We’ll move forward and speak a little about challenges of drug delivery. We already heard a little about this. We agree that the complex anatomy and physiology of the eye makes it a challenge. If we want to overcome the monthly intravitreal injections of different drugs, we need to get access to the retina in terms of obtaining therapeutic drug concentrations. We agree that a challenging task of drug delivery is to overcome the ocular barriers and deliver drugs efficiently to the targeted ocular tissue. This is true not only for the retina but maybe also for the choroid and other intraocular tissues.

The drugs are usually prevented from reaching the ocular tissues by static and dynamic biological ocular barriers. These barriers can be classified or ordered depending on their anatomical location and their functional properties. This means, in general, these barriers can also be classified as interior and posterior segment barriers. In addition to this, we must differentiate between static and dynamic ocular barriers. The static ocular barriers are corneal epithelium, the blood-aqueous barrier, the sclera, the retinal pigment epithelium, and the blood capillary endothelial cells. In addition, the dynamic ocular barriers consist of the tear drainage, conjunctival blood and lymph clearance, and choroidal blood and lymphatic circulations.

Dr Moosajee, can you please review how the blood-retinal barrier is disrupted to allow oral delivery, and how you can overcome this? In addition, I’d like you to discuss a little about the reformulation and penetration to direct drug-delivery systems.

Mariya Moosajee, MBBS, BSc, PhD, FRCOphth:

 Thank you. With inherited retinal dystrophies, the photoreceptor and the RPE [retinal pigment epithelium] layer are the main target layers affected in the disease process, with the end stage being cell death. We very rarely see areas of intact RPE when the photoreceptors have diminished. You can also see these accompanying changes with the choriocapillaris in certain conditions. The blood-retinal barrier, as you very nicely overviewed, has 2 main components. From the posterior side it’s that retinal vascular endothelium and the retinal pigment epithelium; hence, if the RPE is disrupted, we will disturb this barrier. Orally administrated drugs may then be able to penetrate into the retina more easily, especially if those are small-molecule drugs.

In the IRD [inherited retinal diseases] space, several clinical trials are giving drugs, particularly neuroprotectants. For example, a drug called N-acetyl cysteine, which is a high-dose antioxidant and is in phase 2 clinical trials for retinitis pigmentosa. It’s orally administrated, and we’re hopeful that it penetrates into those target cell layers. With regard to reformulation and penetration into the retina, ideally we want to give the drugs to the target tissue: the retina itself. A lot of these drugs may need to be reformulated; therefore we need to do pharmacokinetics and toxicology studies to determine safety penetration half-life and the dosing regimen. The benefit is that we can avoid systemic exposure and potential adverse effects. On the flip side, from some of the work I’ve done and with AMD, there have been whole metabolomic profiling studies that have looked at the metabolites in the blood. For example, in patients with choroideremia we found high levels of oxidative stress, disrupted lipids, and serotonin dysfunction. In these cases, they may not just be isolated eye conditions. There may be a systemic effect, so systemic delivery may not be a bad thing.

Videos

Challenges associated with delivering therapies currently available to treat retinal disorders and methods being explored to improve drug delivery to patients.

Drug Delivery Challenges in Retinal Disease

Surgery in a patient with uveitis presents a number of challenges. First, the visual outcomes of surgery are likely to be worse than in patients without uveitis. The procedure may also be more prone to uveitis-related surgical complications, such as damage to the cornea, iris atrophy or posterior synechiae, cystoid macular oedema (CMO) and epiretinal membranes. Finally, there is also a risk of uveitis recurrence after surgery, even in a patient whose disease had previously been well controlled. The risks of surgery vary greatly, depending on the type and severity of uveitis, the type of surgery required and the patient’s general health and comorbid conditions.

In this article, I will primarily discuss cataract surgery, as it is the surgical procedure most frequently performed in patients with uveitis and the one on which protocols for other types of surgery are based.

Uveitis: A leading and underestimated cause of visual morbidity in patients

The first principle of surgery in patients with uveitis is that their uveitis should be completely and consistently controlled for at least 3 months prior to surgery. This objective is typically easier to achieve prior to an elective procedure like cataract surgery than an emergency repair of a retinal detachment. However, if the situation is urgent in some types of lens-induced uveitis, the surgeon may not have the luxury of waiting for complete and consistent control.

Strategies for controlling inflammation become increasingly aggressive with more severe uveitis. Certain uveitic conditions, including Fuchs uveitis syndrome, do very well with cataract surgery and may not even need extra perioperative steroids. A patient with a history of recurrent acute anterior uveitis that is well controlled with topical steroids, with no recent flareups, may also fare quite well. In these patients, I typically increase the dose of topical steroid (prednisolone acetate 1% every 2 hours), starting a couple of days before surgery and continuing for a month after surgery, tapering back to baseline based on postoperative inflammation. The risk of CMO can peak 3 to 4 weeks after surgery, so it is important not to stop the steroids too soon. I also add a topical NSAID such as bromfenac or ketorolac, provided there is no medical contraindication. NSAIDs significantly reduce the risk of pseudophakic CMO

 and should always be on board in patients with uveitis, even if the surgeon does not use them in routine cataract cases.

