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Heidelberg Engineering: Enhancing the Patient Journey

Clinical

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John Kitchens, MD, is joined by Diana Do, MD, to discuss the PHOTON trial results and their relation to patients with diabetic macular oedema (DMO) in clinical practice. They discuss the half-life of aflibercept in wet age-related macular degeneration and its implications for drug durability. They explore the potential for more frequent dosing of aflibercept for DMO, with a focus on safety monitoring and the use of adjuvant steroids. 

See the key takeaways below, and listen to the full podcast for all the clinical pearls.

Considering aflibercept half-life and higher molar dose in ophthalmology.

Highlighting the variability in intraocular half-life of aflibercept, including factors such as patient characteristics and vitreous liquefaction that may have an impact.

Discussing the concept of nonresponders, and whether frequent dosing may indicate a need for more frequent treatment rather than a lack of response to the drug.

Using aflibercept for DMO, with focus on dosing and response variability.

Discussing whether aflibercept 8 mg every 12-16 weeks is noninferior to 2 mg every 8 weeks in DMO patients.

Using the art of medicine to tailor aflibercept dosing based on patient response.

Using higher doses of aflibercept for DMO, with potential for more frequent dosing.

Mixing steroids with aflibercept may help treat recalcitrant DMO.

Using combination therapy shows improved response in DMO treatment.

Discussing safety signals for hypertension, intraocular inflammation, and retinal vasculitis for patients receiving aflibercept 8 mg.

John Kitchens, MD, is joined by Diana Do, MD, to discuss the PHOTON trial results and their relation to patients with diabetic macular oedema in clinical practice.

PHOTON Results and Their Relation to DME Patients in Your Practice

John Kitchens, MD, is joined by David Brown, MD, to discuss the PULSAR study results and their relation to patients with neovascular age-related macular degeneration in clinical practice. They touch upon dosing strategies and also highlight two new drugs, faricimab and aflibercept 8 mg. They also discuss the potential benefits of increased molar dosing and the importance of maintaining dryness and durability in patient care.

Drug dosing and half-life in retina treatment.

Highlighting developments in ocular drug delivery, including new formulations of existing drugs and potential challenges in the clinic.

Discussing increased molar dosing of aflibercept.

Explaining the variability in patient clearance rates and their impact on treatment outcomes.

Aflibercept 8 mg, including study findings and clinical practice applications.

Clinical practice for aflibercept dosing, including loading doses and extension intervals.

Prioritising individualised approach based on patient's response and disease activity.

The safety and efficacy of a drug for treating retinal diseases.

Extending drug treatment from 8 weeks and onward with positive patient response.

Safety data and potential label change with regulatory agencies.

The importance of manufacturing processes and the challenges of creating fully human antibodies to VEGF.

John Kitchens, MD, is joined by David Brown, MD, to discuss the PULSAR study results and their relation to patients with neovascular age-related macular degeneration in clinical practice. 

PULSAR Results and Their Relation to nAMD Patients in Your Practice

Answering all the questions ophthalmologists may have ahead of the EURETINA Congress in Paris, France

What to expect at this year's European Society of Retina Specialists (EURETINA) Congress

The province's public health insurance scheme, Régie de l’assurance maladie du Québec (RAMQ), covers faricimab for three indications

Québec announces faricimab (Vabysmo, Roche) will be funded for macular oedema secondary to RVO

Salvation of ocular tissues and visual acuity are dependent on early diagnosis, investigators emphasised

Patient outcomes in retinoblastoma impacted by parents' interventional delays

Highlights from the 2025 Heidelberg Engineering International SPECTRALIS Symposium—And Beyond

Recap: The future of imaging is out of this world

New financing will support the company's lead retinitis pigmentosa programme, among other projects

Australian biotech firm Mirugen secures major funding for cell reprogramming therapy

João Pedro Marques, MD, MSc, PhD discusses a retrospective study of 800 patients with inherited retinal diseases 

Gene therapies were a popular part of the programme during the American Society of Retina Specialists (ASRS) annual meeting. But even as clinicians understand more about genetics and inherited conditions, unsolved mysteries prevent patients from receiving vision-saving care.

At this year's ASRS meeting in Long Beach, California, the Eye Care Network spoke with João Pedro Marques, MD, MSc, PhD, about his presentation. He is affiliated with Centro Hospitalar e Universitário de Coimbra in Coimbra, Portugal. Prof Marques spoke about inherited retinal diseases (IRD) and common challenges in genetic testing. He explained that genetic testing can be a pain point for clinicians and patients, and obstacles to accurate testing can have a major impact on the care patients receive.

