Improving Diabetic Retinopathy Treatment

As it turns out, food coloring does not improve eyesight . . . but it might cause rubber ducks to change color.

by Tan Sher Lynn

Caused by microvascular damage to the retina, diabetic retinopathy (DR) is a common manifestation of diabetes mellitus. Thankfully, its course can be altered with anti-vascular endothelial growth factor (anti-VEGF) therapy. In a series of Satellite Symposia at the virtual American Society of Retina Specialists 38 th Annual Scientific Meeting (ASRS 2020), a panel of three retinal experts discussed the efficacy of anti-VEGF therapies in reducing the severity of DR and their potential to reverse disease progression in a session titled, Exercising Trial and Error to Improve the Treatment of Diabetic Retinopathy.

Treating DR: What to look for

Dr. Dilsher Dhoot, vitreoretinal surgeon at California Retina Consultants in California, USA, noted that DR is now the most common cause of severe vision loss in the United States, affecting 9.4% of the population (or 30.3 million people), while diabetes is also the seventh leading cause of death in the country, as is reported by the Centers for Disease Control and Prevention (CDC).

“Until now, the current algorithm for proliferative diabetic retinopathy (PDR) is to wait for DR severity to progress until frank neovascularization is observed. DR progresses in discrete levels, as described by the ETDRS severity scale,” he noted.

Current modalities of treatment for DR include: panretinal photocoagulation (PRP), anti-VEGF therapy, and combined PRP and anti-VEGF therapy.

Dr. Charles Wykoff, medical and surgical retinal specialist at the Retina Consultants of Houston, Texas, USA, said he would “try to get the best of both worlds” when it comes to treating eyes with PDR. “There is a really important role for lasers in my clinic. PRP has a durable effect which I find invaluable. While I am still doing PRP on most eyes with DR, I tend to put anti-VEGF to “quiet down” the eye before proceeding with an anteriorly directed laser pathway,” he said.

Dr. W. Lloyd Clark from the Palmetto Retina Center in South Carolina, USA, agreed with Dr. Wykoff, noting that applying anti-VEGF medication before laser therapy tends to make the treatment smoother.

Subsequently, Dr. Dhoot presented data which showed that the risk of progression to PDR increases with non-proliferative diabetic retinopathy (NPDR) severity. He said: “We can see that 51% of patients with severe NPDR progresses to PDR in one year. Diabetic macular edema (DME) can occur at any stage but it is more common as DR severity increases.”

Showcasing data from the RIDE/RISE clinical trials (which studied intravitreal ranibizumab injections in subjects with clinically significant centerinvolved macular edema secondary to diabetes mellitus), Dr. Dhoot said that at month 24, over a third of the patients had a 2-step improvement from baseline, with 9% of patients (RISE) and 17% patients (RIDE) having a 3-step improvement from baseline. “These are significant improvements compared with patients in the sham group,” he said, noting that the improvement was noticeable very early on, as between 15-19% of patients had a 2-step improvement at 3 months.

“Based on the large body of data, we can establish that patients at level 47 and 53 are really the ones that benefit the most with VEGF suppression,” Dr. Dhoot concluded.

Data from the studies showed that at 2 years, sham-treated patients with moderately severe/severe NPDR at baseline were 6 times more likely to worsen to PDR. In patients with baseline DR levels of 47/53, the proportion of sham-treated patients who progressed to PDR as assessed by the ETDRS DRSS (DRSS level >60) increased over time from 2.3% at month 3 to 18.6% at month 24. In contrast, 0% and 2.7% of patients treated with ranibizumab (0.3 mg and 0.5 mg, respectively) progressed to PDR at month 24.

“The study shows that ranibizumab (RBZ) treatment delayed the time to a new proliferative event and reduced the probability of a patient experiencing a new proliferative event by 3 times compared with sham treatment. It also shows that 12.4% patients who received RBZ 0.3 mg and 11.9% of patients who received RBZ 0.5 mg encountered a new proliferative event at 36 months,” said Dr. Dhoot.

Adding to that, Dr. Wykoff said that anti-VEGF treatment is not a cure

for DR, even if it works really well in suppressing its progression, improving DME and stopping the leakage. “Some eyes will progress and we need to be careful of that. To give an injection every few months indefinitely is a huge burden. In an ideal world, I would treat all eyes with moderate and severe DR to slow their progression, but it is an invasive procedure with risks and costs. So it is an individual choice,” he explained.

Dr. Wykoff added that the biggest challenge in treating DR is to be able to catch it during the stage when it is asymptomatic. “So many patients and practitioners thought that if there aren’t any noticeable symptoms and blurriness, things must be fine. We got to break away from that false perception. This is a disease which does not necessarily lead to blindness. We can slow it down. This is a disease which we are really good at treating (as a field) as long as we can get the patients in early and treat them appropriately,” he emphasized.