Investigators analyse factors associated with patient satisfaction after refractive surgery

In those with any posterior involvement, including significant posterior synechiae, recent sarcoid panuveitis or Behçet’s disease, or any history of macular oedema, much more aggressive measures may be needed. These patients may require regional steroid injections, systemic steroids, and/or systemic immunosuppression—essentially, whatever it takes to control the uveitis before surgery. Although I may give patients a sub-Tenon’s triamcinolone acetonide injection or intravenous steroids at the time of surgery, I generally prefer to also have steroids on board before the day of surgery.

For control of uveitis perioperatively, an intravitreal injection of the dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) or preservative-free triamcinolone acetonide 2–4 mg 2 to 4 weeks prior to surgery is indicated. Remember that intravitreal triamcinolone is opaque and may blur the retinal reflex if it is still in the eye at the time of surgery. If the patient does have an intraocular pressure (IOP) response to the steroid, it typically lasts no more than 2 to 4 months and may be controlled with glaucoma drops.

A longer-lasting implant such as injectable fluocinolone acetonide 0.18 mg (Yutiq, EyePoint Pharmaceuticals) or fluocinolone acetonide 0.59 mg scleral-fixated implant (Retisert, Bausch + Lomb), may be beneficial in a patient who has had local injections in the past and is not a steroid responder. Retisert requires surgical implantation, whereas Yutiq is administered via an in-office injection through a 25-gauge siliconised needle. 

With the longer-duration implants, the patient may have adequate steroid coverage to not only control postoperative CMO but to prevent recurrences of uveitis and macular oedema for several years after surgery. We also have to consider the dose and location of these steroids. Yutiq contains about one-third the dose of fluocinolone acetonide that Retisert does (0.18 mg vs 0.59 mg), and because it sits more posteriorly in the eye, further from the ciliary body, may have a lower risk of inducing glaucoma.

Considering antibiotics use in postoperative endophthalmitis

Studies suggest that long-lasting intravitreal steroids can be as effective as immunosuppressive therapy in controlling uveitis and macular oedema,

 so these are a great option for patients who cannot take oral steroids because of diabetes or high blood pressure, who are medically unable to take immunosuppressive therapy, or who would prefer to avoid these drugs.

Systemic immunosuppressants and local steroids can work very well in combination. For example, if the patient is already well controlled on a single immunosuppressant, I do not usually add another immunosuppressant just for cataract surgery. Rather, I will use steroids in some form as adjunctive therapy.

Being prepared to manage a small pupil is essential when performing cataract surgery in patients with uveitis, as these patients often have synechiae or iris atrophy. In some cases, manual iris stretching techniques may be sufficient, but iris hooks or pupil expansion rings are often required. Iris hooks take more time to place and may cause damage to the iris if placed incorrectly, but they provide a great deal of flexibility. If I run into an intraoperative complication such as zonular dehiscence or a nuclear fragment that is floating peripherally and is difficult to visualise, iris hooks allow me to expand the pupil more in that particular meridian. 

Controlling postop pain, inflammation in cataract patients: drug delivery vs drops (video)

A Malyugin ring, by contrast, provides a fixed pupil size and is a larger piece of hardware that can complicate other aspects of the surgery. However, it is fast and easy to place and a large study suggested that the Malyugin ring and iris hooks are comparably effective.

 In retinal surgery, performing scleral depression and getting a really good view of the peripheral retina will likely be easier with hooks than with a ring. Anyone who performs surgery in uveitic eyes should be comfortable with both types of device.

A femtosecond laser can make cataract surgery easier in uveitic eyes with poor zonular support. However, a FLACS procedure also requires a longer duration of pupil dilation, which can be quite challenging in these eyes. Even with good dilation, it may be more difficult to achieve the laser capsulotomy, as blood from stretching the pupil may affect the focusing ability of the laser. For all these reasons, I typically opt for manual capsulorrhexis and phaco in my patients with uveitis.

Phaco power modulation boosts safety, efficacy in cataract surgery

Postoperatively, these patients may need aggressive cycloplegic therapy to prevent recurrent posterior synechiae. If synechiae do occur, I prefer to intervene quickly to avoid pupillary glaucoma. Unlike many routine cataract surgeries, the postoperative care for patients with uveitis should not be delegated to other clinicians. It is important to monitor carefully for any signs of inflammation or increased IOP, and to be sure to check both eyes in patients with bilateral uveitis, rather than just the operative eye.

