DRCR Protocol V: Eylea vs Laser or Observation
Study finds no clear advantage for anti-VEGF.
■ Data from the DRCR Protocol V study, led by Carl W. Baker, MD, and presented at the 2019 Association for Research in Vision and Ophthalmology (ARVO) meeting, showed little difference in outcomes at year 2 in patients with center-involved DME and good baseline vision (20/25 or better) who were initially managed with either aflibercept (Eylea; Regeneron), laser, or observation. In this randomized clinical trial encompassing an initial 702 eyes, a 5-letter or more decrease in visual acuity at 2 years was not significantly different between groups initially managed with aflibercept (16%), laser photocoagulation (17%), and observation (19%). Eylea was added for the laser photocoagulation and observation cohorts if vision worsened. For eyes with visual acuity that worsened from baseline, aflibercept was started in 25% (60/240) and 34% (80/326) in the laser photocoagulation and observation groups, respectively.
In commenting on the Protocol V findings, Tunde Peto, MD, PhD, and Usha Chakravarthy, MD, PhD, of Queens University of Belfast, UK, caution that a rush to initiate anti-VEGF in these patients can be problematic.
“What Protocol V has not addressed is the effect of the 3 regimens on the patient’s quality of life,” they write. “It is important to understand the effect of the visit schedules, which differed between groups, and the challenge of frequent visits and injections in the prompt aflibercept therapy group, given that those with diabetes already have systemic comorbidities that often contribute to a burden of hospital visits. Prompt initiation of treatment with aflibercept almost certainly results in considerable excess costs, which, if implemented into routine clinical practice, would add to the strain and burden on the patient and overstretched health economies.”
They continue that participants in Protocol V had good control of diabetes and blood pressure, were carefully monitored, and may not reflect the profile of patients with diabetes in routine care. Moreover, real-world data from patients with good baseline VA demonstrated that VA is maintained in untreated eyes with DME over 1 year.
“Findings from Protocol V now give us the confidence to manage patients with DME and good VA conservatively, at least until there is documented reduction in VA,” conclude Drs. Peto and Chakravarthy.
Growing Interest in Plasma Kallikrein Inhibitors
Verseon joins companies pursuing the concept.
■ Another company has joined the ranks of those exploring the potential of plasma kallikrein inhibition as a therapy for diabetic retinal disease. These already include KalVista and Oxurion, which are currently in clinical trials for the treatment of diabetic macular edema (DME), and Rezolute, which is in a preclinical stage.
Plasma kallikrein, an enzyme, is an important component of the body’s inflammatory response and in excess can lead to increased vascular permeability, edema, and inflammation. The latest entrant is Verseon, which has developed a new class of selective small-molecule plasma kallikrein inhibitors for the treatment of DME. In contrast to current customary DME treatments administered as recurring eye injections, Verseon develops drug candidates for oral dosing. The company says several lead candidates have demonstrated efficacy in reducing retinal thickening and retinal leakage, 2 hallmarks of the disease, when administered orally. The company is currently preparing a first DME development candidate for phase 1 trials.
At the 2019 ARVO meeting, Melissa Calton, PhD, Verseon’s ophthalmology program manager, presented preclinical data for the company’s lead development candidate for clinical trials from their new class of plasma kallikrein inhibitors. In preclinical models, the compound showed good efficacy against 2 important drivers of the disease — the kallikrein and VEGF pathways — following administration of a single oral dose.
Meanwhile, KalVista reported at the recent ARVO meeting that 2 of the company’s novel, orally administered plasma kallikrein inhibitors, KV998052 and KV998054, significantly reduced VEGF-stimulated retinal edema in mice. Both compounds provided protection of plasma kallikrein-mediated cleavage of high-molecular-weight kininogen.
Retinal Detachment Handoff Is No Problem
Diagnosing physician need not perform the procedure.
