Addressing Unmet Needs in Retinal Diseases: Highlights From ARVO 2023

The Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting was held from April 23 to April 27, 2023, in New Orleans, Louisiana. Several studies on retinal diseases presented at ARVO 2023 focused on increased dosing durability to reduce the treatment burden in patients with AMD and DME. Additional information on promising treatments in the pipeline for GA also emerged from this meeting. In this article, Veeral Sheth, MD, MBA, FASRS, FACS, partner and director of clinical trials at University Retina in Chicago, Illinois, discusses his takeaways from the meeting and the future direction of care in the retinal space.

There were 2 studies from ARVO 2023 that showed extended dosing durability with high-dose aflibercept 8 mg vs low-dose aflibercept 2 mg in wet AMD and DME. In the phase 3 PULSAR trial (ClincialTrials.gov identifier: NCT04423718), researchers found that 77% of patients with wet AMD who received aflibercept 8 mg with a 16-week dosing interval were able to maintain this dosing schedule.¹ The phase 2/3 PHOTON trial (ClinicalTrials.gov identifier: NCT04429503) had similar results but in the DME population, with 89% of patients who were randomized to the 16-week dosing interval maintaining that treatment schedule after almost 1 year.² Were there any commonalities in patients who were unable to achieve extended durability with high-dose aflibercept?

That is a great question; what you are highlighting is what we are seeing day to day in the clinic, which is variability in our patient populations. Some patients have higher needs than others, and there is no pattern that we have been able to identify so far. We all want to know if there is a way to identify patients who need more or less treatment, but despite looking for these markers, we are not seeing them.

What are your impressions of the PULSAR and PHOTON data so far?

I am encouraged by it, but I would love to see some more optical coherence tomography (OCT) data. We have seen good safety data so far, with aflibercept 8 mg having a similar safety profile to aflibercept 2 mg in PULSAR,¹ but we need more data on safety. We are not seeing significant intraocular inflammation or any retinal vasculitis, and we are familiar with the molecule, which is reassuring.

If aflibercept 8 mg is approved in the wet AMD and DME populations, how do you expect it would be integrated into clinical use?

What we are seeing with newly approved drugs is a step forward. We are looking for better efficacy or better durability without compromising on safety, and suboptimal responders to anti-vascular endothelial growth factor (VEGF) treatment are being switched over to newer agents. If approved, it will be the same strategy for high-dose aflibercept; we will target patients who are on an anti-VEGF, such as aflibercept 2 mg, and who are unable to extend past 6 or 8 weeks. Those are the initial patients we will switch over to the new agent. Eventually, if everything goes well with the new agent, we will begin to use it in the first-line setting. But there are many factors that still need to be decided. What happens with aflibercept 2 mg? Does it get discontinued? How do biosimilars fit in? There are many variables still to consider.

In the SWIFT trial (ClinicalTrials.gov identifier: NCT04264819) and in the study analyzing data from the Fight Retinal Blindness! Registry, reductions in disease activity and visual gains were observed with brolucizumab, but incidences of intraocular inflammation were also seen. In the SWIFT study, 43.6% of patients demonstrated no disease activity by week 16; however, 7.1% of patients experienced intraocular inflammation, 1.7% of patients had inflammation and retinal vasculitis, and 1.4% had inflammation, retinal vasculitis, and retinal vascular occlusion.³ The study analyzing data from the Fight Retinal Blindness! Registry was a retrospective analysis that showed how patients with wet AMD respond to brolucizumab in the real world; of the 72 patients who received at least 2 injections of brolucizumab and who had at least 6 months of follow-up, 44% had no disease activity. However, there were 6 cases of adverse events in patients receiving brolucizumab, including 2 cases of occlusive vasculitis.⁴ With these findings in mind, where does brolucizumab fit within the treatment paradigm?