The outcomes of cataract surgery with a lens implant in several types of uveitis, including juvenile rheumatoid arthritis-associated uveitis, Behçet’s disease panuveitis and Vogt-Koyanagi-Harada disease, can be very disappointing. In some cases, the surgery seems to go well, but the vision just does not improve as much as expected. This may be due to an unrecognised retinal complication, such as an epiretinal membrane or a tractional detachment that could not be seen on preoperative imaging through a dense cataract, but in some cases there is no clear explanation for the poor result. Those with comorbid conditions (e.g. cataract + glaucoma + uveitis) may require multiple, staged procedures to achieve a satisfactory final visual result.

FDA accepts Bausch Health, Clearside Biomedical's resubmitted Xipere NDA

For all these reasons, good patient education is absolutely critical to avoid postoperative dissatisfaction. Patients with uveitis often develop early cataract and may therefore be younger and of working age, and may still have residual accommodation that will be lost after surgery. They have a higher risk of complications and a longer recovery period than non-uveitis cataract patients, so it is important to under-promise (and, hopefully, over-deliver). Patients need to know that they probably will not see 20/20 in the waiting room like their uncle Fred did after his cataract surgery last year. That said, I personally find it more satisfying to give a person with hand-motion vision a 20/40 visual outcome than to improve a routine 20/25 cataract patient to 20/20. With carefully individualised care, we can optimise the chance of good outcomes for our patients with uveitis.

Dr Dunn is a retina and uveitis specialist at Wills Eye Hospital in Philadelphia, Pennsylvania, and has a particular interest in cataract surgery in patients with uveitis. He has no financial disclosures to report. Contact him at 

1. Wielders LHP, Lamermont VA, Schouten JSAG, et al. Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: A systematic review and meta-analysis. 

2. Jaffe GJ, Pavesio CE, Study investigators. Effect of a fluocinolone acetonide insert on recurrence rates in noninfectious intermediate, posterior, or panuveitis: Three-year results. 

3. Eyepoint Pharmaceuticals, Inc. Full Prescribing Information. Yutiq.com. 

https://eyepointpharma.com/wp-content/uploads/2019/01/YUTIQ-USPI-20181120.pdf

4. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group; Kempen JH, Altaweel MM, Drye LT, et al. Benefits of systemic anti-inflammatory therapy versus fluocinolone acetonide intraocular implant for intermediate uveitis, posterior uveitis, and panuveitis: 54-month results of the Multicenter Uveitis Steroid Treatment Trial and follow-up study. Ophthalmology 2015;122(10):1967-75.

5. Balal S, Jbari AS, Nitiapapand R, et al. Management and outcomes of the small pupil in cataract surgery: Iris hooks, Malyugin ring or phenylephrine? 

Articles

While operating on a patient with chronic uveitis presents some challenges, there are a few pearls that may increase success.

Pearls for ocular surgical success in patients with chronic uveitis

We’ll now move forward and speak briefly about anti-VEGF therapy in general. Dr Peto, can you briefly discuss how anti-VEGF drugs have become the mainstay of therapy for so many retinal diseases? What’s the mechanism of action, and why are those drugs so successful?

 These drugs have become very successful because they give the patients hope. We can tell them for the first time that their vision is likely to improve, or at least be stabilized, and there’s only a very small chance that they’ll get much worse and a chance that they’ll get slowly worse if the drug doesn’t work in their eyes. The patients really respond to this, although most times they’re very afraid of the first injections.

In terms of regimens, we try to start the injections on the same day if we can. There’s nothing worse than for them to go home, google or watch a movie, and try to first show we’re going to put the injection in. The patients are very responsive to this care that they receive. We’ve been disadvantaged in the diabetes field by having to prioritize the patients with AMD [age-related macular degeneration] at the beginning of the pandemic, because AMD takes the vision away much quicker than diabetic macular edema. When we had limited footfall, the patients with AMD were injected as a priority. But we know that patients with diabetes need to be treated as well so they’re back on track.

Because we go into the eye, the endophthalmitis is always a risk. It might be different in different units depending on how this physical setup is. We do find that nurses in our units are very good injectors. They usually take very good care of the patient. They have their lists, they get to know these patients who come back, and they’re very good at managing patients with anxiety as well. For us, the nurse injectors—and in some units optometrists and orthoptist injectors—have been a real answer to the question, because we don’t have enough ophthalmologists practically anywhere in the world to deliver this many injections. Of course, ophthalmologists are a lot of the times better used for doing the actual operations or delivering more complicated injections, such as the subretinal injections for gene therapy.

Thank you very much. It’s unique for the United Kingdom and your country [Northern Ireland] for the nurses to be doing the injections. This is not the case in our country. It’s also not the case in France, as far as I know. Dr Korobelnik, there are some more drawbacks. Monthly injections are not the way to go for the next 10 years or so, and the increasing risk of infection with so many injections also exists. In addition to this, we have a big burden to the patient and to the caregivers, especially in working-age people, such as patients with diabetes. Can you give a few words on this as well?