"Even if you use state-of-the-art genetic testing, up to 30% of patients will remain genetically unsolved," he said. These inconclusive outcomes can be highly frustrating, Prof Marques explained. As such, his team conducted a retrospective, single centre study. Its goal was to identify baseline determinants which might predict ifi a patient's IRD can be genetically "solved" and attributed to a specific gene function.

In the study, over 800 patients with IRDs were classified into predetermined phenotypes.

"We found that the age of onset [being] before 18 years of age, the presence of familial consanguinity and the presence of a family history are actually significant determinants to obtain a positive genetic testing result," Prof Marques recounted. "If you put these factors all together, the likelihood of obtaining a positive test is even higher. However, if none of these factors are present, you'll get only a 30% chance of having a positive genetic testing result."

"Our main highlight is actually how real-world data can impact your daily clinical practice," he continued. "This is very important because of access to clinical trials and access to new gene therapies. If you don't have a genetic diagnosis, you won't be able to be enrolled in these kinds of treatments."

Watch the video to hear the complete findings in this new IRD research.

Videos

Helping patients navigate the unsolved mysteries of genetic testing

Christine Curcio, PhD, shares histology update and revised nomenclature for OCT

Christine A. Curcio, PhD, spoke to the Eye Care Network about her presentation at the 2025 International SPECTRALIS Symposium – And Beyond (ISS). At this year's ISS meeting, held on 13 and 14 June in Heidelberg, Germany, Prof Curcio spoke on histology and optical coherence tomography (OCT) interpretation. She recounted details of that lecture in the above video.

Curcio is the emerita professor of ophthalmology and visual sciences at the University of Alabama at Birmingham Heersink School of Medicine, in Birmingham, Alabama. Prof Curcio and her team use volume electron microscopy to correlate high-resolution tissue data with OCT B-scans. New techniques in histology are refining the way clinicians use software tools, and the OCT nomenclature used to describe findings, Prof Curcio said.

“We built on the success of the 2014 international OCT consensus by Staurenghi et al,” Curcio said. She refers here to a landmark framework, developed by clinicians in Italy, the United Kingdom, California and New York, published in 

 The consensus introduced terms, such as ellipsoid zone and interdigitation zone, which are a key aspect of retinal research today. A detailed and accurate imaging framework is crucial to understanding retinal disease, she noted. “Attention to precision is really essential,” she said.

Staurenghi G, Sadda S, Chakravarthy U, Spaide RF; International Nomenclature for Optical Coherence Tomography (IN•OCT) Panel. Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN•OCT consensus. 

. 2014;121(8):1572-1578. doi:10.1016/j.ophtha.2014.02.023

Christine A. Curcio, PhD, shares an update on histology and its critical role in advancing <3 μm optical coherence tomography interpretation 

Refining what clinicians see and treat in outer retinal disease with Christine Curcio, PhD

SriniVas R. Sadda, MD, FARVO, shares key points from his retina presentation at the International SPECTRALIS Symposium

At the International SPECTRALIS Symposium – and Beyond (ISS) in Heidelberg, Germany, a lineup of imaging experts shared their thoughts on the ever-changing field. SriniVas R. Sadda, MD, FARVO, presented a lecture on high-resolution optical coherence tomography (OCT). At the ISS, he said high-resolution OCT shows diagnostic and prognostic promise for atrophic and precursor lesions in age-related macular degeneration (AMD).

Biomarker-based risk stratification is a strategy Dr Sadda already uses in his clinical practice, he said. “We’ve spent a lot of years trying to establish the pathway to the development of atrophy in AMD,” he said. "These biomarkers are very important to recognise."

High-resolution OCT has a stronger axial resolution than standard-resolution OCT, giving structural features of the eye a distinct appearance. This allows clinicians to distinguish true hyperreflective foci from retinal vasculature, for example. Additionally, clinicians can differentiate incomplete retinal pigment epithelial (RPE) and outer retinal atrophy (iRORA) from complete RPE and outer retinal atrophy (cRORA), a vital distinction to make in treating patients with AMD.

Watch the full video to hear how the nuanced monitoring made possible by high-resolution OCT can help diagnose and treat patients.

