level to improve adherence and persistence to anti-VEGF agents would be welcomed.

In addition, there are inherent limitations to data collection in real-world clinical practice; as a result, RWE may vary in quality.

 This is partly because of heterogeneity in data gained from different sources and variability in both the application of RWE methodologies and the interpretation of the resulting evidence. Furthermore, depending on the RWE source, data may be inconsistently collected, misclassified or missed — this is known as information bias.

A recent systematic review analysed 64 real-world ophthalmology data sources from 16 countries for completeness of data relating to different outcomes and only ten scored highly.

 Most of these sources provided information on baseline status, clinical outcomes and treatment, but few collected data on economic and patient-reported burden.

Another issue within ophthalmology is how the treatment regimens, particularly for anti-VEGF agents, are described. Intravitreal aflibercept, brolucizumab, pegaptanib and ranibizumab have indications for retinal diseases, but in some European countries, bevacizumab is used and reimbursed off-label, despite jurisdictional ambiguity and, often, a legal risk for prescribing physicians.

Sometimes, there is a lack of clarity as to whether patients were treated with fixed dosing, pro re nata therapy or treat-and-extend dosing and the degree of adherence to those schedules.

 This makes understanding treatment effectiveness and comparing studies particularly challenging.

Although information bias may be one of the easiest types to identify and quantify, RWE is also prone to other biases. Therapies may be differently prescribed depending on patient and disease characteristics, leading to selection and channelling biases (for example, older patients or those with more advanced disease tending to receive one therapy over another).

In addition, patients or caregivers may be more likely to report only the most recent or impactful events, leading to recall bias; and, in some cases, events are more likely to be captured in one treatment group than another, resulting in detection biases.

 It is important that such limitations are recognised and RWE is interpreted in this context.

Introducing a novel RWE quality assessment tool

Throughout medical school and early in their medical careers, clinicians are taught how to assess the robustness of clinical studies, learning about randomisation, methods of blinding and different types of controls.

 It is similarly important to understand the quality of RWE.

RWE is becoming an increasingly important component of the overall evidence-based treatment of retinal diseases. However, clear guidance on how to assess the rigor of real-world studies and the conclusions and recommendations they generate in the field of ophthalmology is lacking. 

Abbreviations: GRACE, Good Research for Comparative Effectiveness; RWE, real-world evidence.

As shown in Figure 1, an RWE steering committee—a coalition of leading retinal specialists and methodological experts—recently developed a user-friendly framework assessing the quality of available RWE for retinal diseases, including nAMD, diabetic macular oedema and retinal vascular occlusion.

 The goal was to assist ophthalmologists in independently drawing relevant and reliable conclusions from RWE and understanding its applicability to their practice.

Abbreviations: DMO, diabetic macular oedema; ETDRS, Early Treatment Diabetic Retinopathy Study; nAMD, neovascular age-related macular degeneration; OCT, optical coherence tomography; RVO, retinal vein occlusion.

The Good Research for Comparative Effectiveness (GRACE) checklist was selected as the basis of the RWE quality assessment tool. This is an 11-item screening tool that evaluates methodology and reporting to identify high-quality observational comparative effectiveness research.

 The checklist has been extensively validated, has demonstrated strong sensitivity and specificity and can be successfully applied by a wide variety of users with different training backgrounds.

Although the checklist was developed specifically for comparative effectiveness research, many of the items were also considered applicable to non-comparative studies. It was adapted for the retinal diseases field by omitting items that were not considered relevant to a practical, clinically focused ophthalmology audience, and adapting or combining some items for easier application.

Considerations when assessing quality of RWE

The adaptation of the GRACE checklist to be more specific to, and relevant for, ophthalmologists has resulted in the development of the retinal diseases RWE quality assessment tool. Table 2 summarises the retinal disease-specific aspects of the checklist.

This addresses treatment details, how outcomes were assessed/quantified, descriptors of the study population and possible sources of bias. More details and examples of what to consider can be found in the full publication.

The purpose of the tool is to specifically assess the quality of RWE generated by a specific study in a population of patients with retinal disease. Caution should be exercised when comparing RWE across different retinal disease studies because of the heterogeneity mentioned previously regarding the different methodologies employed, as well as heterogeneity in patient populations, disease characteristics and treatment regimens.

RWE is a growing in importance as a source of information that, when evaluated appropriately, can help to support clinical decision-making. Regulators also increasingly accept that RWE may be needed in appraising post-marketing value. The retinal diseases RWE quality assessment tool can help clinicians to understand which findings from real-world studies are most robust and applicable to their practice.