 You’re absolutely right. The burden of those diseases is really high because the patients require frequent visits for control and examination, for injections, and to control their disease. For some patients, we may expand the interval between the injections, and it can become somehow comfortable. Some other patients require extremely frequent injections, and they may require injections in both eyes because quite often in wet AMD and DME [diabetic macular edema] the disease is bilateral. The burden is high for the patients, for their families, and the cost also is quite high because you need to pay for everything: the procedure, the drug, transportation, many things. This will vary a lot from 1 country to another, but it’s adding to the time spent by the patient and their family to come attend the appointments. The burden is very high at the moment, and it’s also a problem for us because we have to cope with all those patients, the ones we’re following and the new ones. As people are living longer, diabetes is becoming more common. We have many more new cases of advanced AMD and diabetic retinopathy. Not only is the burden high for the patients to come, but the pressure is high on us to organize our clinics to deal with all those patients.

Drawbacks and challenges associated with the administration of anti-VEGF injections currently available to treat retinal diseases.

Anti-VEGF Therapy for Retinal Disease

We have to move forward. I’d like to ask Dr Moosajee for her opinion on the treatment options for inherited diseases.

 Thank you. There aren’t many treatment options for patients with IRD [inherited retinal disease]. Conservative management is important; we give a lot of advice about the diet of these patients, such as fresh fruits and vegetables. We know from studies in animal models that there are high levels of oxidative stress in the retina. Therefore, we’re advocating that patients eat fruits that are red, blue, and black and that are rich in antioxidants, such as grapes, raspberries, pomegranates, and strawberries. We ask patients to wear UV [ultraviolet] sunglasses in bright light to protect the retina from any further sun damage. In a lot of IRDs, you can get macular edema; those patients may be put on Diamox [acetazolamide] or Trusopt [dorzolamide] just to help manage that. But we now have the first approved retinal gene therapy targeted toward gene 

, which causes leber congenital amaurosis phenotype and also retinitis pigmentosa. This is called voretigene neparvovec and is widely available across the world. I’ve the seen the results of some of the real-life patients being treated with this, especially in the pediatric cohort. We’re seeing increases in best-corrected visual acuity and improvements in the navigational vision and in the vision in dim light. There are some inherited retinal diseases, such as gyrate atrophy, which is an autosomal recessive disease caused by mutations in the 

 gene. This encodes an enzyme that’s active in our mitochondria to help break down ornithine. If we identify these mutations and we also advise our patients to take a diet that’s arginine restricted to reduce ornithine intake, this can potentially prevent further retinal degeneration. There are several clinical trials underway for gene replacement therapies; we’re hoping to see an increase in availability of treatments to this cohort of patients in the coming years.

Thank you. Maybe you can add a little bit on subretinal injection of gene therapy since we are already speaking about gene therapy in inherited diseases.

 At the moment, the way that we deliver the gene therapy is through subretinal injection. This involves patients having a vitrectomy and then subretinal injection where you have the intact retina and have the injection of adeno-associated viral vectors, which package the 

 gene. We know from clinical trials that there can be some adverse ocular inflammatory events associated with this, so patients are given steroids, pre-, peri-, and postoperatively to try to dampen that response. Gene therapy is a single administration to both eyes. There are concerns: What if there’s a loss of efficacy possibly through neutralizing antibodies? What if we need to consider redosing these patients? Will there be an immune response because the eye has already been almost immunized towards this AAV [adeno-associated virus] vector? These are things we have to bear in mind. There’s also surgical iatrogenic damage that could be seen with these patients. Especially in choroideremia gene therapy trials, when you have a very small central island of potentially friable tissue, you can cause retinal stretch and thinning from a subretinal injection. There’s a lot of research being undertaken to think about other ways we can tackle these problems. There’s a company called 4D Molecular Therapeutics that has undertaken massive high throughput screens looking for evolved AAV vectors that are better at penetrating cells and targeting particular cell types, like photo receptors or RPE. They’re testing whether these vectors can be delivered through the intravitreal route, therefore avoiding subretinal injections. There’s a phase 1 clinical trial underway for choroideremia, particularly delivering the 

 gene through an intravitreal route. We’ll have to wait and see what the results show.

Dr Mariya Moosajee highlights therapies approved as well as under study to improve treatment for patients with inherited retinal disease.

Inherited Retinal Disease: Treatment Overview

 without eyedrops has long been a goal for ophthalmologists. However, whilst it may be possible one day, it is not yet a reality and anti-glaucoma drops currently remain the first-line choice for many ophthalmologists.

