Real-World Management of Neovascular Age-Related Macular Degeneration: Highlights From 2022 ASRS Annual Meeting

The 2022 American Society of Retina Specialists (ASRS) 40th Annual Meeting, held from July 13 to July 16 in New York City, New York, featured engaging discussion of newly approved and investigative treatments in neovascular age-related macular degeneration (nAMD), including long-term data on the Port Delivery System with ranibizumab (PDS) and faricimab, the first bispecific antibody available for use in intravitreal nAMD. Phase 1 safety data on novel agents in the pipeline were also presented, providing a glimpse into possible future treatment of nAMD. 

David Eichenbaum, MD, FASRS, an ophthalmologist and the director of research at Retina Vitreous Associates of Florida in Tampa, shared his takeaways from how the latest study findings from ASRS may translate into clinical practice.

Data continue to accumulate on faricimab and the PDS with ranibizumab, both of which were approved by the US Food and Drug Administration (FDA) in the last year for treatment of nAMD.^1,2 Several studies presented at ASRS included investigations of these treatments. What are key learning points from this research? 

Aleksandra Rachitskaya, MD, FASRS, presented end-of-study results of the phase 3 Archway trial (ClinicalTrials.gov Identifier: NCT03677934), which support what we have seen with the PDS: incredible, game-changing durability.³ Of course, it comes with a balance of being vigilant for certain specific safety issues related to the PDS procedure and device, specifically exposure of the implant and the associated risk of  endophthalmitis. For background, the PDS is a permanent refillable ocular implant surgically implanted in the pars plana that provides continuous intravitreal delivery of ranibizumab. The FDA approval was based on the Archway study, which compared the safety, efficacy, and durability of PDS with ranibizumab treatment every 24 weeks vs ranibizumab injections every 4 weeks.⁴ The primary endpoint was the change in best-corrected visual acuity (BCVA) from baseline averaged over 36 to 40 weeks.⁴ Dr Rachitskaya’s presentation at the ASRS included data up to week 96.

The PDS was noninferior to high-frequency ranibizumab injections through the end of the study. Vision outcomes were generally comparable across treatment arms. Continuous delivery of ranibizumab with the PDS maintained best corrected visual acuity (BCVA) regardless of the presence or absence of retinal fluid. When intraretinal fluid was present in the center 1 mm, there was a trend for better BCVA maintenance seen with the PDS compared with monthly ranibizumab. 

How are you currently using the PDS in your practice? Do the data presented at the ASRS Annual Meeting change anything for you?

I started using the PDS in my daily clinical practice as soon as possible following its approval. It took a little while due to cost and access issues, and because there is another stakeholder involved: the operating room. Our group [Retina Vitreous Associates of Florida] has implanted dozens of these devices into the eyes of patients with nAMD and diabetic macular edema across the phase 2 through phase 4 clinical trials, and we have implanted 5 commercially to date with a 6th patient scheduled for surgery. This 6th patient will be our first with bilateral PDS.

I use this procedure primarily in patients who have been receiving high-frequency ranibizumab injections. These patients do not necessarily want to try brolucizumab or faricimab so they can extend the duration between injections by another 2 or 4 weeks; they want to be finished with shots altogether. Based on the latest long-term data, I can confidently tell patients that with PDS, they will undergo treatment much less frequently. I make sure to educate them on this point, taking time to carefully explain the procedure, its risks, and the need for ongoing examinations and vigilance. 

What is the real-world applicability of the new data about faricimab presented at the ASRS Annual Conference? What did these data teach us?

There were 2 very good presentations on the use of faricimab for patients with nAMD. Arshad Khanani, MD, MA, FASRS, presented 2-year safety, efficacy, and durability data from the TENAYA (ClinicalTrials.gov Identifier: NCT03823287) and in LUCERNE (ClinicalTrials.gov Identifier: NCT03823300), and Carl Danzig, MD, presented promising early results from TRUCKEE, an ongoing retrospective study that assessed the real-world safety and efficacy of faricimab after 1 injection.^5,6

Faricimab, the first intraocular bispecific antibody, has demonstrated increased durability in nAMD, likely due to its dual inhibition of angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A). TENAYA and LUCERNE randomly assigned 1329 patients to faricimab either every 8 weeks or up to every 16 weeks. Year 1 data showed great treatment durability, with up to 40% of patients achieving 16-week dosing with faricimab.⁷ In year 2, patients received personalized, treat-and-extend injections where treatment intervals were extended by 4 weeks (up to a 16-week interval), maintained, or reduced by 4 weeks depending on individual assessments of central subfield thickness (CST), BCVA, and macular hemorrhage. 

If 2 or more of the reduction criteria were met, the treatment interval was reduced by 8 weeks. At the end of year 2, the investigators found that in both the TENAYA and LUCERNE trials, 6 of 10 patients receiving faricimab achieved 16-week dosing, which is unprecedented durability for intravitreal injection therapy relatively early in the disease course. A subset of patients still required 8-week treatment intervals (TENAYA trial, 25%; LUCERNE trial, 18%), and some of them probably had disease that was poorly controlled at that interval. 

