In Denver, Colorado, United States, Dr Sally Tucker, vice president of Ora Europe, describes the complexities that Ora overcomes when designing clinical trials.

Hello, my name is Sally Tucker, and I am the vice president of Ora Europe, overseeing all of our clinical operations across the European region. So as we consider the pathway to the approval of any products, we need to consider the complexities and how we address those to make the pathway as efficient as possible. The aim of this is to speed the time to approval for the products that you bring to market.

The complexities that we face increase the larger the trial, and this is something that we need to address particularly when we are thinking about larger Phase 3 trials in which more patients are required, and in which there's often a requirement to think about global site outreach.

So how can we do these things? The first is through protocol design. We need to consider within the protocol what are the requirements of the regulators. We have experience working with regulators across the globe, the FDA, the EMA, the MHRA, the Chinese FDA, and the PMDA. We will address the regulatory requirements and make sure that they are within the protocol design, depending upon which country approval you are seeking.

The second thing that we need to consider in the protocol design outside the regulatory requirements is whether the protocol is clinically executable. It is really important to engage with investigators across the globe to make assessments of the protocol. Does the protocol makes sense? Can it be done within a clinical setting? And we also need to consult with patients. And this is something that we take great pride of doing. We have numerous patient panels, and we consult with these patient panels. How does the protocol design look? Is it too burdensome for the patient? Are we addressing their hopes, their desires, and also their concerns and fears to increase the likelihood for them to want to be a part of the research and the clinical trial?

The next thing we need to consider is the slight outreach, especially in these large Phase 3 trials in which we might have to consider multiple countries. We need to consider the patient demographics, and where the patients are to be found. (We also consider) the competitive environment and the standard of care health care provision in the country that we approach.

How can we elevate research as a care option to patients to optimize recruitment? We also work with the sites and the investigators themselves who work tirelessly on these clinical trials, helping to bring these projects and these product products to market. How can we support them better - training of staff coaching mentorship, collaboration across sites, feeling that they're part of something bigger, broader? And how can we also assist with pre-screening, helping to identify patients to bring to the sites to speed the overall execution of the clinical trial?

The last aspect that we also consider is our patients. We as scientists, investigators, clinicians, researchers, put patient at the centre of all we do we all want to make a difference to the patients that we serve.

So how can we best do that? We have patient panels that we work with, identifying how we can make the protocols less burdensome for them, and how we can support them on their journey, being a part of the clinical trial, and how we can develop patient facing materials that address their needs. And also engage with them throughout the duration of the clinical trial in a compassionate and empathetic manner so that they feel engaged.

They are reminded why they are in the trial, and they are appreciated for being in the trial. We are committed to all of the stakeholders that we work closely with the companies that work tirelessly to bring novel new products to market that can address the unmet needs of patients, to the sites who work so hard and conducting the clinical trials and the patients for whom we all serve. Thank you.

Videos

Dr Sally Tucker of Ora Europe walks through the clinical trial pathway, describing how Ora addresses complexities to make the path as efficient as possible.

Ora Europe executive outlines pathway for clinical trials 

Dr Jeff Cleland, CEO of Ashvattha, discusses safety data for an at-home subcutaneous injection option being developed for wet age-related macular degeneration (AMD) and diabetic macular oedema (DMO). The anti-VEGF candidate will enter a Phase 2 study later this year.

. ® I'm joined today by Dr Jeff Cleland, CEO of Ashvattha, who will discuss safety data for an at home subcutaneous injection option being developed for wet AMD, and DME (DMO). The anti VEGF candidate will enter a Phase 2 study later this year. Thanks for joining us, tell us about this project.

Thank you, David, Ireally appreciate the opportunity to join you today. The thesis behind this project came about by the fact that right now everyone has to get an injection with a needle in the eye that gets treated for many of these retinal diseases. And often that occurs every 6 to 8 weeks. And so it's really a heavy treatment burden, not just on the patients. Many of the physicians that we've talked to, are really facing a challenge today, being able to actually treat enough patients because of the heavy treatment burden of having to do this administration.