■ Researchers at the University of Wisconsin, led by vitreoretinal fellow Zackery Oakey, MD, set out to determine whether there was any appreciable difference in outcomes between rhegmatogenous retinal detachment (RRD) surgery performed by the diagnosing physician and RRD surgery performed by a surgeon who was not the diagnosing physician. Retrospective chart review was conducted for patients age 18 and older with minimum 2 months of follow-up who had surgery for RRD from 2012 to 2017. Patients were ineligible if they had other ocular disease that may have affected the repair outcome.
Outcomes compared primary anatomic success (PAS), visual acuity at diagnosis, final acuity, presence of proliferative vitreoretinopathy (PVR) before surgery, macular and lens status, gender, and days follow-up. The researchers recorded if the patient underwent surgery by the diagnosing physician or by a referred physician within the University of Wisconsin practice.
A total of 343 cases met the inclusion criteria, with 137 in the same surgeon group and 206 in the different surgeon group. Primary anatomic success was no different between the 2 groups. Preoperative and postoperative visual acuity was also very similar, even when stratifying for lens and macula status. Follow-up duration did not differ, as did preoperative PVR. There was one statistically significant difference between the 2 groups: the time from diagnosis to surgery, with those treated by a different surgeon having less time to surgery (mean 2.91 days) than those in the same surgeon cohort (mean 5.15 days).
The researchers, who presented their findings at the recent ARVO meeting, concluded that both the same and different surgeon groups did not demonstrate a difference in preoperative PVR, visual acuity, gender, or lens or macula status. These results suggest that it is safe for patients to undergo RRD repair without preoperative clinic assessment by the operating surgeon.
Wet AMD Does Not Appear to Affect Life Span
Long-term vision loss, but no increase in mortality.
■ A study initiated by the Princess Alexandra Eye Pavilion in Edinburgh, United Kingdom, found that while wet AMD treated PRN was responsible for a significant long-term decline in vision, it did not have an effect on mortality. In this study, presented at the recent ARVO meeting, 232 eyes from 229 patients with wet AMD were included. Average annual mortality rate over the 10-year period was 4.7%. This compared with a national mortality rate of 7.5% for people older than 75 years. The average age at presentation was 77 and average age of death in the study cohort was 88.2. The most common causes of death were malignancy (36.2%) and circulatory disease (32.5%).
Following PRN anti-VEGF therapy (mean 84 months), there was a mean loss of vision of 33 letters in BCVA. Average BCVA at presentation was 59 ETDRS letters, and average BCVA at last clinic follow-up was 26 ETDRS letters. Patients received a mean of 2.3 injections a year. Approximately 21% of patients were discharged from clinic, 31% were still undergoing treatment, and 23.1% were registered blind.
The researchers found that this study highlights the long-term poor prognosis of wet AMD with this protocol of PRN anti-VEGF treatment. The mortality rate for the cohort appeared to be lower than the average national mortality rate. BCVA outcomes are likely worse than other long-term studies because of the reactive PRN treatment regimen in place in this unit and the relatively low number of anti-VEGF injections per patient per year.
IN BRIEF
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
FDA Approves Eylea for Diabetic Retinopathy
■ The FDA has approved Eylea (aflibercept; Regeneron) to treat all stages of diabetic retinopathy (DR), following earlier approvals for wet AMD, DME, and macular edema following retinal vein occlusion.
“Millions of people have been robbed of their vision due to the progression of diabetic retinopathy,” said David Brown, MD, FACS, an investigator for the pivotal PANORAMA trial and director of research at Retina Consultants of Houston. “The prevention of worsening diabetic retinopathy with EYLEA provides a compelling rationale for early treatment of patients with this disease, particularly since eyes dosed with Eylea as infrequently as every 16 weeks showed significant improvements in the pivotal PANORAMA trial.”
“With this FDA approval, Eylea has once again set a high bar for the treatment of diabetic eye diseases. The PANORAMA trial showed that by 1 year, 20% of untreated patients developed proliferative diabetic eye disease, and Eylea reduced this risk by 85% to 88% when administered using an every 16-week or 8-week dosing regimen, respectively,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron. “In fact, 80% of patients who received the Eylea 8-week dosing regimen had significant improvement in their diabetic retinopathy.”
