Two Rival Treatments Approved for Geographic Atrophy Under the Spotlight

While doctors cautiously welcome the approval of the two drugs, questions have been raised over safety following reports of rare side effects with SYFOVRE. We sat down with renowned retinal specialists Dr. Kenneth Fong (Malaysia) and Prof. Gemmy Cheung (Singapore) to weigh in on the latest developments in the GA saga.

Two newly-approved drugs for geographic atrophy (GA) are under the spotlight following reports of rare side effects, including a potentially blinding condition known as occlusive retinal vasculitis.

GA is an advanced and irreversible form of age-related macular degeneration (AMD) and a leading cause of blindness worldwide, impacting more than one million Americans and five million people across the globe.  Approximately 75% of people living with GA in the United States are believed to be undiagnosed. There is no cure for the disease.

However, two new drugs have been approved this year by the U.S. Food and Drug Administration (FDA) to treat the condition, namely SYFOVRE® (pegcetacoplan injection) developed by biopharmaceutical company Apellis Pharmaceuticals, Inc. (Massachusetts, USA) in February and IZERVAY™ (avacincaptad pegol intravitreal solution) by biotechnology company Iveric Bio (New Jersey, USA) in August.1,2

The FDA’s decision to greenlight IZERVAY comes about six months after it approved SYFOVRE. Although GA cannot be cured, the drugs are meant to slow the progression of the disease.

IZERVAY is given as an injection in the eye once a month for up to 12 months. It works by targeting excessive activation of the complement system, which is the immune system’s early response to harmful pathogens and is implicated in the development of GA. In clinical trials, IZERVAY was shown to reduce the rate of GA lesion growth by blocking excess production of the C5 protein, believed to play a key role in the development and growth of scarring and vision loss associated with GA. By targeting this protein, the drug reduces the activity of the complement system which causes the degeneration of retinal cells.

SYFOVRE, which was the first FDA-approved treatment for geographic atrophy, was also shown to slow the progression of the disease with monthly injections. It targets a different protein that is part of the immune system, protein C3.3-5 It is approved for patients with GA, with dosing flexibility every 25 to 60 days.

Two Rival Treatments Approved for Geographic Atrophy Under the Spotlight

The source of safety issues linked to SYFOVRE found?

Following reports of rare side effects, including a potentially blinding condition known as occlusive retinal vasculitis, which have cropped up with the commercial use of SYFOVRE, Apellis Pharmaceuticals, Inc. on 22 August issued an update on the injection kits supplied by the company and an update on the cases of retinal vasculitis reported in real-world treatment with SYFOVRE for GA secondary to age-related macular degeneration (AMD).6

“As part of the comprehensive investigation into the real-world safety events, internal structural variations were identified in the specific 19-gauge x 1½-inch filter needle included in certain injection kits,” the firm said.

Filter needles are used to withdraw treatment from the vial when preparing for an injection procedure. However, the company said that a causal relationship has not been established between the structural variations in this 19-gauge filter needle and the rare events of retinal vasculitis in the real world.

It recommended that “practitioners immediately discontinue use of any injection kits that contain the 19-gauge filter needle and use injection kits with the 18-gauge filter needle, which are already in distribution.”

While injection kits previously contained one of two types of filter needles (either 18- or 19-gauge), Apellis is now exclusively distributing injection kits with the 18-gauge filter needle.

“Based on the findings from our investigation, we believe it is prudent that practitioners only use the kits with the 18-gauge filter needle, which are already in distribution. This recommendation is out of an abundance of caution as patient safety is our top priority,” said Caroline Baumal, M.D., chief medical officer of Apellis, in a press release.

“To date, more than 100,000 vials have been distributed for commercial use and for administration in clinical trials, and the events of retinal vasculitis continue to be very rare at an estimated real-world rate of 0.01% per injection. We believe SYFOVRE is an important medicine for patients living with this chronic disease and are committed to providing patients with a meaningful and safe treatment,” Dr. Baumal continued.

Over 100,000 SYFOVRE vials have been distributed in the real world and for administration in clinical trials. This includes over 78,000 vials distributed since its launch, including commercial vials shipped and sample vials distributed to physician practices. Over 26,000 vials have been distributed in the third quarter to date.

Approximately 24,000 SYFOVRE injections have been administered in clinical trials to date. In total, eight events of retinal vasculitis (five occlusive, three non-occlusive) have been confirmed. The last confirmed event of retinal vasculitis occurred on June 20, based on a review of adverse events reported to the company.

Two of the patients had their SYFOVRE injection in April, three in May, and three in June. All events of retinal vasculitis were observed after the first injection of SYFOVRE. One patient remained stable at baseline vision, two patients have recovered vision nearly back to baseline, two patients have severe vision impairment which is unlikely to be resolved, and three patients’ outcomes are still pending.

The most common adverse reactions (incidence ≥5%) are ocular discomfort, neovascular age-related macular degeneration, vitreous floaters and conjunctival hemorrhage.

New drug IZERVAY 

On the other hand, Dr. Pravin U. Dugel, president of Iveric Bio, shared with PIE magazine that its drug showed good results across two Phase 3 clinical trials and had a consistent safety profile with no reported cases of retinal vasculitis.

“IZERVAY, a new complement C5 inhibitor, is the only approved GA treatment with a statistically significant reduction in the rate of GA progression at the 12-month primary endpoint across two Phase 3 clinical trials,” he said.