Regarding safety, as with any new agent, we have to be vigilant for ocular inflammation. The rate of inflammation with faricimab at year 2 in TENAYA and LUCERNE trials was 3.0%, which is comparable to the rate observed in the active-control group treated with aflibercept (2.3%).⁵ In commercial use, with more than 70,000 vials of faricimab delivered through July 2022, there does not seem to be any increased danger to patients treated with this agent. That said, real-world problems are reported differently from adverse events that arise in prospective registration trials and there is a risk of under-reporting adverse events. Speaking of the real world, in the ongoing TRUCKEE study, 377 patients from centers across the United States received 1 injection of faricimab (with a total of 421 eyes treated).⁶ The target population includes patients who are treatment-naive and patients requiring frequent injections. In the TRUCKEE study, early data showed that faricimab improved BCVA and yielded anatomic improvements with no reports of inflammation. The investigators hope to present updated data, including findings on treatment durability, at future meetings.

The primary analysis of the phase 3b TALON trial (ClinicalTrials.gov Identifier: NCT04005352) included 737 patients across 20 countries and compared the durability of brolucizumab vs aflibercept in patients with nAMD over 32 weeks.⁸ Safety issues, including concerning rates of retinal vasculitis and/or retinal vascular occlusion, have been reported for brolucizumab.^9,10 What is your analysis of TALON and what impact do these data have on your treatment decisions? 

Brolucizumab showed excellent efficacy in TALON, which was not surprising considering what a potent drying agent it is. With brolucizumab, approximately 38% of patients achieved 12-week dosing vs approximately 19% of patients who received aflibercept.⁸ Brolucizumab was noninferior to aflibercept regarding change in BCVA (+5.3 vs +5.0, respectively; P <.0001), but brolucizumab was superior to aflibercept regarding reductions in CST (-166.9 μm vs -140.0 μm, respectively; P =.006).⁸ 

Intraocular inflammation issues were similar to those reported in the HAWK and HARRIER trials.¹¹ In TALON, 5.5% vs 1.1% of patients treated with brolucizumab vs aflibercept, respectively, experienced intraocular inflammation retinal vascular occlusion and endopthalmitis, with several serious events noted in patients exposed to brolucizumab.⁸

Based on these safety data^10-12 are you consistently using brolucizumab?

No, not anymore. While brolucizumab and faricimab have similar durability, brolucizumab is considered to be an anti-VEGF “sledgehammer.” Our center was a HAWK investigative site, and our group used brolucizumab extensively and published our early commercial experience.¹² Some of our patients experienced some “spooky” inflammatory events and we switched many patients off of brolucizumab after the problems with inflammation became well-characterized. While a small number of my patients continue to do well on brolucizumab, I prefer to select safer agents for treatment initiations or treatment switches. Currently if I need to consider a medication switch for patients who are treatment-experienced, I am switching to faricimab.¹² 

What is your perspective on some early data reported at the ASRS Annual Meeting, specifically 12-month results of phase 1 studies of EYP-1901 (ClinicalTrials.gov Identifier: NCT04747197) and UBX1325 (ClinicalTrials.Gov Identifier: NCT04537884).^13,14 What are your impressions of the current findings, and can you comment on the mechanism of action of these agents? 

EYP-1901 is a tyrosine kinase inhibitor with activity against all isoforms of VEGF. The mechanism of action of UBX1325, a novel small molecule inhibitor of retinal Bcl­xL and a senolytic agent, is a bit more mysterious. The thought is that it goes after and inactivates senescent cells in patients with AMD and functions to some degree as a “the fountain of youth” to restore healthy retinal vasculature. Both agents seem to be safe injections based on the phase 1 data. 

The 12 patients enrolled in the UBX1325 trial did not experience dose-limiting toxicities or concerning adverse events such as inflammation, hemorrhage, or elevated intraocular pressure.¹⁴ In the DAVIO trial (ClinicalTrials.gov Identifier: NCT04747197), EYP-1901 had a favorable safety profile as maintenance treatment for patients with nAMD previously treated, with no serious ocular or drug-related systemic adverse events reported among the 17 patients enrolled.¹³ It is too early to draw efficacy conclusions, but the potential for these alternative mechanisms of action to provide clinical benefit in nAMD is compelling. 

In an analysis of the Intelligent Research in Sight Registry (IRIS) database, which sought to identify nAMD care gaps in the United States, the study found that certain patient subgroups were insufficiently treated over a 1-year period, which led to worse BCVA.¹⁵ What were your takeaways from this study and what are the learning points for retinal specialists?

This interesting study found a care gap between patients who were White vs non-White regarding what is considered appropriate treatment for nAMD, defined as at least 7 eye injections during the first year of treatment. These data are compelling. Patients who were Asian, Black, and Hispanic were less likely to receive sufficient treatment compared with White patients. Patients who were not insured by Medicare and patients seen by nonretinal specialists were also less likely to receive sufficient treatment. 

The treatment disparity was significant, where patients who were sufficiently treated received approximately 9 injections and patients who were insufficiently treated received approximately 4 injections in 1 year. This had a direct impact on BCVA. At 1 year, patients who were properly treated gained 3.4 letters and patients who were insufficiently treated lost 0.1 letter compared with baseline.

I think we need new ways to deliver patient-friendly, accessible care that helps to improve the equity of our very effective treatments. That is probably even more important than the development of new drugs. I love innovation, but I am disturbed by the absence of equity in our specialty, which I thought was fairly egalitarian and doing a good job. The IRIS study was an eye-opener for me and I hope it was a wakeup call for the retina community at large. It renewed my enthusiasm to build pathways to get into the community and deliver appropriate care to all patients.