We’ve looked at it, even from the early days and when I worked at Genentech, is there a way we can deliver the drug systemically, and really have the same effect as an ejection in the eye without the safety side effects? And so that's been our goal and our challenge with our product.

What we are able to show at this year's ARVO is that we are able to dose very safely a very potent anti-angiogenic agent to patients using a subcutaneous administration. And this allows us then to have at-home use of the product by the patients so they can self-administer. Eventually, we will get to market with an auto injector similar to what they do already with an insulin device or something like that. And so it makes it much easier on the patient, also easier on the physician. They still have to routinely go back and obviously be checked by the retina ophthalmologist, but at the same time, they wouldn't have to come back in for regular injections into the eye. We think this is going to be a real alleviation of the treatment burden for patients and providers. Many patients over time do get burned out and stop coming back for treatment. So maybe we can save a few patients vision over the long term as well.

Ultimately, what can this mean for patients?

I think the great advantage of this is that the patients that maybe don't even want to consider a needle in the eye will now have an option that's better, and provides them a chance to continue to maintain their vision and make it easy for them to self-administer at home. Eventually, and we're working on this now in the background as well, a possible oral dosage form of the same product. We can offer patients a pill at some point in the future, instead of having an injection in the eye.

You alluded to it, but what's the next step for this study?

So the next step is that we're about to start enrolling patients and a Phase 2 program. These are wet age related macular degeneration patients and diabetic macular oedema patients. They've already been treated with an anti-VEGF previously, and they've shown a response to that, but they have to keep coming back in for those intravitreal injections. And so instead of having their next intravitreal injection, they would come back in and get an injection of Eylea or aflibercept. We'd see how long they respond to that injection. So we have a control baseline. And once they have a return of subretinal fluid back to baseline, they'll get a subcutaneous dose of our drug, and we'll again follow them and see how long they respond and how well they respond to our drugs. Each patient becomes their own control in the first part of the study. We think this will be a very powerful study to show that the drug actually does have the potential for therapeutic benefit in these patients.

Thank you so much for taking a little time to catch up again with us and I appreciate it.

Note: This transcript has been lightly edited for clarity.

Jeff Cleland, PhD, CEO of Ashvattha, discusses safety data for an at-home subcutaneous anti-VEGF injection option in development for the treatment of wet AMD and DMO.

Phase 1 trial finds at-home subcutaneous injection option safe, effective for the treatment of wet AMD, DMO

This is a sub-analysis of a larger trial looking at a compound called OC-01 (varenicline solution) as a treatment for symptoms and signs of dry eye.

This larger study involved hundreds of patients that had different symptoms and signs compromising the dry eye umbrella. And the question we wanted to ask, because there are so many different phenotypes within dry eye, is: How would this compound do in patients with autoimmune-associated dry eye?

And we defined autoimmune pretty broadly: anyone who had an associated comorbid autoimmune disease. And the rationale for this is because the hypothesis may be these patients have a more severe dry phenotype and would be less likely to respond to treatment. And so that is the question that we aimed

We identified 31 people out of the larger trials who had a comorbid autoimmune disease, and we look to see how they did. This was a placebo-controlled study, so, how the cases who were treated compared to placebo, and how overall they compare to the larger study findings.

The punch line is that they did just as well as patients without autoimmune-associated dry eye. Which is great; it means that we're still trying to understand how OC-01 will be used in the general dry eye population, but it doesn't seem that patients with autoimmune disease do any worse than patients without autoimmune disease. And so that is the main takeaway, and a really important one for clinicians.

When you're looking at the data, the biggest wow effect was in terms of dry eye signs. A majority of individuals that were treated with OC-01 had a greater than 10-millimetre improvement in Schirmer at four weeks compared to controls. Symptoms, as is the case in most dry studies, were more variable. But either way, there was an improvement in both signs and symptoms. The side effects, most common was a sneeze, and most common were reported as mild, and that's in the whole population.

