Geographic Atrophy Treatment Breakthrough, Strengthened Doses Headline Historic 2023 for Ophthalmology

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Chief among a flurry of clinical advances in retina disease this year were the FDA approvals of complement inhibitors for GA and a higher-dose aflibercept for diabetic retinopathy. What comes next?

A pivotal year in medicine is not defined only by the groundbreaking innovations shaping treatment or by the tools revolutionizing clinical practice, but how these advancements embody a better tomorrow for patient care.

Throughout 2023, the field of ophthalmology underwent a notable transformation. First-time treatments for geographic atrophy (GA) and a high-dose therapy for retinal diseases were approved by the US Food and Drug Administration (FDA), while positive data from clinical trials explored new mechanisms of action and screening technologies. Top of FormBottom of Form

These developments all reinforce the trajectory of ophthalmology in recent decades: prioritizing novel treatment options, reducing treatment-related burden, and focusing on innovations aimed at better disease management. Bottom of Form

“There have been very exciting developments in ophthalmology this past year,” Diana V. Do, MD, a professor of ophthalmology and vice chair of clinical affairs at the Byers Eye Institute, Stanford University, told HCPLive. “I think the area of GA and newly approved complement inhibitors is an exciting option for patients. And, of course, these new generations of anti-vascular endothelial growth factor (VEGF) agents also offer our patients a better chance of disease control with fewer injections.”

An advanced form of dry age-related macular degeneration (AMD), GA is a disease characterized by the loss of photoreceptor cells, retinal pigment epithelium, and choriocapillaris. Over time, its progression can lead to substantial, irreversible vision loss. More than 1 million people in the United States are impacted by GA; owing to a lack of treatment options, many patients progress to blindness.

In 2023, the debut of 2 FDA-approved therapies marked a milestone in GA treatment. This novel treatment landscape has marked this year as one of the most important in recent decades. Although these agents do not provide tissue restoration, many consider it the first step in meeting an unmet need and impeding the progression of a significant vision-threatening disease. Top of FormBottom of Form

“I think the biggest highlight in retina this year is the introduction of drugs to treat GA, a patient population that has had limited expectations in terms of any treatment modality that can interrupt their disease process,” W. Lloyd Clark, MD, of Palmetto Retina Center, told HCPLive.

Granted FDA approval in February, Apellis Pharmaceuticals’ pegcetacoplan injection (SYFOVRE) was the first treatment made available for GA. A complement C3 inhibitor targeting C3 and C3b pathways to help regulate complement overactivation in patients with GA, approval was based on pivotal 24-month data from the phase 3 OAKS and DERBY trials.

More recently, data from the GALE extension trial of OAKS and DERBY showed increasing treatment effects over 3 years. The data showed reductions in GA lesion growth in both the monthly (35%; P <.0001) and every other month (24%; P <.0001) treatment arms versus sham.

“Although this data for the GA drugs is somewhat modest in terms of its efficacy, it’s an important first step for our patients with vision loss from dry AMD,” Clark said.

However, recent reports have concerned clinicians and patients alike about the safety of the therapy. An ongoing report from Apellis in October confirmed 10 cases of retinal vasculitis, including 7 occlusive and 3 non-occlusive cases, related to pegcetacoplan injection. Although safety data is still being collected and evaluated, the company has noted the rarity of these adverse events, with more than 100,000 commercial and sample vials distributed since approval.

In August, a second complement inhibitor was approved for the treatment of GA: avacincaptad pegol (IZERVAY) from Iveric Bio. A specific inhibitor of complement C5, avacincaptad pegol slows disease progression by preventing the progression of terminal, active C5 products, C5a and C5b. In both the randomized, double-masked sham-controlled GATHER1 and GATHER2 trials, during the 12-month study period, slowing of disease progression was seen as early as 6 months, with up to a 35% reduction in the first year of treatment.

Two-year data from the GATHER2 trial showed that the treatment effect of avacincaptad pegol continued to increase over time and more than doubled over 2 years, compared to 1-year data. A statistically significant year-over-year reduction of 14% in the mean rate of GA growth was observed at 2 years with every-month dosing (P = .0165) and 19% with every-other-month dosing (nominal P-value = .0015).

Further GATHER2 data showed mostly positive safety of the agent—a single case each of non-serious intraocular inflammation (IOI) and culture-positive endophthalmitis were reported in the data, without any cases of ischemic neuropathy or retinal vasculitis.

These 2 agents have represented not just a first-time treatment for GA, but have captured the public consciousness and ushered in a new conversation surrounding eye health. Many doctors have described the renewed attention to the plight of GA and the need for increased screening and checkups with eye care providers.