According to Dr. Dugel, in each registrational trial (GATHER1 and GATHER2), over a 12-month period, the primary analysis showed a statistically significant reduction of GA growth in patients treated with IZERVAY compared to sham. “IZERVAY slowed loss of photoreceptors and disease progression as early as six months with up to a 35% reduction in the first year of treatment,” he added.

Across the GATHER clinical trial program7,8, the most common adverse reactions (≥ 5%) reported at 12 months in patients who received IZERVAY 2 mg were conjunctival hemorrhage (bleeding beneath the clear lining of the eye: 13%), increased intraocular pressure (increased fluid pressure of the eye: 9%) and blurred vision (8%).

The safety of IZERVAY was evaluated in over 700 patients with AMD.

“Across the GATHER clinical trial program, IZERVAY had a consistent safety profile and was well tolerated. There have been no reported cases of retinal vasculitis, retinal occlusive vasculitis or hemorrhagic occlusive retinal vasculitis,” said Dr. Dugel.

Iveric Bio was completely acquired by Astellas Pharma, Inc. (Tokyo Japan) on 11 July 2023.9

Ray of hope for GA patients

Dr. Kenneth Fong, managing director and consultant ophthalmologist at OasisEye Specialists, Malaysia said: “The approval of SYFOVRE and IZERVAY is a ray of hope for the millions of patients who are facing irreversible blindness.”

SYFOVRE is a complement factor C3 inhibitor and was approved based on the OAKS and DERBY trials which showed a 17% reduction of GA lesion growth over 2 years, he said. IZERVAY is a complement factor C5 inhibitor and was recently approved as a treatment for GA. It blocks the complement factor cascade further downstream compared to SYFOVRE. The GATHER1 and GATHER2 trials showed a 35% reduction of GA lesion growth over 6 months. 

“For the reporting of GA clinical trials, we can no longer use visual acuity improvement and OCT macula thickness as markers of drug efficacy. Modern retinal practices now need to acquire imaging tools like scanning laser ophthalmoscopes that are able to perform fundus autofluorescence imaging that can accurately measure the GA lesion size at the macula and track its progression,” he explained.

“Intraocular inflammation is one of the feared adverse events from intravitreal injection and post-approval monitoring of patients receiving new medications is essential,” he added.

While such adverse events were not highlighted in the pre-approval OAKS and DERBY trials, 8 cases of retinal vasculitis after SYFOVRE injection were reported by the American Society of Retinal Specialists (ASRS), he pointed out.

“The cause is uncertain but the manufacturers suggest that this may be due to the 19 g filter needle that was supplied with the medication. This is a disappointing event as the drug itself requires a dosing schedule of every 25 to 60 days for at least a year to have some effect to slow progression.”

Patients will not expect to see any improvement in vision with administration of either drug, he noted.

Professor Gemmy Cheung, head and senior consultant of the Medical Retina Department at Singapore National Eye Centre, said the two drugs were not yet available in Singapore.

“Of course it is exciting to have treatment approved for GA for the first time. Although there appear to be fewer patients with GA in Asia, there are definitely some patients who could benefit from these therapies,” she said.

At least the ASRS, however, expressed caution due to the reported cases of vasculitis linked to SYFOVRE, and said that this may affect doctors’ decisions in prescribing the drug.

According to studies, GA is uncommon in Asian populations compared with those of European ancestry. Even within Asia, geographic differences in GA prevalence were seen, with prevalence in South Asia compared with East Asia.


  1. Apellis Press Release. 17 February 2023. Available at: 
  2. Astellas Pharma Inc. Press Release. 05 August 2023. Available at: 
  3. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. Ophthalmology. 2020;127(2):186-195. [Epub 2019 Jul 16]
  4. Liao DS, Metlapally R, Joshi P. Pegcetacoplan treatment for geographic atrophy due to age-related macular degeneration: a plain language summary of the FILLY study. Immunotherapy. 2022;14(13):995-1006. [Epub 2022 Jul 21]
  5. Hoy SM. Pegcetacoplan: First Approval. Drugs. 2021;81(12):1423-1430. 
  6. GlobeNewsWire. Apellis Press Release. 22 August 2023. Available at: 
  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. 
  8. Patel SS, Lally DR, Hsu J, et al. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye (Lond). 2023; Mar 24 [Online ahead of print]
  9. Astellas Pharma, Inc. Press release. 12 July 2023. Available at:
Dr Ken Fong (1)

Dr. Kenneth Fong is recognized as an ophthalmologist in the United Kingdom, Australia and Malaysia. He graduated with a medical degree from the University of Cambridge in 1998 and trained to be an eye surgeon in London. Dr. Fong then spent two more years training in the U.K. and at the Royal Perth Hospital in Australia to subspecialize in retina. After 18 years of working in the U.K. and Australia, he returned to Malaysia in 2009 to serve as associate professor, consultant ophthalmologist and retinal surgeon at the University of Malaya in Kuala Lumpur. He is currently the managing director of OasisEye Specialists in Kuala Lumpur. Dr. Fong is the president of the Malaysian Society of Ophthalmology and serves as a council member for the APVRS. [Email:]

Gemmy Cheung pic (1)

Prof. Gemmy Cheung is currently a professor at Duke-NUS Medical School, National University of Singapore, and head of the Medical Retina Department at Singapore National Eye Center (SNEC). Her research focuses on retinal diseases, including age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and myopic macular degeneration, as well as risk factors for these conditions that may be unique to Asian populations. Prof. Cheung has more than 200 peer-reviewed publications and serves on the editorial boards of several journals, including the American Journal of Ophthalmology, Retina and Eye. [Email:]

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