The takeaway of this study is that there doesn't seem to be a specific dry eye phenotype that does better or worse. And so we'll still have to look and see how this does in the global landscape of dry eye, but patients with autoimmune-associated dry eye did just as well as patients without autoimmune dry eye in responding to this compound.

Takeaway: there doesn't seem to be a specific dry eye phenotype that does better or worse.

OC-01 (varenicline solution) investigated as possible treatment for dry eye symptoms, signs

At ARVO 2022, Dr Allen C. Ho presented Phase 1/2a data RG6501 (

), a retinal pigment epithelium cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (AMD). His presentation, entitled, “Safety and Efficacy of a Phase 1/2a Clinical Trial of Transplanted Allogeneic Retinal Pigmented Epithelium (RPE, OpRegen) Cells in Advanced Dry Age-Related Macular Degeneration (AMD),” detailed the full results of the trial, which met its primary endpoints and will be moving onto the next phase of research.

Dr Ho serves as the Wills Eye Institute Attending Surgeon and Director of Retina Research, and he is a professor of ophthalmology at Thomas Jefferson University.

I'm Allen Ho, and I am a retina surgeon at Wills Eye Hospital, Mid Atlantic Retina and the director of retina research.

So the OpRegen trial is a cell therapy trial, looking to explore potential safety and efficacy for patients with advanced dry age-related macular degeneration (AMD).

If you think about this group of patients — which are growing as baby boomers are enlarging — this is a study to attempt to address the dry form, we currently have treatments for the wet form, including injections, and we're developing treatments for the dry form. This is an attempt with cell therapy to see if we can slow down, stop, or even potentially reverse, vision loss in this group of patients.

There is a great unmet need for patients with advanced dry macular degeneration. In other words, there's no specific treatment for geographic atrophy. We have some programs now — and it's kind of exciting — that are thinking about slowing down the progression of aging, or atrophy, in patients with this condition.... [and] they involve injections.

This is a study looking at a different approach using cell therapy. And in this phase 1/2, non-randomized study, we're seeing a good safety profile with this stem cell line surgically placed under the retina. And most of the patients who had any issues that were reported on safety, were with respect to, for example, the surgical procedure itself with some redness of the eye.

We did see some epiretinal membrane formation, three of which was significant and required surgery in the study. And this is three out of 24 only.

To reiterate, the safety profile of the OpRegen program is very well-tolerated. I want to also add that when you put cells in an eye — [and] these are human allogeneic cells — you have to watch carefully for inflammation, either acute or delayed, or rejection of the cell line. We saw none of that, so the cells are very well-tolerated.

With respect to the different cohorts in observations there, it kind of makes sense that if you try and solve a problem... for example, when the house is not totally burned down, like the initial cohorts that were legally blind with larger areas of atrophy, we saw good safety there and some signals of activity of the cells. But when we looked at cohort four, which was 12 out of the 24 subjects, again, good safety, but also some very promising signs of activity that need to be explored in a larger randomized program.

Specifically, we saw about a seven-letter improvement — 7.6 letter improvement — in cohort. Four of those patients with smaller areas of atrophy, and better vision ... about 21/25 starting vision. And we saw interesting structural changes on the OCT, overlying what we presume was the cell deposition in areas of atrophy and some improvement in the retinal architecture where we had transplanted the cell line.

So we're seeing some promising results that need to be explored more, both with respect to anatomy and activity, and even vision with the caveat that this is an open label study. We need to understand these results in the context of a randomized trial. I think we're beginning to understand and refine who the right patient group is. Again, if you think about the goal of trying to slow, or stop, or even reverse aging in any part of your body is a lofty goal but we're seeing promising signals that really need to be explored in a randomized fashion so that we can generate data with confidence and hopefully deliver this to patients in the future.