Eylea is the only VEGF inhibitor approved with 2 dosing options for DR, allowing physicians to customize treatment to their patients’ needs. In DR, Eylea may be dosed every 8 weeks following 5 initial monthly injections, or every 4 weeks.
Early “Real World” Luxturna Results for IRD
■ Researchers at Mass Eye and Ear reported their first post-approval results with Luxturna (Spark Therapeutics) for the treatment of RPE65-mediated retinal dystrophy. They presented their data at the recent ARVO meeting.
Eight eyes of 4 patients with biallelic mutations in RPE65 (ages 13-34, visual acuity 20/50 to light perception) underwent bilateral subretinal injections of Luxturna at Massachusetts Eye and Ear. Pretreatment and post-treatment testing included visual acuity, full-field light sensitivity threshold, contrast sensitivity, reading speed, Humphrey visual field mean deviation, Goldmann perimetry, ERG, OCT, and autofluorescence.
Following injections of Luxturna, full-field light sensitivity threshold improved in all eyes tested (median change 2.3 logs, range 0.7-2.9 logs), including an eye with light perception vision that improved 2.1 logs. Visual acuity and visual field mean deviation either stabilized or improved in all eyes tested. All 4 patients tolerated the treatment well and with no complications.
Researchers concluded that the data confirm that Luxturna improves light sensitivity in patients with RPE65-mediated retinal dystrophy over a broad range of disease severity. The magnitude of the effect did vary in individual patients and may be associated with patient-specific factors such as age and baseline visual function.
Many AMD Patients Overestimate Their Vision Deficit
■ In a study initiated by researchers at the Duke University School of Medicine, AMD patients were asked to estimate their visual acuity on a scale of 0 (blind) to 5 (excellent). Of 56 participants with AMD, 21 (38%) displayed a discrepancy between visual acuity and self-reported vision and of those, 19 (90.5%) reported vision worse than their visual acuity. Discrepant and nondiscrepant participants did not significantly differ based on age, gender, race, years of education, depression score, cognition or AMD type (wet vs dry).
The researchers, who presented their findings at the recent ARVO meeting, concluded that future research is needed to investigate other potential contributors to this discrepancy, such as near visual acuity, timing and course of visual changes, and patient expectations.
The Value of Povidone-Iodine Prophylaxis
■ A UK study of 10,825 intravitreal injections found that patients who had no or reduced preoperative povidone-iodine prophylaxis were at greater risk for endophthalmitis (1 in 200 injections) than patients who received full-strength povidone-iodine prophylaxis (1 in 2,500 injections). The researchers, who presented their findings at the recent ARVO meeting, recommended that practitioners find prophylactic alternatives to patients with povidone-iodine sensitivity.
Gender Differences in Retinal Detachment Repair
■ Researchers at Stanford University’s Byers Eye Institute hypothesized that women have lower rates of rhegmatogenous retinal detachment (RRD) repair and that surgical intervention is often delayed compared to men. To test their theory using a large-scale private payer claims base, they identified 21,807 documented RRD patients over a 9-year period: 9,600 women (44%) and 12,207 men (56%). Any surgical intervention occurred in 11,513 (53%).
There was a statistically significant gender difference in the rate of surgical intervention for RRD, with 48% of women receiving any surgery compared to 57% of men. The time from diagnosis to surgical intervention was longer for women compared to men. Among patients who received RRD surgical intervention, 59% received repeat surgical intervention within 3 months. There was no significant difference in the rate (60% women, 59% men) or time to secondary surgical intervention.
The researchers, who presented their findings at the recent ARVO meeting, concluded that in a broad commercial claims database, women were less likely than men to have surgery for RRD and that for women, intervention was more often delayed than for men. The reason for this gender difference remains poorly understood and requires further investigation.
Managing Wet AMD via a Telemedicine Program
■ Researchers from the Mayo Clinic set out to determine the success of a program that uses telemedicine to treat wet AMD patients in rural areas of Minnesota.