Meanwhile, Dr. Lloyd stressed the importance of treating the “right” patient. “From this data, we know that patients with level 53 retinopathy are excellent candidates for treatment. But when the DR severity is reduced, the ROI in terms of treatment is very, very low. So, the key is to know who you are treating and to pick the right patients,” he explained.

Optimizing DR treatment: The future is now

The panel then discussed optimizing DR treatment, as Dr. Charles Wykoff presented data from the PANORAMA trial, a phase 3, double-masked, randomized study of the efficacy and safety of intravitreal aflibercept in 402 eyes with moderate to severe NPDR (DRSS level 47 and 53). The objective of the trial was to demonstrate 2-step improvement for the use of aflibercept in DR, and to achieve regulatory approval. It involved 2 different dosing [levels], with the primary endpoint at 6 months and 1 year.

Results show that the proportion of patients with ≥2-step DRSS improvement was significantly greater with aflibercept compared to sham. “In the 2q16 fixed-dose group, there’s stability of 2-step improvement in about two-thirds of eyes, while in the 2q8>PRN population, there’s up to 80% of eyes that achieved 2-step improvement up to 1 year. Moving to the second year, we see stability for the 2q16 group, which is an important clinical take-home point — fixed quarterly dosing maintains that level of improvement,” he said.

“In year 2, none of the patients in the 2q8>PRN group who received 3 to 6 injections developed proliferative disease or central-involved DME. This suggested that consistent, long-term dosing probably slows the disease progression. Meanwhile, 57.7% of eyes in the sham population developed vision threatening complication (VTC) or central-involved DME. There is a 75% reduction of risk in the aflibercepttreated population. Unfortunately, even with aflibercept treatment, we are still seeing disease progression in approximately 1 in 5 patients.”

The doctors agreed that the PANORAMA datasets are excellent for facilitating discussion with patients, and are helpful in convincing them that antiVEGF treatment is a reasonable choice for the treatment of DR.

Factors that increase the need for anti-VEGF treatment

DRCR.net Protocol V is the only trial in the modern era studying well-sighted eyes with central-involved DME in three different treatment paradigms: aflibercept; FLT plus deferred aflibercept; and observation plus deferred aflibercept. Primary outcomes at 2 years show that there were no significant differences between the three treatment modalities.

“The baseline factors associated with receiving aflibercept dosing, which is central subfield thickness, DRSS and fellow eye treatment. These factors were put into multivariable modelling and all three maintain significance. Looking at the dose-response at each category, we can see that thicker retinas correlated with an increased rate of needing aflibercept dosing. “In summary, among eyes with centerinvolved DME and good central VA, clinical factors associated with an increased probability of needing treatment are: more advanced DR severity, greater amount of DME and fellow eye treatment of DME,” said Dr. Wykoff.

VEGF is not the sole cause of DR

In the final discussion, Dr. Wykoff talked about 5-year outcomes after initial aflibercept, bevacizumab or ranibizumab treatment for DME (Protocol T Extension Study).

“Following the 2-year core trial where patients are treated as SOC, single visits are made at 5 years after Protocol T enrollment, 4 visits were made annually in years 3 to 5, with 32% of patients receiving no anti-VEGF injections and 68% receiving at least 1 injection. The average is 4 anti-VEGF injections over 3 years,” he said.

“On average, there was a 5-letter loss from years 2 to 5. This VA loss was observed in both patients with better vision at baseline, as well as worse vision at baseline. Nevertheless, the anatomy was relatively stable from year 2 to 5, suggesting that DME was not the reason for vision loss. We also saw that the DRSS was relatively stable, with worsening of the more severe levels of DR,” explained Dr. Wykoff.

Thanks to the large dataset, the doctors came to the conclusion that VEGF is not the sole cause of DR and DME. Other factors, like the neurodegenerative pathway of DR, can play a part in the worsening of VA.

Editor’s Note:

This satellite symposium at ASRS 2020 was held on 3 rd August 2020. Reporting for this story also took place during the session.

INDUSTRY UPDATE

AI-based OCT Analysis Shows Superiority Over Retina Specialists

Big news for machine learning: Data analysis from AREDS 2 shows that the Notal OCT Analyzer (NOA;

Notal Vision, Manassas, Virginia, USA), demonstrates superior performance to identify, quantify and map intra- and subretinal fluid in nAMD, as well as a higher level of accuracy compared to retinal specialists (who had imperfect accuracy and low sensitivity in detecting retinal fluid).

“The study results show how challenging it is to identify fluid especially when it is not very obvious,” said Michael Elman, MD, a co-author of the article. “In many cases, the fluid that was missed was clinically meaningful. The analysis points at the potential benefit of an AI-assisted image review in routine clinical care when the time is limited.”

NOA had significantly higher sensitivity than retinal specialists (82.2% vs. 46.8%, respectively), with only moderately lower specificity (86.5% vs. 97.0%, respectively). This showed that retina specialists correctly identified retinal fluid in fewer than half of the cases. The substantially higher sensitivity of NOA is an important advantage, since the NOA-generated fluid thickness heatmaps drew the physician’s attention to areas of fluid that otherwise might have been missed during volume scan review.