The OpRegen trial is a cell therapy trial, looking to explore potential safety and efficacy for patients with advanced dry age-related macular degeneration (AMD).

Cell therapy shows promise for patients with dry AMD, geographic atrophy

Dr Oscar Otero-Marquez, a research fellow with the New York Eye and Ear Infirmary of Mount Sinai, discusses his poster presentation titled, 

Retinal Blood Flow Measurements in Healthy Subjects with OCT Doppler, 

that was presented at the ARVO 2022 annual meeting held in Denver, Colorado, United States.

Hello. So my name is Oscar Otero, I am a research fellow at New York Icahn Infirmary of Mount Sinai. I'm working at Dr Rosen’s lab. My poster presentation is titled 

Retinal Blood Flow Measurements in Healthy Subjects with OCT Doppler.

The purpose of our study was to assess retinal blood biomarkers using a new prototype OCT. The idea is that we can measure retinal biomarkers such as blood flow volume, average velocity, and vessel diameter with new prototype.

What we found is that there is no difference in the supratemporal, infratemporal arcades in healthy human subjects. The idea of doing this study is that so far, we do have data available in the US population. All the previous studies have been done on Asian populations. So this is the first time that we can measure retinal blood flow biomarkers in a US population.

The next step is to image subjects with retinal diseases or with glaucoma. The idea is to use this prototype to image subjects with glaucoma, or CRVO. We think that these conditions might predispose to less blood flow within the eye. That means it is not proven yet that, for example, subjects with glaucoma have less blood flow within the eye. And that is a theory that still needs to be proven. So with this device, we can measure the blood flow within the large vessels that are different with OCT-A.

With this prototype, we are measuring the blood flow within large vessels close to the optic nerve. That way, we can see if there is a decrease in the blood flow in conditions such as glaucoma or, for example, in patients with CRVO, and retinal vein occlusions. There is a difference between the non-affected and the affected brain. One good thing is that we expect to measure if there is a difference within the same eye, for example, before and after treatment. If we see we are treating a patient with glaucoma, and we see that with one of our treatments the blood flow increases with medical or surgical therapy, we can reassure the patients that the treatment is good for them. And we can expect to use this as a clinical tool for our patients or for monitoring all kinds of diseases.

Note:This transcript has been lightly edited for clarity

The study assesses retinal blood biomarkers using a new prototype OCT, aiming to measure retinal biomarkers such as blood flow volume, average velocity and vessel diameter with a new prototype.

Retinal blood flow biomarkers measured with OCT Doppler

Dr Fatema Ghasia, director of the Ocular Motility Laboratory at the Cole Eye Institute, sat down with 

executive editor David Hutton to discuss her talk at the 2022 ARVO meeting held in Denver, CO.

Thank you for having me. So the talk was on looking at fixation eye movement abnormalities and how it affects binocular visual functions and amblyopia.

Since we know amblyopia is lazy eye, it affects about 5% of children. And previously, amblyopia was primarily thought to be a problem where vision in one eye is weaker than the other. But recent research has suggested that it has implications on your binocular vision, so the talk was on looking at how fixation eye movement abnormalities differ in patients who have good binocular visual functions versus those who don't.

So in this experiment, what we have done is we specifically measured suppression. So amblyopia is now increasingly thought to be a problem with the suppression of images from the weaker eye. And so there are newer treatments that are coming out that aim to reverse this interocular suppression. And so what we basically found is that if you had certain eye movement abnormalities, and by that I mean, certain forms of nystagmus that are seen, then you're more likely to have poor binocular visual function, as well as possibly can have more interocular suppression.

You know, now, the fact that we realize that, you know, the suppression plays a major role in in amblyopia — so, there are newer anti suppressive amblyopia, treatments — and so if we know of the eye movement abnormalities they have, if you knew ahead of time, it may give us insights into prognosis of the condition and, and also perhaps give us insights into response to treatment.

