Anti-VEGF Advancements Take Center Stage at AAO 2022

Plastics, penicillin, and the microwave oven were all accidental inventions, discovered in pursuit of different outcomes, that have nonetheless gone on to change society. Less pervasive, but with no small impact of its own, anti-vascular endothelial growth factor (VEGF) drugs were not initially designed for the treatment of ocular disease. Although it was known that VEGF plays a role in ocular neovascularization, the first anti-VEGF therapeutic was indicated for use in treating colon cancer. That product, bevacizumab, is still off-label for the use of ocular disease. But a number of new options designed specifically for retinal diseases — such as neovascular age-related macular degeneration (wet AMD) and diabetic macular edema (DME) — have since come along, and with them, new findings, advanced delivery options, and reductions to the necessary dosing schedule of these potentially vision-preserving therapeutics.¹

Research on the use of anti-VEGF drugs in ocular disease now fills the pages of ophthalmic research journals and provides hours of education for conferences. At the American Academy of Ophthalmology (AAO) 2022, held in Chicago September 29 to October 3, poster presenters and session speakers alike explained how these drugs influence the practice of ophthalmology, the imaginations of researchers, and, most importantly, patients’ vision.

Patient Burdens of Intravitreal Injections

The need for frequent injections is a detractor, potentially driving patients out of treatment, explained Carl Regillo, MD, of the Wills Eye Hospital in Philadelphia, who spoke on behalf of the ARCHWAY (ClinicalTrials.gov Identifier: NCT03677934) study during the neovascular age-related macular degeneration (AMD) portion of the retina subspecialty day at the AAO 2022.² 

“Everyone is aware of the poor long-term visual outcomes in neovascular AMD treatment, and we know that there are multiple reasons for this. But, among the main reasons, are the limited durability of our standard of care biologics, and the need for frequent treatments, which is difficult for our patients to adhere to over time,” Dr Regillo said.² 

Research has taken a 2-pronged approach to this issue: First, several trials are evaluating new drug options that could reduce the frequency of necessary injections. Second, clinical investigators are reviewing patients who have been implanted with a device that could deliver established anti-VEGF therapeutics but replace the need for frequent intravitreal injections. 

Extended Dosing Possibilities in Wet AMD

In 2019, 2 studies, TENAYA (ClinicalTrials.gov Identifier: NCT03823287) and LUCERNE (ClinicalTrials.gov Identifier: NCT03823300) were launched that compared the use of faricimab, a bispecific antibody that acts through dual inhibition of both angiopoietin-2 (ang-2) and vascular endothelial growth factor A, with that of aflibercept. Faricimab combines anti-ang-2 and anti-VEGF into a single molecule. “The background for ang-2 is that, for physicians, it’s sort of an unknown molecule. VEGF is required for development of blood vessels, and ang-1 is required for the maintenance of normal blood vessels. But ang-2 is a ‘bad actor.’ If you have ang-2 upregulated in the presence of VEGF, you really have foreign angiogenesis, activation of blood vessels, and loss of pericytes,” explained Amani Fawzi, MD, in discussing the studies, as part of her review of the previous year’s top retinal research in the symposium “What You Need to Know From the Past Year’s Literature.”³  

“TENAYA and LUCERNE were 2 prospective conducted randomized clinical trials in the US and abroad to register faricimab for the treatment of neovascular AMD,” explained retinal surgery expert Rishi Singh, MD, president of Cleveland Clinic Martin hospitals.⁴ 

First year data on faricimab has previously been established, and researchers have been able to show noninferiority to aflibercept at weeks 40, 44, and 48. This research looked at patients starting at week 60, when they were placed on a protocol-driven treat-and-extend personalized treatment interval (PTI). “That takes into account vision, anatomy, and the presence of a submacular hemorrhage as a retreatment criteria. If any of these criteria are met, the patients could then be adjusted to receive the drug more frequently, as frequently as every 8 weeks, or it could be extended to go up to every 16 weeks during the course of this second year,” said Dr Singh.⁴

The patients treated with faricimab during the PTI period needed fewer and less frequent injections than those given aflibercept in the PTI period to achieve the same visual results. “On average patients gained about 4.3 letters from baseline up into year 2” across both groups, according to Dr Singh. The patients dosed once every 16 weeks “at 1 year 45% of faricimab treated patients were on 16 weeks of dosing. You’d expect that if we pushed them too far, there might be some regression of these patients over time,” said Dr Singh. “In fact, we’ve seen that 69% of patients were able to be maintained [on 16 week dosing] during the second year of the trial.”

There was also a continual reduction of retinal thickness in year 2 with patients in the faricimab group, who were dosed an average of 3 injections in the second year, averaging 148.4 µm. Those in the aflibercept group, who were dosed on average 6 injections in the second year, averaged a retinal thickness of 144.0 µm. The patients in the faricimab groups experienced “very good control of central subfield thickness over time with no compromise in visual acuity,” Dr Singh said.