High-resolution optical coherence tomography illuminates crucial biomarkers in age-related macular degeneration, Dr Sadda said

Robert Sergott, MD, describes fluorescence lifetime imaging ophthalmoscopy (FLIO) and the International SPECTRALIS Symposium – And Beyond (ISS) in Heidelberg, Germany.

Robert C. Sergott, MD, of Wills Eye Hospital, presented during the New Technology session at the International SPECTRALIS Symposium (ISS), 13-14 June, in Heidelberg, Germany.

During his lecture, Dr Sergott discussed fluorescence lifetime imaging ophthalmoscopy (FLIO), an emerging imaging modality for ophthalmic and neurologic pathologies. He highlighted the potential FLIO demonstrates in diagnostics and therapeutic monitoring for retinal disease and neurodegeneration.

According to Dr Sergott, FLIO's relationship to optical coherence tomography (OCT) mirrors that association between positron emission tomography (PET) was to magnetic resonance imaging (MRI). In other words, FLIO is ushering clinicians from structural imaging toward functional imaging. Dr Sergott is the Margaret and Richard Hayne Distinguished Director at the Annesley EyeBrain Center at Jefferson University, partnered with Wills Eye Hospital. There, he and his colleagues are focused on using FLIO to distinguish patterns of mitochondrial dysfunction and protein misfolding which can be biomarkers of neurodegenerative diseases including multiple sclerosis, Alzheimer andParkinson disease.

Watch the full video to hear more about the promise of FLIO, including the possibility of personalised disease modeling, drug testing and more.

FLIO ushers clinicians from structural to functional imaging, said Robert Sergott, MD, in a presentation at the International SPECTRALIS Symposium

Fluorescence lifetime imaging ophthalmoscopy (FLIO) reveals the brain's best-kept secrets

Anat Loewenstein, MD, describes her presentation on remote imaging for age-related macular degeneration and geographic atrophy at the International SPECTRALIS Symposium, in conversation with Hattie Hayes of Ophthalmology Times Europe

Anat Loewenstein, MD, co-chaired the retina session and presented in the distributed care session at this year’s International SPECTRALIS Symposium (ISS). She is the director of the division of ophthalmology at Tel Aviv Medical Center in Israel.

Prof Loewenstein commented on trends in the contemporary imaging landscape, a key segment of her ISS presentation on home monitoring. “Something that comes up loud and clear is we need to find ways to correlate between function and morphology,” Prof Loewenstein said. “Everyone looks for imaging that will show biomarkers that are predictive of progression.”

Prof Loewenstein said that, along with optical coherence tomography (OCT), advanced technologies like OCT angiography (OCT-A) and fluorescence lifetime imaging ophthalmoscopy (FLIO) are quickly changing what is possible in diagnostics. That's good news for patients with age-related macular degeneration, geographic atrophy and other retinal pathologies. However, she warned that technology alone is not enough to improve and preserve patients’ health outcomes.

“You cannot use remote monitoring as a standalone [tool.] Everyone wants to use AI and remote monitoring, but you need to coordinate with your health system,” she advised. “[Remote monitoring] needs to be supported by the community of retina physicians and of ophthalmologists, so the healthcare system and the payers will be in agreement with the need to use it in our system.”

Watch the video to hear Prof Loewenstein’s full interview and learn about her presentation at the ISS in Heidelberg, Germany.

Anat Loewenstein, MD, presented real-world results of remote imaging at the International SPECTRALIS Symposium


Modern monitoring strategies remove major barriers to retina care

Tyson Brunstetter, OD, PhD, shares key takeaways from his keynote at the International SPECTRALIS Symposium

Heidelberg Engineering holds its 21st International SPECTRALIS Symposium (ISS) in its eponymous hometown of Heidelberg, Germany, on 13 and 14 June, 2025. The first ISS held in the newly-opened Heidelberg Congress Center will include a keynote address by two scientists from the US-based National Aeronautics and Space Administration (NASA).

Tyson J. Brunstetter, MBA, OD, PhD, FAAO, FAsMA, is a US Navy aerospace optometrist at the NASA Johnson Space Center in Houston, Texas. He is the clinical lead for NASA’s research into spaceflight-associated neuro-ocular syndrome (SANS), a condition which is common among astronauts, especially during long-duration missions.

Dr Brunstetter discussed the keynote address. He delivered the keynote in conjunction with Warren “Woody” Hoburg, who is part of the NASA astronaut class of 2017 and logged a total of 186 days in space on his first flight.