So, you know, if you had certain fixation, eye movement abnormalities and you have worse, then there is a likelihood that after treatment, your recovery or binocular visual functions may not, you know, be complete in the sense that you can still have improvement in your visual acuity, but your binocular visual functions may not recover completely. I think it would help us understand response to treatment and give us some ideas about the prognosis.

So the next steps would be to continue to, of course, you know, we would like to create a database of amblyopia patients, and kind of understand how fixation eye movement abnormalities can help us better gauge the pattern of visual function deficits that we see.

Amblyopia affects, you know, not just the visual acuity of one eye; it also has effects on contrast, sensitivity, it has effects on your depth perception, we now increasingly recognize the role of interocular suppressions, and we also know that it not only affects the lazy — or the weaker — eye, but it also has effects on the so-called good eye.

What we're trying to ultimately do is do a battery of tests on these patients before treatment, and then kind of follow them as they're doing the more conventional treatments of patching and eyedrops, versus the newer treatments that have recently been implemented, which are dichoptic treatments, which are anti-suppression treatments, and kind of see how fixation eye movements can help us figure out the pattern of visual function deficits that we see because we know that not all patients have all of the problems that I just described.

And so it will kind of help as this missing link between understanding the pattern of visual function deficits, as well as, to kind of see how the visual functions improve with that conventional and newer treatments.

The study found that if certain forms of nystagmus that are seen in patients, then there is a higher chance of poor binocular visual function, as well as higher interocular suppression.

Binocular vision affected by amblyopia, research suggests

Dr Ayellet Segrè presented her work on trying to understand the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide, which is primary open angle glaucoma during the 2022 ARVO annual meeting, held in Denver, Colorado.

I'm David Hutton of Ophthalmology Times. The ARVO 2022 annual meeting was held recently in Denver, and our team continues to talk to physicians who presented papers at the conference. Today, I'm joined by Dr Ayellet Segrè, who presented a paper at the event. Thank you for joining us. Tell us about your presentation.

 Thank you for having me. So I presented work on trying to understand the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide, which is primary open angle glaucoma.

It's characterized by gradual retinal ganglion cell death that leads eventually to the degeneration of the optic nerve head and visual field loss and can lead to blindness. And the underlying causes, the genes and processes that lead to the disease, are not very well understood. So we use the approach that integrates both very large population-based genetic study that covered over 100 regions in the genome with common DNA changes associated with risk for developing primary open angle glaucoma and integrated that with additional functional genomic information that tells us about what the different DNA changes in the genome do to gene expression, and in which cell types in eye tissues both in the front and back of the eye in which cell types they're expressed. And by developing a method that integrates both genetic associations from these very large population-based studies, what we call genome wide association studies, together with gene expression in single cells both in tissues in the front of the eye, for example, the outflow pathway through which the aqueous humour flows and it's the blockage of its drainage has been thought to affect and lead to elevated intraocular pressure, which is one of the major risk factors of primary open angle glaucoma, as well as looking at expression in the back of the eye and in the optic nerve head and in the retina and the optic nerve head where the retinal ganglion cell death occurs. And by integrating both pieces of information we found we're able to uncover genes and biological processes we think may be affecting the risk for developing this form of glaucoma. And we found that a lot of the genes tend to be expressed both in the conventional and the unconventional outflow pathway, also genes associated with intraocular pressure, there's a major risk factor.

But also an interesting fact is that about 40% of patients with primary open angle glaucoma have an intraocular pressure in a normal range of pressure. And that suggests that there may also be intraocular pressure independent mechanisms that lead to the degeneration of the optic nerve. And we found that many of the genes that map to the genomic loci associated with risk for developing primary open angle glaucoma, enrich for expression in microglia cell types in the retina and around the optic nerve — so these are cell types that support the metabolic supply and structural support of the retinal ganglion cells that you know that may be affecting itself and ability to survive.