“AI-based software could assist physicians in detecting retinal fluid and informing patient management and treatment decisions once confronted with large amounts of images from patients regularly self-imaging on a future homebased OCT device,” said Gidi Benyamini, Notal Vision’s chief technology officer and director of the Notal Vision Innovation Center.

INDUSTRY UPDATE

DOG Celebrates “Father of Modern Ophthalmology” Albrecht von Graefe

The 150-year anniversary of the death of famous Berlin ophthalmologist Albrecht von Graefe was recently commemorated in a wreath-laying ceremony by the society he founded in 1857: the Deutsche Ophthalmologische Gesellschaft (DOG; German Society of Ophthalmologists). Considered to be the “father of modern ophthalmology,” Dr. von Graefe died at the young age of 42 from tuberculosis in 1870.

Among his contributions to ophthalmology, he was the first to describe numerous eye diseases and make considerable progress in ophthalmic surgery, by developing iridectomy to reduce intraocular pressure (IOP) in glaucoma patients. He also developed a cataract surgery technique using the Graefe knife, which was used until the second half of the 20th century.

Today, he continues to receive praise as a “role model in medical and moral terms,” according to DOG President Prof. Dr. Hans Hoerauf.

“We should remember von Graefe´s principles, which emphasized empathic medical work for the benefit of the patient and the transfer of knowledge and skills to his many students,” said Prof. Dr. Hoerauf. “He teaches us not to be discouraged by difficult conditions, but to gain motivation from the joy of ophthalmological work and research, to maintain our own independence, and to consistently pursue our own ideals.” Throughout his lifetime, Dr. von Graefe was committed to serving the socially or economically disadvantaged. From 1851- 1852, he set up a private eye clinic in Berlin, which soon became world famous.

“It was always important for von Graefe to balance between socially underprivileged and wealthier patients,” said Prof. Dr. Hoerauf. “The income from the private clinic served also for the free treatment of destitute patients.”

Berlin commemorates Albrecht von Graefe with several memorial sites, most important the von Graefe memorial at the Charité Clinic. Further, the DOG has proclaimed 2020 as “von Graefe Year.”

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TRY DIFFERENT LETTERS IN YOUR PRESCRIPTION FOR DMEDME

DME, diabetic macular edema; OCT, optical coherence tomography. 1. Nehmé A and Edelman J. Invest Ophthalmol Vis Sci 2008;49(5):2030–2038. 2. Holekamp N. The role of corticosteroid implants in DME. Available at: http://retinatoday.com/ 2015/04/the-role-of-corticosteroid-implants-in-dme. Accessed March 2020. 3. Campochiario PA et al. Am J Ophthalmol 2016;168:13–23. 4. Malclès A et al. Retina 2017;37(4):753–760. 5. Matonti F et al. Eur J Ophthamol 2016;26(5):454–459. 6. Aknin I and Melki L. Ophthalmolgica 2016;235:187–188. 7. Allergan. OZURDEX ® . Summary of Product Characteristics. October 2019. 8. Boyer SB et al. Ophthalmology 2014;121(10):1904–1914.

INDICATIONS & USAGE: OZURDEX® contains a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO), for the treatment of non-infectious uveitis affecting the posterior segment of the eye, and for the treatment of patients with visual impairment due to diabetic macular edema (DME) who are pseudophakic or who are considered insu ciently responsive to, or unsuitable for non-corticosteroid therapy. DOSAGE & ADMINISTRATION: For ophthalmic intravitreal injection only. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. DOSAGE FORMS & STRENGTHS: Intravitreal implant containing dexamethasone 0.7 mg in the NOVADUR™ solid polymer

drug delivery system. CONTRAINDICATIONS: Ocular or periocular infections. Advanced glaucoma. Aphakic eyes with ruptured posterior lens capsule. Eyes with ACIOL, iris or transscleral  xated IOLs and rupture of the posterior lens capsule. Hypersensitivity. WARNINGS AND PRECAUTIONS: Intravitreal injections have been associated with endophthalmitis, eye in ammation, increased intraocular pressure, retinal detachments, and implant migration into the anterior chamber. Patients should be monitored following the injection. Patients who has a tear in the posterior lens capsule (e.g., due to cataract surgery), or who had an iris opening to the vitreous cavity (e.g., due to iridectomy) are at risk of implant migration into the anterior chamber. Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance establishment of secondary ocular infections due to bacteria, fungi,

or virus. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. ADVERSE REACTIONS: In controlled studies, the most common adverse reactions reported by 20–70% of patients were cataract, increased intraocular pressure and conjunctival haemorrhage.

Licenses may vary by country, please consult your local Summary of Product Characteristics. Adverse events should be reported to your Ministry of Health and local Allergan o ce. Date of preparation: March 2020 INT-OZU-2050060

OZURDEX ® is not licensed for use in DME in China.