Dr Brunstetter provided deep background on SANS and its distinctions from other neuro-ophthalmic pathologies. Additionally, he encouraged audiences to think outside the box—or, when necessary, outside gravity—in their own day-to-day lives.

Dr Brunstetter, a US Navy Aerospace Optometrist at the NASA Johnson Space Center in Houston, Texas, delivered the lecture at this year's ISS alongside his colleague Warren Hoburg

Viha Vig, MBChB graduate student at the University of Auckland, New Zealand, discusses her poster presentation on the relationship between mitochondiral disease, Alzheimer disease, and other types of dementia.

At the 2025 Association for Research in Vision and Ophthalmology meeting in Salt Lake City, Utah, Viha Vig presented a poster mitochondrial eye and systemic diseases. Vig is a MBChB graduate student at the University of Auckland, New Zealand. Her work examined the relationship between mitochondiral disease, Alzheimer disease, and other types of dementia, including vascular dementia. Here, she shares some of the key findings from her research. Watch the video to hear the full details from her poster presentation.

Editor's note: The below transcript has been lightly edited for clarity.

"We're investigating the relationship between mitochondrial eye and systemic diseases and Alzheimer disease, vascular dementia, and other types of dementia. So this is one of the first studies in humans to investigate the relationship between mitochondrial diseases and different types of dementias...This is a retrospective cohort based longitudinal study, and our results indicated that there was a higher prevalence of dementia, higher in the ocular mitochondrial disease, than the systemic mitochondrial disease. In people with both those ocular and systemic mitochondrial disease had a much higher prevalence as well. And all three groups, ocular, systemic, and the combined mitochondrial disease group also had a pretty high incidence of all different types of dementia as well."

"The clinical takeaway is that mitochondrial dysfunction is a part of the shared neuropathic physiology of different types of dementia as well as mitochondrial diseases. And we know some of this already. We use PET scans in our clinical practice as standard of care to detect dementia. The clinical application is that mitochondrial dysfunction can be used as biomarker or a target for pharmacological therapies to reduce cognitive decline, because mitochondrial dysfunction does happen before the onset of symptoms in dementia, and there's enough studies in the literature supporting this...If we can quantify the mitochondrial dysfunction in the retina through direct methods FLIM imaging or indirect methods like electroretinograms, then we have an idea of dementia progression over time and the pathology going on in the brain...This would be a much less expensive and less invasive way to detect dementia."

"At the moment, there's two thoughts amongst the scientists who are investigating eye disease and dementia. One school of thought is focused on retinal neurodegeneration and vascular changes in the retina, and that directly correlates with what's happening in the brain. And that's a direct correlation. Another school of thought is a little bit of an indirect correlation...Vision loss leads to social isolation, which is a huge risk factor for dementia. So both these theories, I believe, are quite valid...When talking about the mitochondrial disease study, specifically, I think that [mitochondrial disease] would be a really good target for pharmacological therapies, and because we already know that mitochondrial dysfunction, it has a huge role to play in dementia. That's a well established thing, and it's more well established in animal models. And mitochondrial dysfunction happens before the onset of symptoms of dementia. So it gives us a chance to reduce the rate of cognitive decline, and if I'm going to be ambitious, may also give us a chance to, you know, reverse dementia to an extent. I think it will mainly just reduce the rate of cognitive decline."

Detecting mitochondrial dysfunction may give clinicians a chance to reduce the rate of cognitive decline in patients with dementia

ARVO 2025: Ocular and systemic mitochondrial diseases may be key to dementia diagnosis

Alfredo Sadun, MD, PhD, chief of Ophthalmology at the Doheny Eye Institute, University of California Los Angeles, shared exciting new research with the Eye Care Network during the Association for Research in Vision and Ophthalmology (ARVO) meeting on the subject of Leber hereditary optic neuropathy (LHON).

Alfredo Sadun, MD, PhD, chief of Ophthalmology at the Doheny Eye Institute, University of California Los Angeles, shared some exciting new research with the Eye Care Network during the Association for Research in Vision and Ophthalmology (ARVO) meeting.

In Salt Lake City, Utah, Prof Sadun detailed a recent project examining Leber hereditary optic neuropathy (LHON). When the research produced an unexpected result, Prof Sadun said, it opened new possibilities for adeno-associated virus (AAV) delivery of gene therapies.