So it suggests that we did not see actually genes enriched for expression in the retinal ganglion cells themselves suggesting that, you know, thinking about in the future different developing new therapies might be important to think about targeting the neuronal support cells in addition to maintaining the health of the retinal ganglion cells.

 What’s the next step for your research?

Yeah, so the next step we're planning on kind of following up on these results, seeing if they replicate, reproduce in an independent secondary study both of single nucleus RNA sequencing of additional healthy eye tissues from from donors, as well as in an even larger population based study looking for genetic risk factors associated with primary open angle glaucoma, that looked at maybe over 10,000 additional cases, and identify now over 300 genomic loci. So we're planning on doing this analysis with an even larger set of risk factors for glaucoma together with the single cell data and see if the results stand. And we can learn more about the underlying genes and biological processes. And then down the line we're interested in, in collaborating with experimental biologists here at Mass Eye and Ear to test some of the hypotheses of what genes and pathways may be functioning in particular cell types.

 Ultimately, what can this mean for patients?

 This work suggests that there may be both what is better understood, you know, pathophysiological path that's affecting a risk of POAG through regulation of intraocular pressure, and it's suggesting certain cell types in the front of the eye, some that have been more well established, and others were suggesting particular genes. So the hope is, currently there are medications that reduce IOP but my understanding is that some patients they might not be as effective. So having maybe this knowledge of the particular genes that are perturbed and in the particular cell types might help design even better intraocular pressure reducing medications. And the other thing is a kind of uncovering the potential role for particular cell types such as the neuronal support cells in the retina and the optic nerve head. This might open a new avenue for developing drugs that will will be helping the neuro protection of the retinal ganglion cells so could open a new avenue for therapies that are for helping treat patients that develop primary open angle glaucoma. And that is not dependent on the intraocular pressure being elevated, but maybe more has to do with the sensitivity of retinal ganglion cells. But that's that's uh, you know, there's work here at Mass Eye and Ear and trying to study the genetic predisposition to what we call normal tension glaucoma.

Presented at ARVO 2022, research from Mass Eye and Ear hopes to open a new avenue for therapies that are for helping treat patients that develop primary open angle glaucoma.

POAG study hopes to open a new avenue for therapies that are for helping treat patients that develop primary open angle glaucoma

At ARVO 2022, Dr Carlos Quezada Ruiz, senior medical director at Genentech, presented his talk entitled, “Predicting optimal treatment regimen for patients with neovascular age-related macular degeneration using machine learning.”

This year at ARVO, we are presenting our data on a pilot study looking at machine learning and its ability to predict treatment regimen for patients with neovascular AMD. We believe that personalized health care and personalized treatment for patients with neovascular MD is the way that we are going to be treating patients and the retina in the future.

And at Genentech Roche, we are committed to better understanding how machine learning fits into this picture and how it can help us evolve into getting to that personalized approach for patient treatment and patient counselling as well, which is so important.

In this work, we evaluated 324 patients who were enrolled in the AVENUE and the STAIRWAY trial, and who received ranibizumab or faricimab for the treatment of neovascular AMD. We evaluated the baseline characteristics of those 324 patients, which included age, sex baseline BCVA, CSD treatment regimen arm. We also included image-derived characteristics from the spectral domain OCTs of all of those patients. We then implemented different machine learning algorithms. In the results, we actually realize that one of them, XG boost, was the one who came with the with the highest R square. This is basically the highest prediction rate for treatment interval for these patients.

Now, what this means for patients is basically that if this algorithm is able to work, in the future we may be able to predict at baseline during that initial visit how a patient might respond over time with regards to BCVA response, but also what would be the most appropriate treatment regimen, meaning the least frequent regimen that would give the best BCVA outcomes for that individual patient.

And while we recognize this is a pilot study of only a small proportion of patients, we do think that we need bigger datasets and more diverse datasets as well to better replicate these results and be able to extrapolate it to a broader population as well.