Numerous surgical procedures and minimally invasive devices are also available to lower intraocular pressure (IOP). Some have been around for a long time, but within the past few years, numerous devices have entered the market with unknown long-term results and there are more still in the pipeline.

Eliminating the potential land mines in glaucoma surgery

Despite great progress in the field, the question remains as to which glaucoma treatment(s) can achieve and maintain the desired IOP level and prevent progression, according to Dr Janet B. Serle, professor emeritus of ophthalmology, Icahn School of Medicine at Mount Sinai, New York, United States.

Clinicians can adhere to the general guidelines that have been established for target IOPs for different glaucoma stages, however, how well they work for individual patients remains to be seen. “For each patient, it is important to assess the risk parameters in addition to the stage of the disease,” Dr Serle said. “In some patients, we can hopefully get ahead of progression by treating the glaucoma aggressively, and in other patients we may be able to step back, accept higher target IOPs and carefully assess the most appropriate therapies.”

Many large clinical trials have evaluated specific procedures over different follow-up periods of time. The trials have generated widely varying outcomes regarding medication use and wide-ranging IOP results postoperatively. These range from no medications needed in 78% of patients followed for 3 years after selective laser trabeculoplasty (SLT)

 to studies of minimally invasive glaucoma surgeries (MIGS) and gonioscopy-assisted transluminal trabeculotomy that resulted in a wide range of medications needed postoperatively.

Dr Serle suggested that surgeons look outside the treatment box, rethink the current order by which they select treatment and determine if they should adjust that order. For example, should surgeons consider an SLT, an earlier SLT or a MIGS procedure, if appropriate, or should patients be treated more aggressively earlier in the disease process, especially in the case of young patients with potentially longer life spans? Another challenge, she pointed out, is identifying and diagnosing patients with early disease.

“I do not think it is time to abandon the traditional more invasive procedures, particularly in advanced disease, because these more consistently result in lower IOPs,” she commented.

Currently, however, although there are numerous non-medical options that are available for glaucoma management, physicians cannot now achieve successful IOP control in all patients without relying on medical therapy.

Using pivotal study data to guide glaucoma patient management decisions

Dr Serle emphasised that to manage and control glaucoma without eyedrops, there must be a more “robust” way to identify patients with glaucoma, especially those with early disease. Acceptance and incorporation of other, newer treatment options by patients and physicians should occur.

If intervention is successful, the progression curve may change, she said, and she noted the importance of demonstrating that surgical devices and procedures achieve satisfactory target IOPs for long durations during a patient’s life. The current devices meet the target IOPs in some patients, but the long-term results are unknown.

Dr Serle said that it should be a goal to reduce the medication burden as much as possible. “Physicians can think about how they select treatment,” she said. “For patients with early-stage glaucoma, consider options other than medications.”

Precision management to revolutionise glaucoma diagnosis and treatment

She added: “In moderate and late-stage disease, treatment with laser and/or MIGS and/or traditional surgery may reduce or eliminate the need for medications in some patients. For late-stage disease, more invasive surgeries may be more successful at achieving the required IOP with fewer or no medications.”

Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. 

This article is adapted from Dr Serle’s presentation at the American Glaucoma Society’s 2021 virtual annual meeting. Dr Serle is a consultant to Aerie Pharmaceuticals, Allergan, Bausch + Lomb and Qlaris.

Ophthalmologists should consider numerous options for treating individual glaucoma patients, including non-medical interventions.

Dropless glaucoma treatment: An elusive path to ease burden

When we come to the management of diabetic macular edema, the treatment options are much more diverse. Dr. Korobelnik, could you focus a little bit on anti-VEGF [vascular endothelial growth factor] therapy, steroids, implants, and combination therapy? Perhaps you could also address your opinion concerning micropulse laser treatment? Possibly as a monotherapy and in combination setting?

 I truly agree with that. For DME [diabetic macular edema], we have more options than for wet AMD [age-related macular degeneration]. Of course, we use the same VEGF inhibitors as we used in AMD. As Tunde said, we use them based on local regulation and how the drugs are covered. However, for DME we can use steroids; maybe not as a first-line treatment, it can be in some cases, but it’s definitely something that is to be considered in DME patients. As you said, we have laser treatment. Micropulse is something that is interesting, but we miss some truly demonstrative studies to be sure that it is effective. Now we also have targeted photocoagulation in [INAUDIBLE] that has been abandoned since VEGF inhibitors came. It is now able to be done precisely based on the fundus photo of the fluorescein or late ICG [indocyanine green angiography]. For DME, we definitely have the choice. Each one has to consider whether they want to do first. However, most often the first choice is VEGF inhibitors. Many patients are responding. However, depending on the patients’ response and the capacity of the patients being able to attend appointments, we may select other options. Of course, do not forget to look for, check, and control glycemia to control blood pressure. Those systemic parameters are extremely important for DME. We see some patients when their blood pressure is well controlled, their glycemia is well controlled, and things get much better.