I'm a neuro-ophthalmologist with a great interest in one particular disease, which is Leber hereditary optic neuropathy. This is a genetic disease where you do just fine until you turn 20 or so, and then you suddenly go blind, first in one and then the other eye, very dramatically and very unfortunately. So we've been doing research together with GeneSight from Paris, France, for gene therapy for this disease. In doing so, we have found out that, at least in some patients, an injection of the gene via AAV2 intravitreally can lead to some improvement. 

This trial both succeeded and failed, enormously, because of the same phenomena. An injection in one eye somehow mysteriously caused improvement of vision in both eyes. This was a failure in the sense that, the FDA said, "You get approval if you can show the injected eye does much better than the other eye," but they both got much better. So they are not on the way for approval, as of right now. 

But the amazing thing is that they got more bang for the buck. Both eyes got better. The agency, GeneSight, thought this is because the virus went into the brain and came back down via the other optic nerve. I have a PhD in ocular anatomy, and said that didn't sound very likely. 

So we've been doing these investigations where—fortunately for us, but very unfortunately for the families—not one, but two patients who had undergone gene therapy died. And we had an opportunity of analysing the eye. In looking for products of the of the virus and of the transfer gene, we were able to find that it 

 in the other eye. So in this sense, the company was correct. 

But the concentrations of the virus did not get weaker. As you went back from the uninvolved eye, they got greater; meaning it got to the eye and then diffused back to the brain, not that it got to the injected eye, to the brain, and diffused forward into the eye. So we're still not sure how it got from one eye to the other, but it does not seem to be via the brain. 

Point number one is that we have misunderstood the directions of these vectors and how the infection leads to transfer. And so clearly, in [LHON], not only does this tell us a lot about treatment of that disease, but it tells us about AAV2 virus being a different story than we thought, which will apply to [Leber congenital amaurosis, LCA] and other diseases that might be using gene therapy for treatment. 

The other thing...it's going to be a fantastic opportunity when we finally understand how it works, but there are a lot of limitations. In LCA, they found out that it works really well in the short-term, but there's some decay of the effect, perhaps because we're putting in a good variant of the gene, but the old variant is still around, and they're in competition with each other. Somehow, when you have competition, usually the native protein wins. 

There are a lot of other issues at play here. [LHON] tends to affect people in their late teens and mid-20s. It's very sad, because people who expected to have their plans in their lives that have been interrupted enormously and shockingly and quickly. Most of our patients for the gene therapy trial were, therefore, in their early 20s. We only looked at patients who had lost vision within the last year, hoping that it was still salvageable, because the longer you wait after that, the optic atrophy would have put a ceiling on how much improvement we could have gotten. That's the nature of the disease. That's the nature of our experiments, the nature of when the gene therapy would work. But there is something that comes out of that which is unexpected, also. 

We initially started with 2 different groups: 0 to 6 months after loss of vision and 6 to 12 months. The 6 to 12 month group was plan B. [Our team was] thinking we're going to miss some of these patients because the diagnosis doesn't occur that quickly, since there are not too many neuro-ophalmologists around.

We expected the results to be much better in the 0 to 6 months [since diagnosis] group, because the optic atrophy had not really developed. There were more salvageable cells. 

To our shock, the 6 to 12 months patients did better than 0 to 6. Furthermore, when we did a subgroup analysis, amongst the 0 to 6, the only ones who did well were those who lost vision 5 or 6 months before the injection. And amongst the 6 to 12, the ones who did best were the ones around 11 to 12 months. 

So later is better. That's such a shocking thing that we went back and looked at the literature...for a medical treatment with an agent called idibenone, amongst the same patients. And it's not published yet, but I'm working on a paper that's entitled, "Later is better."

What we're looking at [next] is other tissues. We're looking at vascular tissues, lymphatic tissues. I mean, it's just a wild guess. I don't mean to suggest that I have a deeper insight than anyone else, but I think that maybe the glymphatics, the fluid, the [cerebrospinal fluid, CSF] around the brain, not the brain itself, might have been the conduit for this. In which case, you would expect it to sort of mix throughout the brain, to concentrate in areas that are the cul-de-sac of the CSF flow. The biggest cul de sac is the optic nerve head, just at the juncture of the optic nerve in the retina. So, that gradient we saw, which was highest there and going down further back, would make sense.

At the 2025 ARVO annual meeting, Prof Sadun shared an exciting update in our understanding of Leber hereditary optic neuropathy

ARVO 2025: Alfredo Sadun, MD, PhD, says "later is better" for some LHON interventions

At this year's Association for Research in Vision and Ophthalmology (ARVO) meeting in Salt Lake City, Utah, Nitish Mehta, MD, shared highlights from his research documenting real-world results of aflibercept 8 mg for patients with diabetic macular oedema.