Dr Carlos Quezada Ruiz, senior medical director at Genentech, discusses “Predicting optimal treatment regimen for patients with neovascular age-related macular degeneration using machine learning.”

Predicting optimal treatment regimen for patients with nAMD using machine learning

Gloria B. Chiu, FAAO, FSLS, sat down with 

executive editor David Hutton to discuss her poster, "Impact of Delayed Corneal Crosslinking in Keratoconus Patients," presented at ARVO 2022 in Denver, Colorado, United States.

This transcript has been lightly edited for clarity.

Hi, David, thank you so much for this opportunity to be here with you today. Well, it's exciting, first of all, that ARVO was able to bring so many people back in-person to discuss research and all the exciting things we've been learning about and not able to communicate with each other over the last two years.

So my poster, as you mentioned, is titled, "Impact of Delayed Corneal Crosslinking in Keratoconus Patients." Now this poster is really only a sampling and giving us a taste of what we've been seeing in clinic, we would like to in the future share more of a case series including more patients, and the changes we saw on their eyes.

In this particular poster, my colleagues and I from the USC Roski Eye Institute in Los Angeles, discussed data from three patients. So essentially, in summary, the impact of delayed corneal crosslinking in patients who are candidates for this treatment can be very devastating.

And this was seen through these three patients. Due to various reasons, insurance being one of them, lost to follow up, and also the pandemic, we had challenges managing these patients ideally.

So because they were diagnosed with keratoconus, [and] they were young, we wanted to get them this treatment, but many of them had challenges getting insurance approval. Now, as we know, [the] FDA approved corneal crosslinking in the United States in April of 2016. So some of these patients that I was following were referred for crosslinking around that time, around 2017. Insurance coverage wasn't as good as it is now, so back then we really had challenges getting them the coverage they needed.

So we shared three cases on this poster. The first was a 26-year-old female. Essentially, she presented with keratoconus more in her left eye than the right. She had no scars in her right eye but some striae in the left eye. She was referred for crosslinking but because it wasn't covered by her insurance at that time, she couldn't get the treatment. She ended up getting fit with scleral contact lenses in 2017, but as we know the contacts didn't do anything to help the progression of the disease. So unfortunately, even though she could see better, she developed scarring. Then we kind of lost her to follow-up didn't see her back until November of 2020 when we noticed significant progression in her keratoconus. Now she had scars in both eyes, and her glasses were no longer functional. And it's been really challenging and just devastating to see the impact on her eyes and her vision, given that she's a young 20 year old.

Another case, we shared another young Caucasian male. Similarly, he had moderate keratoconus presented in 2017. And he had RGP contacts for many years. But over the years between 2017 to 2019, we followed his corneal tomographies and he looked okay, but then in 2020, when he came back we saw a significant progression. And now we saw central corneal scarring and the right eye. So with keratoconus, we look for changes through the slit lamp, such as corneal thinning, corneal striae corneal scarring. So when we saw this scarring, we referred him immediately for crosslinking. He had it done in March of 2021, in his in his right eye, and then May of 2021, in his left eye. But again, due to the pandemic, which, you know, started in about March of 2020, we weren't able to get him treated as early as we would have liked. And so we did see unfortunately steeping in his corneal topographies.

And with our last patient, he's 44. But, you know, although we generally expect keratoconus to progress in the teens and 20s, it certainly can still progress, especially if there are environmental factors such as eye rubbing. So this patient, 44-year-old, he had significant ocular allergies, floppy eye lid syndrome, and lots of eye rubbing. So he was referred for crosslinking as well, he were RGPs (rigid gas permeable lenses). He had crosslinking in one eye in his in his left eye in August of 2018. Thankfully, however, with his right eye, he had no scars. And he was referred out for improvement in his contact lens fitting, so he got Sclera Lenses, and with changes noted in his right eye later on. So he came back for his routine Scleral Lens care. But then we saw scarring in his right eye when previously we hadn't noted it. And when we sent him out for cross linking for his other eye, we again notice challenges with insurance coverage, even though he had it done in his other eye.