“I think 2023 brought a lot of attention to GA, it’s an underrecognized condition,” Aleksandra Rachitskaya, MD, an assistant professor of ophthalmology at Cole Eye Institute, Cleveland Clinic told HCPLive. “As we now have approved treatments, I think that the recognition of GA is going to be better. I think it has been underappreciated how much it affects a patient’s quality of life and their vision.”

Another landmark agent of note also received approval in August: aflibercept 8 mg (EYLEA HD) for the treatment of wet AMD, diabetic macular edema (DME), and diabetic retinopathy. The standard dose of aflibercept 2 mg was first approved for wet AMD in November 2011, for DME in June 2014, and in May 2019 to treat all stages of diabetic retinopathy.

The approval of high-dose aflibercept was based on 48-week results of the phase 3 pivotal PULSAR and PHOTON trials evaluating aflibercept 8 mg to a 2 mg dose. Both PULSAR in wet AMD (n = 1009) and PHOTON in DME (n = 658) demonstrated non-inferior and clinically equivalent vision gains at 48 weeks with both 12- and 16-week aflibercept 8 mg dosing regimens, compared with an 8-week aflibercept 2 mg after initial monthly doses. Most patients randomized to aflibercept 8 mg 12- or 16-week dosing regimens were able to maintain their intervals through 48 weeks.

“I think this has been a fantastic year for the field—we have seen the approval of 3 agents: pegcetacoplan injection and avacincaptad pegol for GA, and aflibercept 8 mg for nAMD and DME,” Arshad Khanani, MD, the director of clinical research at Sierra Eye Associates, said. “Both for physicians, as well as patients, we can address retinal diseases so our patients can keep vision longer.”

The introduction of 3 new agents into a clinician’s armamentarium has been substantial for the growth of the treatment landscape. If the end goal is fighting vision loss, these new additions to the treatment landscape serve to benefit both the clinician and the patient, by reducing treatment burden and clinic visits.

“2023 is a year, where before, it was easy and simple. We had, let’s say, 3 drugs: bevacizumab, ranibizumab, and aflibercept 2 mg,” Jean-Francois Korobelnik, MD, PhD, the head of the department of ophthalmology at Bordeaux University Hospital, explained to HCPLive. “In 2024, the landscape is going to be very busy to treat those patients with retinal conditions. At the end of the day, it’s good for the patients.”

But this year was not measured only by FDA approvals. Clinical data primarily presented at major ophthalmic meetings provided a hint of what’s to come in ophthalmology, from new mechanisms of action to promising gene therapies and new screening technologies. First-time results on the feasibility of home optical coherence tomography (OCT), a home-based version of the non-invasive imaging test, offered a look at future comprehensive, personalized regimens in treating retinal diseases.

At 6 months of study, home OCT showed statistically significant reductions in treatment frequency, with an increase in treatment interval from 8.0 to 15.3 weeks (P <.01), in patients with nAMD. Both the patient and technology performed well, with an average of 6 scans per week and a total of 40 home OCT-triggered visits. Of these visits, 39 were confirmed based on in-office imaging, and treatment was recommended in 37 cases.

“The current landscape for AMD and DME has been, you just inject, and you inject how often they need it, and I would love to see it move to a more custom treatment paradigm,” Sumit Sharma, MD, an assistant professor of ophthalmology, Cole Eye Institute, Cleveland Clinic, told HCPLive. “Home OCT is very exciting for that, and we’ll have to wait and see where home OCT will fit into some of these treatment paradigms.”

Gene therapy continued to be an area of great promise in ophthalmology, with phase 2 data providing a look into the future of retinal disease treatment, with some of the most advanced gene therapy programs, including ABBV-RGX-314 from Regenxbio and 4D-150 from 4D Molecular Therapeutics, as treatments for nAMD.

A one-time in-office injection of investigational RGX-314 was linked to clinically meaningful improvements in disease severity and reduction in vision-threatening events in patients with non-proliferative diabetic retinopathy. One-year results from the phase 2 ALTITUDE study showed dose level 2 of RGX-314 prevented disease progression in all patients, with approximately 70% of patients achieving disease improvement.

Interim results from the phase 1/2 PRISM trial showed 4D-150, an investigational, single-dose, intravitreal genetic medicine, was safe and well-tolerated at a range of doses in patients with nAMD. Dose-response was demonstrated in favor of the highest tested dose of 3E10 vg/eye, with a 100% reduction in supplemental anti-VEGF injections at 36 weeks in 4 of 4 patients with high anti-VEGF need.