 Can I add something to that before you ask your next question? There might be some listeners who are from countries where anti-VEGF agents are not widely available, or people need to buy them and they can’t afford them. You always should do a clinical examination and try to figure out if laser, if you have, might be useful. Some patients will be helped by laser treatment initially. If that is the case, then it’s important it is done. Additionally, laser treatment has been used in a lot of anti-VEGF and steroid trials. Sometimes it is possible to treat; to give an additional laser treatment and make sure those patients who might not be able to afford more treatment injections are able to get some benefit from that treatment as well.

 I fully agree Tunde. One very important thing to consider in diabetic patients is not to focus only on the macula but look at the periphery. You can have diabetic retinopathy, lung perfusion, and, in some cases, proliferation of new vessels. We do see from time to time in some patients that are being treated for DME, and they have proliferative disease that was underdiagnosed. You must evaluate the periphery in those patients.

 This is becoming a real issue during COVID-19 when people did not get their injections. Suddenly, they come back with bad diabetic eye disease, with rubeotic glaucoma, because it was the injection that kept it at bay. Good examination and laser treatment would be very helpful for a lot of patients still.

Anyhow, our focus for today is diabetic macular edema. I fully agree that we must look for those people as well, and we must look for systemic control and retinal periphery.

A discussion regarding the roles of various treatments available for diabetic macular edema and considerations for selecting and sequencing therapy.

Diabetic Macular Edema: Treatment Overview

I would like to move forward to the treatment of those diseases. I would like to review the current treatment landscape firstly for the management of AMD [age-related macular degeneration]. Dr. Peto, could you say a few words on patient factors which influence our treatment strategy when we consider [a] specific agent?

 Several countries have different legal allowances as to which drug you can use. It is very important that people stay within their legal framework and what has been registered in their own countries. In several countries, we have 2 or 3 drugs available for treating age-related macular degeneration. Which one you start with tends to be somewhere between personal preference or what your system allows you to do. We always need to think about the vision, potential outcomes, and potential comorbidities. If the patient has just had a stroke or heart attack, we might not be able to treat them with the agent of choice. We also need to think about how many times the patient would be able to come back to clinic. All of these need to be discussed right at the beginning, because we are likely to see the patient very often in the first year of treatment at least. We must tell them that we do not really fully understand as to who will respond very well to treatment and who might have slightly less treatment frequency in the second and third year, while others may require very frequent injections for the duration of the disease. We might have to also tell them that their vision might be going up and down depending on if they might have a hemorrhage. It is important that we warn them about all of the complications of the disease as well.

An overview of the current treatment landscape for age-related macular degeneration and factors that impact treatment selection.

Age-Related Macular Degeneration: Treatment Overview

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

Results from 5 years of follow-up show that minimally invasive 

 (MIGS) with simultaneous implantation of two trabecular microbypass stents (iStent Inject, Glaukos) combined with phacoemulsification is safe and provides durable moderate lowering of intraocular pressure (IOP). It also reduces the burden of topical ocular hypotensive medications, according to Dr Karsten Klabe.

Dr Klabe is in private practice at the Breyer, Kaymak and Klabe Eye Surgery Practice in Düsseldorf, Germany, and is a partner at the International Vision Correction Research Centre of the Heidelberg University Hospital. “A number of MIGS procedures are now available, and [although] they have shown encouraging initial results in pre-marketing clinical trials, data are needed to understand their long-term efficacy and safety,” said Dr Klabe.

Personalising glaucoma surgery: The role of MIGS

“Our experience using combined iStent Inject implantation and 

 shows that with selection of appropriate candidates, patients will rarely need further intervention for their glaucoma, and the majority can become medication-free,” he said. “Considering the latter benefit, adding the iStent Inject when patients need cataract surgery addresses the adherence issues we face when prescribing glaucoma therapies and their potential to cause ocular surface disease so that patients have a higher quality of life.”

Dr Klabe’s study of outcomes after combined cataract surgery with implantation of the iStent Inject was a retrospective review that included 164 eyes in 103 patients. The cohort had a mean age of 75.4 years and the majority were male. Primary open-angle glaucoma was the predominant diagnosis (82%) and the remaining eyes had pseudoexfoliation glaucoma (18%).

Preoperatively, the 164 eyes had a mean IOP with medication of 18.5 mmHg. The average mean deviation on the visual field was -6.19 dB MD and mean cup/disc ratio was 0.59.

Twenty-nine eyes (18%) had previously been treated with selective laser trabeculoplasty (SLT), and eight eyes had undergone previous surgery, which included placement of the Xen Gel Stent (Allergan), canaloplasty, trabeculectomy or iridotomy. All of the previous interventions were performed more than 3 months prior to the combination cataract/MIGS procedure.