We have patients on brolucizumab because nothing else works. It is very difficult, in this day and age, to take an agent with a 7% inflammation rate and a somewhat notable number of cases of vision loss from vasculitis and sell it to patients or clinicians. It is my understanding that brolucizumab is being used very sparingly and only with a lot of patient education and follow-up, as patients need to understand the tradeoff they are making. Brolucizumab is a great drying agent with good durability; I have switched patients to brolucizumab and they were able to extend to every 16-week injections from 6- to 8-week injections. Some patients want to stay on the drug because they feel like they are doing well and do not want to come in as often. But many clinicians have taken patients off of it even if patients were okay with the risk because we, as clinicians, were not comfortable with it. With the approval of faricimab and data showing it has up to 16 weeks of durability,⁵ I would rather prescribe my patients this agent.

The phase 3 GATHER2 study (ClinicalTrials.gov identifier: NCT04435366) aimed to assess the safety and effectiveness of ACP 2 mg compared with a sham injection in patients with GA. This study addressed an unmet need, as no approved treatments for GA were available until the approval of pegcetacoplan injection in February 2023.⁶ The previous clinical trials, including GATHER1 (ClinicalTrials.gov identifier: NCT02686658), had already investigated ACP. Considering this background, what insights can we gather from the GATHER1 data, and how does the GATHER2 data contribute to our understanding?

We know from the 12-month GATHER1 that patients treated with ACP had slower lesion growth in terms of noncentral GA than patients who received sham therapy.⁷ Both GATHER1 and GATHER2 were positive studies; patients receiving ACP had a significant reduction in GA lesion growth; GA patients treated with ACP 2 mg had a 56% risk reduction in the rate of persistent vision loss compared with those who received sham treatment.⁸ That is important because these trials are looking at lesion growth, but clinically speaking, what is possibly more relevant for the everyday retina provider is that we need to be able to communicate to the patient how GA impacts their vision and why they should be treated regularly. Patients do not often think of the disease in terms of lesion growth, but they know what their vision is like. ACP is currently under review by the FDA with a decision expected in August; I expect it to go through given the 2 positive studies. We have not seen cases of retinal vasculitis or severe vision loss from what I understand. We will be on the lookout for potential cases of choroidal neovascularization, which we did see in the clinical trials for the now FDA-approved pegcetacoplan.⁶

There were 2 abstracts on gene therapy for wet AMD presented during ARVO 2023: a phase 1/2a trial on the subretinal delivery of RGX-314 (ClinicalTrials.gov Identifier: NCT03066258), which is a single gene therapy intervention using adeno-associated virus (AAV) vector serotype 8 (AAV8) to provide continuous anti-VEGF therapy, and the phase 1/2 PRISM trial (ClinicalTrials.gov identifier: NCT05197270) on 4D-150, a single-dose intravitreal retinotropic AAV vector carrying 2 transgenes encoding aflibercept and a microRNA (miRNA) sequence targeting VEGF-C. Both treatments were well-tolerated at this stage and decreased the injection burden. In PRISM, there was a 96.7% overall reduction in the mean annualized anti-VEGF injection rate.⁹ In the RGX-314 trial, patients experienced up to a 67% reduction in the mean annualized injection rate from the year prior to treatment; patients in cohort 3 had improved visual acuity (VA) (mean +12 letters), while patients in cohort 4 had stable VA.¹⁰ What are your impressions of these data and of the promise of gene therapy for wet AMD?

Gene therapy is an exciting field because we are talking about potentially programming cells in a targeted way to provide therapeutics so that we can back off the need for frequent anti-VEGF treatments for these patients. That is a big plus. The big minus is that this is still in a nascent stage as far as what we know about it and its long-term effect at the cellular level. There is still a lot to learn, but there is some early data on safety and signals of efficacy in reducing the treatment burden. We are treating patients with these therapies 1 time, and the ultimate goal is for the majority of patients to not need rescue therapy afterward. But looking at the bigger picture, it is just as important for patients receiving this type of treatment to have a subsequent reduction in their overall anti-VEGF treatment burden. These 2 agents, RGX-314 and 4D-150, are also different approaches; 4D-150 is an intravitreal injection, which is exciting because we are very familiar with the route of administration, while RGX-314 is either a subretinal injection, done at the time of vitrectomy, or a suprachoroidal injection, which we can do in-office, but this is different than what we are used to doing. There is a lot to figure out, but the science and early evidence are promising and potentially game-changing.

Do you have any other thoughts from ARVO 2023 that you would like to share?