“It has been encouraging and exciting to delve into the world of AMD – there are intravitreal gene therapies and subretinal gene therapies that we can deliver surgically now spanning into the AMD world and outside of the inherited retinal disease world for gene therapy,” Christine N. Kay, MD, the director of electrophysiology, retinal genetics, and clinical trials at Vitreoretinal Associates in Gainesville, Florida, told HCPLive. “I’m excited to see what the next frontier will be for wet AMD and dry AMD involving gene therapy.”

Other mechanisms of action included OCS-01 eye drops, a novel, high-concentration (15 mg/ml) topical formulation of dexamethasone. Pending potential approval, OCS-01 would become the first topical preservative-free eye drop for the treatment of DME. Results from the phase 2/3 DIAMOND trial showed OCS-1 drops had significant reductions in central macular thickness (CMT) and significant visual gains in patients with DME, compared to sham.

“I think new therapeutics and new modes of treatment are the interesting space that we’re in ophthalmology,” Hani Salehi-Had, MD, of Retina Associates of Southern California, said. “Any modality of therapy that is not the routine of us doing monthly therapies is exciting. I certainly think OCS-01 eye drops as a route of delivery of medications to the eye are very interesting.”

In just a single year, ophthalmology has achieved remarkable feats, transforming the specialty with innovative, longer-lasting therapies, groundbreaking mechanisms of action, and advanced screening technologies—factors that will continue to shape and reshape ophthalmic care for decades to come.

“The continued drive for innovation and treatments against retinal blindness has been very appropriately focused on what is clinically important,” Marco A. Zarbin, MD, PhD, a professor of ophthalmology at Rutgers New Jersey Medical School, summarized. “By inhibiting additional pathways, we get drugs that last longer, and we are more likely to get appropriate and adequate treatment for patients, and the logistics of treatment don’t interfere with access to care.”


  1. Iapoce C. Diana v. do, MD: 96-week results of the photon study. HCP Live. November 3, 2023. Accessed December 7, 2023.
  2. What is geographic atrophy? Cleveland Clinic. Accessed December 7, 2023.
  3. Iapoce C. W. Lloyd Clark, MD: Management of NAMD Using Home Oct Monitoring. HCP Live. November 5, 2023. Accessed December 7, 2023.
  4. Iapoce C. FDA approves Pegcetacoplan Injection for geographic atrophy. HCP Live. February 17, 2023. Accessed November 28, 2023.
  5. Iapoce C. Charles Wykoff, MD, PhD: Increasing effects of Pegcetacoplan in Gale Study. HCP Live. November 4, 2023. Accessed November 28, 2023.
  6. Iapoce C. Apellis releases update on retinal vasculitis associated with Pegcetacoplan Injection. HCP Live. October 12, 2023. Accessed November 28, 2023.
  7. Kunzmann K. FDA approves Avacincaptad Pegol for geographic atrophy. HCP Live. August 5, 2023. Accessed December 7, 2023.
  8. Iapoce C. Arshad Khanani, MD: Two-year results from gather2 trial. HCP Live. December 1, 2023. Accessed December 7, 2023.
  9. Iapoce C. Aleksandra Rachitskaya, MD: Effect of GLP-1 agonists on diabetic retinopathy. HCP Live. November 6, 2023. Accessed December 7, 2023.
  10. Campbell P. Aflibercept 8 mg (eylea HD) approved by FDA for wet AMD, DME, and Diabetic retinopathy. HCP Live. August 23, 2023. Accessed December 7, 2023.
  11. Iapoce C. Jean-Francois Korobelnik, MD, Phd: 96-week pulsar data on Aflibercept 8 mg. HCP Live. November 17, 2023. Accessed December 7, 2023.
  12. Iapoce C. Sumit Sharma, MD: 6-month results from phase 2 ripple-1 trial. HCP Live. November 5, 2023. Accessed December 7, 2023.
  13. REGENXBIO presents positive interim data from and the expansion of Phase II altitude® trial of RGX-314 for the treatment of diabetic retinopathy using suprachoroidal delivery. Regenxbio Inc. November 3, 2023. Accessed December 7, 2023.
  14. Iapoce C. Phase 1/2 prism trial reports positive interim data on Intravitreal 4D-150 for NAMD. HCP Live. July 30, 2023. Accessed December 7, 2023.
  15. Iapoce C. Christine N. Kay, MD: Results of tease-1 study on stargardt disease. HCP Live. November 17, 2023. Accessed December 7, 2023.
  16. Iapoce C. Hani Salehi-had, MD: Efficacy of OCS-01 eye drops in diabetic macular edema. HCP Live. November 4, 2023. Accessed December 7, 2023.
  17. Iapoce C. Marco A. Zarbin, MD, Phd: Benefit of faricimab for DME with BCVA ≤20/50. HCP Live. November 8, 2023. Accessed December 7, 2023.