Endoscopic cyclophotocoagulation adds cumulative advantage to MIGS

Of the 164 implanted eyes, 157 had 24 months of follow-up; 129, 85 and 61 eyes were seen at 26, 48 and 60 months, respectively. Mean IOP decreased to 16 mmHg at 1 month after surgery and to 15.5 mmHg at month 6, and stabilised at that level (±0.5 mmHg) for the remaining follow-up duration.

At baseline, patients were taking a mean of 1.47 medications to lower IOP (range 0–4). Throughout follow-up, no patients were taking more than two medications and the mean of medications used daily ranged from 0.17 to 0.23 without any evidence of an increase over time.

The two microstents are injected into the eye using a specially designed applicator. (Image courtesy of Dr Karsten Klabe

Highlighting the safety of the combination procedure, Dr Klabe reported that there were very few complications in the series. The majority were minor and related to the MIGS procedure. They included hyphaema in 11 eyes (6.7%), persistent hypotony (IOP < 10 mmHg for more than 1 month) in two eyes (1.2%) and iris incarceration in two eyes (1.2%). In addition, there were seven cases (4.3%) of stent occlusion.

“The cases of occlusion were observed later than 3 months after surgery and were related to implantation that was too deep,” Dr Klabe said. “It is very important to hold the injector in place without pushing it forwards during implantation. However, the introduction of the iStent [inject] with a wider flange solved the risk of over-implantation.”

Study examines pairing phacoemulsification with implantation of stents

Data regarding the need for further glaucoma surgery provided further evidence of the efficacy of the combination surgery. Over the 5 years of follow-up, only seven eyes (4.3%) underwent a second procedure: placement of the Xen Gel Stent in three eyes, implantation of the Preserflo MicroShunt (Santen) in two eyes, SLT in one eye and cyclophotocoagulation in one eye.

The two microstents are pre-loaded in a specially designed applicator in a procedure that has a short learning curve but requires minimal additional settings and instruments, according to Dr Klabe. “When combined with phacoemulsification, the glaucoma portion of the procedure can be done either prior to or after the cataract surgery, according to the surgeon’s preference,” he said.

SMILE procedure offers low enhancement rate after nomogram adjustment

Dr Klabe explained that he prefers to perform the stent implantation at the end of the surgery, noting that the deep anterior chamber offers excellent visibility and lowers the risk of iris damage. “On the other hand, the main incision in my cases is only 2.2 mm and prevents the loss of [the] ophthalmic viscosurgical device and flattening of the anterior chamber,” he said. “Use of a Vold Gonioprism (Volk Optical) with retention ring may be helpful because of the low pressure on the cornea that guarantees good visibility.”

Dr Klabe is a consultant/adviser to, study investigator for and recipient of travel stipends from Glaukos and other companies that market devices for MIGS.

Retrospective review highlights the sustained efficacy of combination procedure.

Combined MIGS and cataract surgery option offers positive results

Periodic aflibercept (Eylea; Regeneron Pharmaceuticals) treatment for moderate to severe nonproliferative diabetic retinopathy (NPDR) resulted in fewer patients developing PDR or centre-involving diabetic macular oedema (DMO), although no positive effect on visual acuity (VA) was seen, according to Raj K. Maturi, MD, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, who reported the interim 2-year results of the DRCR Retina Network Protocol W study.

“Eyes with moderate to severe NPDR are at high risk for disease progression and development of vision-threatening complications,” Maturi stated, underscoring the importance of determining whether aflibercept prevents development of PDR and centre-involved DMO as well as the potential for a visual benefit at the later 4-year point.

Protocol W is a randomised multicentre clinical trial of adults with type 1 or 2 diabetes and severe NPDR in at least 1 eye. Included patients had no evidence of neovascularisation on fluorescein angiography and a best-corrected VA letter score of 79 or higher, ie Snellen acuity of 20/25 or better. Patients were randomly assigned to receive either 2 mg of periodically administered intravitreous aflibercept or sham injection. Monthly injections were administered for the first 3 visits and followed by injections at months 4, 8 and 12. Before 2 years, injections were administered at each visit, with subsequent treatment with aflibercept only if the diabetic retinopathy exceeded mild NPDR.

Evaluating patients for a retinal disorder (video)

The primary outcome was the cumulative probability of development of PDR or centre-involving DMO with vision loss. Treatment was deferred if the eye had no worse than mild NPDR. Aflibercept was administered in both groups if centre-involving DMO with vision loss or high-risk PDR developed.

A total of 399 eyes of 328 patients were included (mean age, 56 years), all of whom had moderate to severe NPDR. Of these, 200 were randomised to aflibercept and 199 to sham treatment; data from all these patients were included in the primary analysis.