“This is an ongoing program,” said Sophie Bakri, MD, one of the researchers. “It is designed to make sure that the original diagnosis and decision to inject — and which medication and which paradigm is made by the retina specialist. After that, the general ophthalmologist can do the injections according to the request of the retina specialist.”
The researchers examined all patients with wet AMD who were receiving intravitreal anti-VEGF injections from September 1, 2015, through August 31, 2017, using electronic consults at a single academic center and health system. There were 200 electronic consults placed during this time period for 83 eyes of 59 patients. Data collected included the retina specialist recommendations: intravitreal agent, interval between injections, number of injections, and when the patient was to follow up. There were 14 (7.1%) consults that did not comply with the recommendations of the retina specialist. The majority of these were due to other medical comorbidities leading to missed appointments or scheduling errors.
The researchers, who reported their findings in the American Journal of Ophthalmology, concluded that in an integrated health care setting, patients with wet AMD were able to be effectively managed using a telemedicine system. They believe that in an appropriate setting, telemedicine could assist in the management of patients with wet AMD.
Eyenuk Launches 2-Step DR Screening Program
■ Eyenuk has launched the EyeScreen Human + AI Diagnostic Service for DR, which combines the proven accuracy of AI disease detection with expert human grading. The service connects primary care and diabetes care clinics with eye care specialists and is designed to increase access to DR screening, reduce wait times, and improve patient compliance with receiving necessary screenings. By offering DR screening in clinic, Eyenuk says any physician can identify silently progressing DR sooner and begin intervention faster, thus improving patient outcomes and reducing the incidence of vision loss due to DR.
Eyenuk says the EyeScreen service is a novel approach to disease detection that utilizes independent, unbiased interpretation by a human expert and a validated autonomous AI system that does not rely on humans interpreting complex assistive AI reports. After the retinal images are independently assessed by both the AI disease detection system and specialist human graders separately, an ICD-10 compliant report is sent to the physician. In the event that the AI and human graders disagree, the images are adjudicated by another experienced human expert.
Time to Failure in Retinal Detachment Surgery
■ Australian researchers set out to determine how much time needs to pass before retinal detachment surgery can be considered successful. The researchers studied 188 retinal detachment failures (both oil-filled and non-oil-filled) and found that the average time for oil-filled failure was 25 days and the average time for non-oil-filled failure was 28 days, calculated from date of surgery to date of failure. Overall, the researchers, who presented their findings at the recent ARVO meeting, concluded that if a surgery passed 4 months without failing, it could be considered a success, as eyes discharged at 4 months have a less than 1% chance of subsequently detaching.
Aerie to Conduct Trial for Its Sustained-Release Therapy
■ Aerie Pharmaceuticals said the IND for its sustained-release AR-13503 implant, a novel multikinase (Rho kinase/protein kinase C [ROCK/PKC]) inhibitor, is now in effect, allowing Aerie to initiate human studies in the treatment of wet AMD and DME. Aerie expects to initiate a first-in-human clinical study in 2019.
The AR-13503 implant is a bioerodible polyesteramide polymer implant that provides controlled release of AR-13503 over a sustained period. It is designed to be administered approximately once every 6 months by intravitreal injection. Preclinical studies suggest that AR-13503 has the potential to inhibit angiogenesis, preserve the blood–retinal barrier, and reduce retinal fibrosis in retinal diseases such as wet AMD and DME, while potentially reducing the treatment burden associated with more frequent intravitreal injections.
“While the standard-of-care anti-VEGF therapies are effective for many patients with wet AMD and DME, there are many patients who do not respond adequately to these therapies or who lose their initial gains in vision over time,” said Vicente Anido Jr., PhD, chairman and CEO, in a news release. “By targeting multiple disease processes that underlie progression in these common, sight-threatening retinal diseases, our research suggests that ROCK/PKC inhibitors such as AR-13503 may prove useful as alternative or additive therapies to the currently available treatments.” RP
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