Additionally, the researchers found that more than half of the patients who, during the trial’s first year, were dosed once every 8 weeks, were able to be delayed to once every 12 or 16 weeks in the second year.⁴ 

Extended Dosing Possibilities in DME

Another pair of studies published earlier this year, the phase 3 YOSEMITE/RHINE (Clinicaltrials.gov NCT03622580/NCT03622593), explored faricimab’s use in patients with DME.⁵ It also found visual gains and anatomical improvements with adjustable dosing up to every 16 weeks, according to presenters at the AAO. Much like the design of the TENAYA/LUCERNE trials, the YOSEMITE/RHINE trials compared 2 years worth of data on patients with DME treated with aflibercept or faricimab either once every 4, 8, 12, or 16 weeks.^5,6 

In the PTI arm, 78% of patients treated with faricimab were able to be extended to once every 12 weeks or more at week 96, with 62% able to be extended out to once every 16 weeks. These patients also maintained the same vision gains and anatomic improvements as patients managed with aflibercept. The presentation at the AAO also shows that most patients who were able to be dosed once every 12 or 16 weeks by week 52 (79%) were able to maintain a once every 12 weeks (or longer) dosing schedule without seeing intervals reduced to fewer than once every 12 weeks through week 96. Fewer than 9% of patients remained on 8-week dosing intervals throughout the 2-year trials.⁵

“More patients treated with faricimab every 8 weeks, and up to every 16 weeks, achieved absence of DME, as well as absence of intraretinal fluid, throughout the study year 2,” explained presenter Caroline Baumal, MD, a vitreoretinal surgeon, ophthalmology professor, and director of retinopathy of prematurity service at New England Eye Center, Tufts Medical Center. “In this new post hoc analysis, we looked at the time for the 75th  percentile of patients to achieve absence of DME. More patients treated with faricimab every 8 weeks, and up to every 16 weeks, achieved absence of DME earlier, and with fewer injections than aflibercept.”⁶ 

The patients who were dosed on a PTI schedule at week 20 (after receiving a mean 4.2 injections), achieved similar incidence of absence of DME compared with the patients on a fixed dose (who received a mean 4.8 injections). The patients treated with aflibercept were not able to match that level of DME absence until hitting week 36 and receiving a mean 6.7 injections.⁶

Delivery Methods 

While the reduced need for injections could potentially ease a significant patient burden, the findings raise the question: What if injections were not necessary at all? That’s the concept behind the Port Delivery System (Genentech), an intraocular implant that received FDA approval a year ago for the treatment of wet AMD. It comes preloaded with 100 mg/ml of ​​ranibizumab that is slowly released in the course of 6 months. This dosing schedule allows patients to undergo in-office treatments as little as twice a year. The AAO presentation by Dr Regillo shows 3 years worth of data, 2 from the phase 3 ARCHWAY study itself, and another from the extension of that trial, Portal (Clinicaltrials.gov Identifier: NCT03683251).  

The Portal trial shows mean change in best corrected visual acuity through 144 weeks. “We’re seeing very good maintenance of visual acuity throughout the entire time frame, with only about a 2 to 3 letter decline at week 144, compared to baseline,” said Dr Regillo. In fact, for patients who had been managed previously with the Port Delivery System, their acuity at week 144 was 20/38, which is similar to outcomes for patients initially treated with conventional monthly ​​ranibizumab injections who had acuities of 20/34.²

“For exudative control, as measured by [optical coherence tomography] the center point thickness was very well maintained over the course of the 3 years,” he added. “We see essentially no difference between the 2 arms, minimal fluctuation, and minimal change from baseline to week 144. This was all achieved with very few supplementation over the 3 years, hovering around 5% or less at each refill exchange interval over the course of ARCHWAY and into Portal.”  

Supplemental anti-VEGF treatments are an option for patients implanted with the Port Delivery System, but, the Portal trial shows, 95% of patients required no such additional injections.

Patient Behaviors

Satisfaction with treatment modalities may not seem as crucial as safety and efficacy; but, practicing clinicians know that treatments can only be effective when patients opt to receive them.

The research presented throughout the AAO acknowledges that the purpose behind these new technologies is to reduce the patient burden. Some relevant findings are already being uncovered. For instance, a patient preference questionnaire distributed to patients in the Portal trial shows that 88% prefer the Port Delivery System to monthly injections.² 

When patient satisfaction is not met, fewer will seek necessary treatment, and many will lose vision that could have been saved. A presentation at the meeting reviewed the loss to follow-up in patients with wet AMD treated with anti-VEGF therapy in the US. For this presentation, researchers relied on data from the Intelligent Research in Sight (IRIS) Registry to show that these patients frequently cease to return for their scheduled intraocular injections. The researchers looked at data from January 2013 to December 2018 and found that, of 191,694 participants, approximately 11% did not return to the ophthalmologist for at least 12 months after a previous intravitreal injection.⁷ 

“We found that advanced age was more likely to be lost to follow-up,” explaine​​d presenter Rahul Khurana, MD, of the Northern California Retina Vitreous Associates, who also serves as a clinical associate professor of ophthalmology at the University of California San Francisco. Patients older than 75 years were significantly less likely to appear for an additional treatment within 1 year, the study shows. “We found a high loss to follow up in patients with neovascular AMD treated with anti-VEGF therapy, nearly 1 in 9 patients were lost to follow up. Risk factors included increasing age, male sex, African-American and Hispanic ethnicity, unilateral involvement, and Medicaid insurance. Improving adherence would be key to improving long-term outcomes,” he said. “We really need to devise new strategies to have better compliance and adherence if we want to maximize the benefits for our patients.”⁷

Many of these new strategies are already underway, and more are certain to come as technologies improve and anti-VEGF therapeutics become more accessible and acceptable to all patients.