It is an exciting time with many options that could come through the pipeline shortly. We are still trying to figure out where all these treatments fit. I am encouraged to see new therapies get approved in the past year with likely more to come in the upcoming months, and we are finally hitting unmet needs such as GA. This is arguably the most exciting time in retina since the approval of the first anti-VEGF.

This Q&A was edited for clarity and length.

Disclosures

Veeral Sheth, MD, MBA, reported affiliations with Genentech, Inc; Alimera Sciences, Inc; Apellis Pharmaceuticals; Novartis Pharmaceuticals Corporation; EyePoint Pharmaceuticals, Inc; Iveric Bio, Inc; Graybug Vision, Inc; Regeneron Pharmaceuticals, Inc; Vial; Allergan, Inc; Opthea; Oxurion NV; Recens Medical; F. Hoffmann-La Roche AG; Regenxbio, Inc; Ionis Pharmaceuticals, Inc; Santen; SamChungDang; Gyroscope Therapeutics, Ltd; Chengdu Kanghong Pharmaceutical Group Co, Ltd; SalutarisMD; NGM Biopharmaceuticals, Inc; Outlook; 4D Molecular Therapeutics; Ashvattha Therapeutics; Olix Pharmaceuticals; Janssen Biotech, Inc; and OcuTerra.

References

1. Spitzer MS. Intravitreal aflibercept 8 mg injection in patients with neovascular age-related macular degeneration: 48-week results from the phase 3 PULSAR trial. Abstract presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; April 23-27, 2023; New Orleans, LA. Abstract 461.
 
2. Brown DM. Baseline disease characteristics of patients who maintained 12- and 16-week aflibercept 8 mg dosing versus patients with shortened treatment intervals through week 48 in the phase 2/3 PHOTON trial. Abstract presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; April 23-27, 2023; New Orleans, LA. Abstract 2813.
 
3. Tadayoni R, Souied E, Cruezot-Garcher C, et al. Disease control at week 16 of brolucizumab in adult patients with suboptimal anatomically controlled neovascular age related macular degeneration – the SWIFT study. Abstract presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; April 23-27, 2023; New Orleans, LA. Abstract 465.
 
4. Gillies M, Dang T, Nguyen V, et al. Six-month outcomes of brolucizumab in routine clinical practice: data from the Fight Retinal Blindness! registry. Abstract presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; April 23-27, 2023; New Orleans, LA. Abstract 466.
 
5. FDA approves Genentech’s Vabysmo, the first bispecific antibody for the eye, to treat two leading causes of vision loss. News release. Genentech, Inc. January 28, 2022. Accessed May 8, 2023. https://www.gene.com/media/press-releases/14943/2022-01-28/fda-approves-genentechs-vabysmo-the-firs
 
6. FDA approves SYFOVRE™ (pegcetacoplan injection) as the first and only treatment for geographic atrophy (GA), a leading cause of blindness. News release. Apellis Pharmaceuticals, Inc. February 17, 2023. Accessed May 3, 2023. https://www.globenewswire.com/news-release/2023/02/17/2610967/0/en/FDA-Approves-SYFOVRE-pegcetacoplan-injection-as-the-First-and-Only-Treatment-for-Geographic-Atrophy-GA-a-Leading-Cause-of-Blindness.html
 
7. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027
 
8. Iveric Bio announces new functional vision loss reduction data from avacincaptad pegol GATHER trials presented at ARVO Annual Meeting. News release. Iveric Bio, Inc. April 23, 2023. Accessed May 3, 2023. https://investors.ivericbio.com/news-releases/news-release-details/iveric-bio-announces-new-functional-vision-loss-reduction-data
 
9. Khanani AM, Hershberger VS, Kay CN, et al. Interim results for the Phase 1/2 PRISM trial evaluating 4D-150, a dual-transgene intravitreal genetic medicine in individuals with neovascular (wet) age-related macular degeneration. Abstract presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; April 23-27, 2023; New Orleans, LA. Abstract 5055.
 
10. Sisk R. Subretinal delivery of RGX-314: a gene therapy for neovascular age-related macular degeneration (nAMD). Abstract presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; April 23-27, 2023; New Orleans, LA. Abstract 5061.

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