At 2 years, more patients randomised to sham therapy developed DMO or PDR compared with those randomised to aflibercept (44% vs 16%, respectively; adjusted HR, 0.32; P < .001), Maturi reported.

The time to development of PDR was 33% in the sham group and 14% in the aflibercept group. The time to development of DMO was 15% in the sham group and 4% in the aflibercept group. “The criteria for the development of the first PDR and/or DMO [were] met in 35 patients in the aflibercept group and 81 patients in the sham group,” Maturi said.

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Most patients in both groups developed neovascularisation of the disc and/or neovascularisation elsewhere, 4 patients in each group developed vitreous haemorrhage and 1 patient in the sham group developed neovascularisation of the iris compared with no patients in the aflibercept group.

VEGF therapy was administered to 3 patients in each group, and focal or grid laser for DMO was administered in 1 patient in the sham group.

Analysis conducted to determine a correlation between the baseline NPDR severity and development of DMO or PDR indicated a definite relationship based on more severe disease.

“Among patients with the lowest levels of NPDR, only 3% in the aflibercept group went on to develop DMO or PDR compared with 24% in the sham group,” Maturi said. “Among patients with severe NPDR, 36% went on to develop DMO or PDR in the aflibercept group, and 68% did so in the sham group despite regular treatments.”

Analysis of the change in the severity of diabetic retinopathy at 2 years showed that 5% of patients in the aflibercept group had a 2-step worsening of disease compared with 12% in the sham group. Regarding improvement, 45% of patients in the aflibercept group had a 2-step or greater improvement compared with 14% in the sham group.

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Comparison of the 2 treatment groups showed almost no difference in adjusted mean VA over 2 years. The central subfield thickness improved slightly and nonsignificantly by –6 microns in the aflibercept group and –1 micron in the sham group.

About 5 injections of aflibercept were administered for DMO and 0.3 in the sham group; over 2 years, the aflibercept patients received 8 injections and the sham-treated patients received 1.1 injections.

Adverse events associated with aflibercept included 3 cases of endophthalmitis, 2 of retinal detachment, 13 of IOP spikes of 10 mm Hg or higher and 8 of IOP elevations of 30 mm Hg or higher. In the sham group, 2 patients had retinal detachments, 12 had IOP spikes of 10 mm Hg or higher and 3 had IOP spikes of 30 mm Hg or higher.

Common types of retinal disorders explored (video)

Hypertension was the systemic event seen in more patients, with 18 in the aflibercept cohort and 13 in the sham group.

The major study findings indicated that among eyes with moderate to severe NPDR, the proportion that developed PDR or centre-involving DMO was lower with periodic aflibercept treatments compared with sham treatment through the 2-year point. Preventive treatment with aflibercept did not confer a VA benefit compared with anti-VEGF initiated after PDR or DMO development.

Maturi pointed out that this 4-year study may be important to determine whether preventing PDR and centre-involved DMO improves the long-term outcomes.

This article was adapted from Maturi’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

The proportion of eyes that developed PDR or centre-involving DMO was lower with periodic aflibercept treatments compared with sham treatment through the 2-year point.

Study evaluates periodic aflibercept injections in NPDR treatment

 We all agree that we also have to focus on longer injection intervals and less treatment burden for the physician, the patient, and their caregivers. In addition, we need to modify the drug-delivery systems, which may help us prolong the administration intervals. This means we need to focus on pharmacokinetics, immunogenicity, biodegradation, tolerability and toxicity. Dr Peto, what are some of the technological requirements that could be considered when we should give or can give advice to the manufacturer? Of course, we have to focus on clinical performance and stability as well.

 In terms of the drugs, ideally it doesn’t have to be injected as often as we have to do it at the moment; it’s well-tolerated, sterile, and doesn’t cause any inflammation or infection; it can’t get into the eye; and it’s durable. What we’d like to achieve would be to have some biomarkers at the beginning when we see the patient; therefore, we’d know which drug will work and why we should give it to a patient. We haven’t gotten as far as some of the inherited retinal diseases people have. Looking at the genes, they’d be able to say if a treatment is likely to work. Unfortunately in AMD [age-related macular degeneration] and in diabetes, we don’t have that. We’d like to be able to take a history, do a genetic test, take a liquid biopsy from the anterior chamber and from the aqueous humor, and characterize that patient to the point where we can say, “From the armament of the drugs we can choose, these are likely to work for you.” We are unfortunately not there, but if we had the right choice of drug that we can give them, it would mean that both ourselves and the patients could be much better treated and much better looked after.

Following a discussion regarding drug delivery challenges in retinal disease, a panel of global experts suggest what types of technological requirements and improvements they would like to see occur in the field.

Combined MIGS and cataract surgery option offers positive results

Study evaluates periodic aflibercept injections in NPDR treatment

Addressing Drug Delivery Gaps in Retinal Disease