Editors from the Eye Care Network are onsite at this year's Association for Research in Vision and Ophthalmology (ARVO) meeting in Salt Lake City, Utah. During the conference, we spoke with Nitish Mehta, MD, an assistant professor at New York University Langone Health in New York, NY. He shared highlights from his research, which documented real-world results of aflibercept 8 mg for patients with diabetic macular oedema (DMO).

"In the PHOTON trial, aflibercept 8 mg achieved non-inferiority visual acuity outcomes, with fewer injections to aflibercept 2 mg, in patients with diabetic macular oedema through 96 weeks," he said. "Real-world evidence for the use of 8 mg [aflibercept] could also be very helpful for our clinical practices."

The cohort study Dr. Mehta presented aimed to describe real-world outcomes in treatment-naïve patients with DMO. After applying inclusion and exclusion criteria to data from the IRIS Registry and Vestrum Health database, investigators had data from approximately 2,113 eyes. 

"Injection intervals were assessed in eyes that had at least two injections in the initial dosing phase, and in eyes that had at least one injection in the post initial dosing phase," he said. Visual acuity change from initiation to 30 days post-loading was assessed where the data was available.

"On average, patients with treatment naïve [DMO] achieved injection intervals of around 75 days," Dr. Mehta said. "That's around 11 weeks with aflibercept 8 mg."

Additional analyses, with longer follow-up periods, are ongoing, he added, and will assess the long durability and visual outcomes for patients with treatment-naïve DMO.

ARVO 2025: Nitish Mehta, MD, provides real-world insights from aflibercept 8 mg for treatment-naive diabetic macular oedema

ARVO 2025: Anat Loewenstein, MD, shares data from herself and her colleagues on meeting needs of patients with diabetic retinopathy

Clinicians from around the world have convened in Salt Lake City, Utah, for the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). One of those experts is Anat Loewenstein, MD. Prof Loewenstein is director of the division of ophthalmology at Tel Aviv Medical Center in Israel. She is also a 

In a conversation with the Eye Care Network, Prof Loewenstein described her presentation, results from a Delphi consensus on the management of diabetic retinopathy. The consensus group was composed of a smaller cohort of five retina specialists, as well as a larger group of health care providers (including more retina experts). This population of practitioners were administered three surveys, which they used to record results on the current treatment protocols and outcomes for patients with diabetes.

"There were a few topics that achieved consensus," Prof Loewenstein said. Physicians in the cohort agreed on many of the unmet needs of patients, especially those which cause patients to have a high treatment burden and poor visual acuity. "One topic that achieved high consensus was the lack of possibility of very early intervention and noninvasive therapy," Prof Loewenstein said. "Another unmet need considered the lack of addressing additional pathological and paramechanistic paths." In particular, Prof Loewenstein said, diabetic macular oedema may need to be treated via more than just one pathway, in order to combat its multi-factorial origin. "That might bring along better visual acuity outcome, maybe with decreased burden for our patients," Prof Loewenstein said.

Prof Loewenstein and a cohort of colleagues assessed the current treatment outlook for patients with diabetic retinopathy

ARVO 2025: Anat Loewenstein, MD, and colleagues on meeting needs of patients with diabetic retinopathy

 I think the port delivery system [PDS] can have a very significant clinical impact on the treatment of wet AMD [age-related macular degeneration]. We’re all aware of the treatment burden patients have with frequent intravitreal injections. In addition, we know the peaks and troughs of anti-VEGF injections can affect the recurrence of wet AMD. Given that it is a continuous delivery of anti-VEGF therapy, not only can this potentially reduce the treatment burden for patients, there is also a possibility for disease modification with the port delivery system.

The fact that many patients in the LADDER study did not even meet refill criteria, and that 98% of patients in the ARCHWAY trial did not need any additional treatment before the first refill, implies that we may be actually modifying the disease to the point of even potential quiescence for some of these patients.