So these are just three instances of keratoconic patients who experienced challenges in getting timely corneal crosslinking that has led to permanent changes in their corneal structure, as well as best-corrected vision. And that's what the poster shows, with some of the images, the tomography that we have. Ultimately, we want to avoid advanced signs, such as corneal scarring, which we know will impact vision. And in our table, we just show essentially the delay these patients experienced and in our case, it wasn't just weeks or months. In some cases, it was years, because they were seen, you know, so soon after the FDA approval, and insurance coverage back then in 2017, wasn't as robust as it is today.

So we noticed changes in their prescription getting higher, decreased best-corrected vision steepening in their K measurements (their keratometry measurements), as well as thinning in their corneas. So with these changes — thinning, also, the development of scarring — these are things that cannot be reversed.

Through this poster — through these three cases — we really want to get the point out that we should initiate crosslinking as soon as possible in good candidates, particularly young individuals, and especially those with ocular allergies or who have history of eye rubbing, because these actions can lead to progression of the disease more rapidly. So particularly with the last couple of years in access to care, delays due to the pandemic, a lot of our patients unfortunately struggled with getting timely treatment; but now, hopefully moving forward once we make the proper diagnosis, and also confirm that they either have progressive keratoconus or ectasia following refractive surgery, we can get them the care they need as soon as possible.

The study evaluates three separate cases, each of which experienced irreversible changes in their corneal structure caused by challenges in getting timely treatment due to various reasons, including insurance, lost to follow up, and the COVID-19 pandemic.

Ill-timed corneal crosslinking led to permanent changes in corneal structure in patients with keratoconus

At ARVO 2022, Dr Steven Yeh reviews the results of the Phase 3 PEACHTREE and AZALEA integrated study, revealing significant BCVA gains and low adverse event incidence in the Xipere (triamcinolone acetonide injectable suspension, Bausch + Lomb) arm.

Dr Yeh is a professor of ophthalmology and the Director of Retinal Disease and Uveitis at the Stanley M. Truhlsen Eye Institute at the University of Nebraska Medical Centre.

This integrated analysis looked at patients who received macular oedema for noninfectious uveitis. In PEACHTREE specifically, we treated patients with macular oedema due to noninfectious uveitis. And the AZALEA study looks specifically at safety in this cohort of patients.

And in this study, we looked at the efficacy signals as well as the safety signals, integrating these two cohorts of patients. What we found is that patients who received Xipere showed a significant best corrected visual acuity gain of up to two to three lines of visual acuity improvement at the week 24 time point when we combined the clinical trial data.

This is also reflected in reduction of macular oedema, specifically found that patients who received Xipere showed approximately 150 micron reduction in central subfield thickness, and this was sustained for the duration of the trial.

The other aspect that's very important related to this new technique for the treatment of posterior segment conditions is safety. What we found is that intraocular pressure rates were very favourable. In the Xipere arm specifically, about one in eight individuals showed elevation of intraocular pressure, compared to the slightly higher one and seven of individuals in the patients who were in the sham control arm.

When we broke this down further to the patients in the sham arm who received rescue therapy, we found that 25% of individuals who receive local intravitreal therapies showed an elevation of intraocular pressure, which is really compelling when we think about Xipere as a therapy that's nuanced, and a new technique for the treatment of macular oedema due to noninfectious uveitis.

Other adverse events were very well tolerated, and we're very excited about both the efficacy outcomes, as well as the safety variables as well. Again, visual acuity is very important to all of our patients and again, is related to the quality of life and what patients care about most. This is a new drug delivery technique that we're really looking forward to not only for uveitis, but other posterior segment conditions in the future.

The Phase 3 integrated PEACHTREE and AZALEA study data revealed strong safety and efficacy for triamcinolone acetonide via suprachoirodal injection.

ARVO