Robert P. Finger, Vincent Daien, James S. Talks,Taiji Sakamoto,Bora M. Eldem,Monica Lövestam-Adrian and Jean-François Korobelnik

Prof. Finger is based at the Department of Ophthalmology, University of Bonn, Bonn, Germany; Prof. Daien at the Department of Ophthalmology, Gui De Chauliac Hospital, Montpellier, France and The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, Australia; Mr Talks at the Department of Ophthalmology, Royal Victoria Inﬁrmary, Newcastle upon Tyne, UK; Prof. Sakamoto at the Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima and J-CREST, Japan; Prof. Eldem at the Faculty of Medicine, Ophthalmology Department, Hacettepe University, Ankara, Turkey; Dr Lövestam-Adrian at the Department of Ophthalmology, Lund University Hospital, SUS Lund, Sweden; and Prof. Korobelnik at CHU Bordeaux, Service d’Ophtalmologie, Bordeaux, France and the University of Bordeaux, INSERM, BPH, U1219, Bordeaux, France.

The authors have no commercial interests in relation to the article. Medical writing and editorial support for preparation of the article, under the guidance of the authors, was provided by ApotheCom, which was funded by Bayer Consumer Health.

1. Talks J, Daien V, Finger RP, et al. The use of real-world evidence for evaluating anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration. 

2. Okada M, Mitchell P, Finger PM, et al. Non-adherence or non-persistence to intravitreal injection therapy for neovascular age-related macular degeneration: a mixed-methods systematic review. 

3. Lauer MS and D’Agostino RB Sr. The randomized registry trial--the next disruptive technology in clinical research? 

4. United States Food and Drug Administration. Real-world data (RWD) and real-world evidence (RWE) are playing an increasing role in health care decisions. 2020; Available from: https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence.

5. Egan C, Zhu H, Lee A, et al. The United Kingdom Diabetic Retinopathy Electronic Medical Record Users Group, Report 1: baseline characteristics and visual acuity outcomes in eyes treated with intravitreal injections of ranibizumab for diabetic macular oedema. 

6. Bhandari S, Nguyen V, Fraser-Bell S, et al. Ranibizumab or aflibercept for diabetic macular edema: comparison of 1-year outcomes from the Fight Retinal Blindness! registry. 

7. Rayess N, Vail D and Mruthyunjaya P. Rates of reoperation in 10,114 patients with epiretinal membranes treated by vitrectomy with or without inner limiting membrane peeling. 

8. Faramawi MF, Delhey LM, Chancellor JR and Sallam AB. The influence of diabetes status on the rate of cataract surgery following pars plana vitrectomy. 

9. Calster JV, JacobJ, Wirix M, et al. A Belgian retrospective study in patients treated for macular edema secondary to CRVO: 1-year real-world intravitreal aflibercept data. Presented at EURETINA 2018.

10. Korobelnik JF, Daien V, Faure C, et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. 

11. Fajgenbaum MAP, Neffendof, JE, Wong RS, et al. Intraoperative and postoperative complications in phacovitrectomy for epiretinal membrane and macular hole: a clinical audit of 1,000 consecutive eyes. 

12. Bolislis WR, Fay M and Kühler TC. Use of real-world data for new drug applications and line extensions. 

13. Leahy TP, Ramagopalan S and Sammon C. The use of UK primary care databases in health technology assessments carried out by the National Institute for health and care excellence (NICE). 

14. Finger RP, Daien V, Talks, JS, et al. A novel tool to assess the quality of RWE to guide the management of retinal disease. 

15. Daien V, Eldem BM, Talks JS, et al. Real-world data in retinal diseases treated with anti-vascular endothelial growth factor (anti-VEGF) therapy–a systematic approach to identify and characterize data sources. 

16. Bro T, Derebacka M, Jørstad ØK, Grzybowski A. Off-label use of bevacizumab for wet age-related macular degeneration in Europe. 

17. Blonde L, Khunti K, Harris, SB, et al. Interpretation and impact of real-world clinical data for the practicing clinician. 

18. Moher D, Jaded AR, Nichol G, et al. Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. 

19. Dreyer NA, Bryant A andVelentgas P. The GRACE Checklist: a validated assessment tool for high quality observational studies of comparative effectiveness. 

Articles

A recently developed tool can help ophthalmologists to assess the quality of findings from real-world studies in retinal diseases. This will help them decide which results are most robust and applicable to their practice. 

Assessing the quality of real-world evidence in retinal diseases 

: Before we conclude, I would like to get some final thoughts from all of you. Let’s start with Dr Korobelnik. Can you say a few words on the future of dry AMD [age-related macular degeneration]?

 We have seen a lot of research activities for new long-duration treatments in wet AMD and in diabetic retinopathy. There is also a lot of research and developments for advanced dry AMD, for geographic atrophy, and there are currently 2 ongoing phase 3 trials from 2 companies that are looking at inhibition of the complement cascade. We should know later in 2021, or in 2022, [whether] those drugs are beneficial to slow down the progression of the disease. If it works, this will be interesting because it’s a completely unmet need [right now]. We’ll see.