Now that we have the port delivery system as an approved option, it’s important to consider how it can fit into our treatment plan. I have plenty of patients who require monthly or Q2 monthly [every 2 months] intravitreal injections. I think these are the patients I will first have a discussion with, and talk to them if they’re interested in potentially having a longer-term delivery of intravitreal anti-VEGF. Reducing the treatment burden will be very appealing for many of these patients. Of course, the risk and benefits of surgery need to be weighed carefully for such patients. One of the factors that I consider for PDS is the frequency of injections that the patients have. I also will look at the stability for these patients. If these patients can be stable on a monthly or every 2 months setting, we may still discuss it. However, if they’re having recurrent fluid, I think I’ll be much more likely to discuss the port delivery system. If a patient happens to be very stable with injections only every 3 or 4 months, the port delivery system may not be as appealing for some of these patients, unless they’re against getting transscleral intravitreal injections. With respect to insurance approval, of course many of these questions are yet be answered. However, we certainly hope and anticipate for insurance to cover this procedure. It is yet to be determined if it will be a step-wise approach, but I surely hope these critical patient-care decisions are left up to the physician, with explanation and discussion with the patient, and not mandated policy.

Having performed many of these surgeries already during the clinical trials, I can say that the patients who have received the port delivery system are quite happy. They do notice a stability of their disease. In addition, with the refill procedure, although technically it is very different from an intravitreal injection, and the surgeon has to be very aware of the different techniques, for the patient experience, it’s quite nice. It’s more tolerable because there’s no transscleral penetration of a needle. Patients often report that this was a much more comfortable and easier process to do. In terms of the implantation, it’s also considered to be quite painless. Most patients may have a little bit of itchiness or mild irritation immediately in the first 1 to 2 days of the postoperative period. Otherwise, it is a very well-tolerated procedure, and patients seem to have a very good experience.

With the approval of the port delivery system for neovascular AMD, I think the future for this platform is quite interesting; it has a lot of great potential. Studies are underway for both diabetic macular edema, as well as diabetic retinopathy. In addition, as we develop better compounds that may be more efficacious, such as bispecific molecules, marrying the PDS platform with these new molecules may yield even better results for our patients. I think there are a lot of exciting possibilities for the PDS platform.

As our retina specialty embarks upon a new era for the treatment of wet macular degeneration, I think as colleagues, it’s important that we utilize all the resources available. I highly encourage you to use all of the information, as well as surgical device liaisons, for example, in order to help maximize our patient outcomes.

Closing out his discussion on the port delivery system in retinal diseases, Chirag Jhaveri, MD, considers how this approach has impacted the treatment landscape. 

Clinical Implications of Port Delivery System in Retinal Diseases

As we all start performing more of these surgeries, since it is now approved for the use of neovascular AMD [age-related macular degeneration], it is going to be very important to review videos prior to implantation of the PDS [port delivery system] in our patients. In addition, there are surgical simulators that can give you great hands-on experience. I anticipate many of these simulators to be available at many of our meetings, including ASRS [the American Society of Retina Specialists] and AAO [American Academy of Ophthalmology]. It’s also very important to have a good relationship with your surgical device liaison. These individuals are going to be very helpful in guiding you through your first few surgeries. They will be present as needed in your operating room, and they will definitely be there for your first few cases. I highly recommend utilizing them, as they’re wonderful resources to help guide you through your first few cases.

The surgical device liaisons are individuals who you can get in touch with through the company representatives. They are individuals who are there for your resource, and to help guide you in learning any of the tips, pearls, and steps that you would like to discuss for the PDS implantation.

A detailed description of both the implantation and the refill is going through publication approval. These will also have associated videos. In addition, if you would like more videos, you can also discuss this with your surgical device liaison, and they’re happy to provide additional teaching techniques and videos.

Concise insight on education and training strategies that will optimize use of the port delivery system in retinal diseases.

PDS in Retinal Diseases: Practical Advice on Education and Training 

The LADDER trial was a phase 2 trial that showed overall good safety and efficacy for the port delivery system [PDS] for the treatment of neovascular AMD [age-related macular degeneration]. It looked at varying doses of ranibizumab in the PDS implant. Patients were dosed at 10-mg, 40-mg, and 100-mg concentrations. Interestingly, and this is different than the ARCHWAY study which we’ll talk about shortly, patients were only given a refill of ranibizumab if they met criteria of worsening fluid, vision, or new submacular hemorrhage. The 100-mg concentration, which is what is approved, showed that about 80% of patients were able to go 6 months or longer before needing a refill; the median time for needing the first refill in the 100-mg group was nearly 16 months.

Overall, the port delivery system procedure was very well tolerated. As mentioned before, after the modification of the technique, patients did not have any vitreous hemorrhage within the first month. The refill procedure was also very well tolerated, and was able to be done in an in-office setting.