 Thank you. So it’s all about inflammation at this time?

 Dr Moosajee, do you have some concluding remarks?

 I am truly excited by my field. For the first time in our careers, we can now say that there is an approved gene therapy available for patients with inherited retinal disorders, with a wealth of trials to follow up. I would like to see more genes being covered, and that, at the moment, is still a very costly process, so maybe it’s targeting more common pathways. There are gene therapies that are being developed towards a factor called rod-derived cone viability factor, which essentially helps cones to uptake glucose and to convert that into energy and work better. Hopefully that kind of universal treatment will be able to be accessed by more patients with inherited retinal disorders rather than on a gene-based system. It is a promising field and we will learn a lot from the work that is being done in AMD and diabetic retinopathy, in terms of the devices that you’re using and trialing now, and how we can apply that to our field.

 Thank you. Dr Peto, some words from your side?

 I completely agree that we live in an exciting era of diagnostics and treatment. Something we’ve learned from the pandemic is that patients adapt very well to the new environment. We are now seeing patients over the age of 90 who will happily have a virtual consultation with us. We are seeing people who are using home monitoring devices, and we’re also seeing patients who happily come to virtual clinics where they spend very little time, get images quickly, and then only come back to a busy clinic if they need injections or treatment. We need to learn from these developments, we need to cherish them and go on with providing the best service because this helps us to strategize and restratify our clinics and get everyone to the right clinical pathway.

 Do you think this digital world will reduce the quality? Five years ago we all spoke about multimodal imaging, high-quality images, and combining images from different modalities, just to be more secure and do more sophisticated diagnostics. Now everything is digital. We do images with devices at home, which don’t have the quality as compared with devices in a big hospital, and you can’t combine different images. Do you think the quality will go down a little bit?

 What we need to do is to make sure that the quality of those images that we get supplied with go up. When they started the anti-VEGF [vascular endothelial growth factor] injections, we didn’t have SD OCTs [spectral domain optical coherence tomography], we had time domain OCTs. As soon as more people used them, more people needed to have an OCT, and more people needed more details—suddenly the price dropped, and a lot of new functions appeared. I’m hoping that the home monitoring devices will undergo the same type of development. We must remember that, in a lot of patients, we only need to decide if they need to come in or not, and if they need an injection or not. So we might not need every single time and every bit of imaging that we usually do at diagnosis. If we’re clever about it and we get good images, then we might be able to change the dynamic of a clinic to those who are higher risk.

 We must differentiate between initial visit baseline to make the diagnosis, then we need multimodality and follow-up. For follow-up, OCT probably does it all. So home monitoring with OCT can be promising. We don’t need multimodality on each visit.

 I think that’s why we call it monitoring, because, for diagnostics, you need to get the diagnosis right. They can have all sorts of other diseases that mimic AMD, and old patients with diabetes can have a lot of other diseases as well. We need to establish a secure diagnosis, especially if we don’t see them regularly in the clinic.

 Thanks to all of you and to our viewing audience. We hope you found this 

 discussion to be rich and informative. Thank you very much.

Key takeaways from a discussion on the management of age-related macular degeneration, diabetic macular edema, and inherited retinal disease and insight regarding what to look forward to as the field advances.

Optimizing Care For Patients With Retinal Disorders

 As a concluding remark: We have all been affected by the COVID-19 pandemic, and our retinal practices have changed dramatically. What will last from this experience and from the changes in our practices?

 My cohort of patients were deemed nonurgent in the pandemic. So a lot of the practitioners were told to cancel appointments to allow for capacity for AMD [age-related macular degeneration] and the serious diabetic patients. However, I quickly converted to virtual consultations. Especially in genetics, what we call teleogenetics, is extremely accessible through virtual platforms. Virtual consultations are something that we will continue to do going forward. From an inherited eye disease point of view, we can limit the amount of follow-ups that we give patients and maybe try to reduce that referral to a specialist center, but have joint care with local district general hospitals so patients aren’t traveling so much. Maybe we can introduce home monitoring and use digital technologies moving forward. We can also instigate more diagnostic hubs in local areas, where patients can get their autofluorescence and OCT [optical coherence tomography], then we, as clinicians, can remotely monitor those patients following up with more virtual consultations.

The impact of the COVID-19 pandemic on the management of patients with retinal disorders and considerations for how new practices may be adopted into future practice.

Author | Jean-Francois Korobelnik, MD

Articles

Assessing the quality of real-world evidence in retinal diseases

Optimizing Care For Patients With Retinal Disorders

Managing Retinal Disorders: Lessons Learned From COVID-19

Future Gene Therapy for Inherited Retinal Disease