Coming from very good results from the LADDER trial, ARCHWAY was the phase 3 trial, which was a 2-year study comparing monthly ranibizumab to the PDS implant with 100 mg ranibizumab and refills [every] 6 months. The patients enrolled in this study were patients who had wet AMD, were diagnosed within 9 months of screening, and who were responding to anti-VEGF treatment. The ARCHWAY trial showed that 98% of patients were able to go without any additional treatment in the PDS group. The PORTAL trial is an extension study that will be looking at how patients do beyond 2 years. The safety and tolerability of the procedure were also consistent with the LADDER study, particularly with respect to very low incidence of vitreous hemorrhage, as well as the procedure being very well tolerated.

The patients who were included in the ARCHWAY study were recently diagnosed with neovascular AMD. All the patients had to be diagnosed within 9 months of their screening visit, and they all had to show a good response to anti-VEGF therapy.

The ARCHWAY study so far shows that patients are tolerating the port delivery system very well, even in a long-term manner. We’re also showing that patients have good, consistent visual recovery, as well as good stability of their macular thickness. We also analyzed patients with fluid fluctuations, and showed that patients with the port delivery system have good minimization of fluid fluctuations, similar to having monthly ranibizumab injections. I’m also excited about learning what longer-term data are going to show in the PORTAL study. The PORTAL study is looking at patients well beyond 2 years, as well as multiple refills beyond 2 years.

Chirag Jhaveri, MD, reviews the trial design and results of the LADDER and ARCHWAY studies, which tested the port delivery system in neovascular AMD. 

PDS in Retinal Diseases: Interpreting the LADDER and ARCHWAY Studies

The port delivery system is an ocular delivery system that is surgically inserted via the pars plana area in the superotemporal quadrant of the eye. It provides continuous delivery of ranibizumab to the posterior segment. It has a reservoir chamber where a higher concentration of ranibizumab is held, and there is slow release into the vitreous cavity. It has been approved for use in patients with neovascular AMD [age-related macular degeneration], although other indications, including diabetic macular edema, are also being investigated.

With the approval of Lucentis [ranibizumab] for the indications of neovascular AMD, the treatments for neovascular AMD were revolutionized. However, there still is a significant treatment burden for many of our patients who require frequent, often monthly, injections. The treatment burden for both the patients and the family can be quite high. In addition, although we’re delivering a nice bolus of anti-VEGF treatment, there is a waning of the amount of medication in the vitreous cavity. Therefore, a more sustained, endurable treatment modality was needed. Like most devices, the port delivery system was started in the preclinical stages, where it was developed and then tested in nonhuman subjects. Once its safety was verified, it went on to trials to verify safety in human patients, and then to look at the efficacy.

In the phase 2 LADDER study, the technique that was done in human patients initially showed an increased risk for vitreous hemorrhages. The technique for implantation was modified to include laser cautery of the corneal bed]. After this, the incidence of vitreous hemorrhages dropped precipitously. Prior to the amendment, there were 6 out of 10 cases of vitreous hemorrhage. After the amendment, there were no cases of vitreous hemorrhage out of 48 patients within the first month, which is generally considered the postoperative period. At 2 months, there was 1 patient who did have a vitreous hemorrhage.

Although the procedure is generally well tolerated, since it is surgical procedure, there are some potential complications that surgeons and patients should be aware of. Initially, in the LADDER study, there was a higher rate of vitreous hemorrhages. A modification of the procedure has since reduced those rates tremendously. Any surgery has a risk of infection, and with respect to the implant itself, if the conjunctiva is not closed properly or not covering the implant adequately, there is a possibility of the implant being exposed. Also, if the conjunctiva is very thin, there is a possibility of erosion. Therefore, presurgical evaluation and meticulous care to close the conjunctiva are very important.

When evaluating a patient preoperatively, you want to take note of a few things. Particularly, you want to take note of the conjunctiva to see if it’s very thin, and if there’s good mobility of the conjunctiva, so that you can adequately access the subconjunctival and sub-Tenon space. In addition, you also want to note any areas of potential scleral thinning, so that when you’re making your wound you’re aware, and so you don’t start making your wound too deep. In addition, you may also want to avoid those areas, so that there isn’t a risk of dehiscence or any other potential issues with the wound.

Expert insight on the history of the port delivery system in neovascular AMD and how it has impacted patient experience and outcomes.

The Development and Safety of Port Delivery System 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]?

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.

Retina

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