Avacincaptad Pegol Shows Promise as a Geographic Atrophy Slowing Therapy

Image Credit: Paul Whitten/ Science Source
Carolyn Majcher, OD, discusses potential changes in the optometrist’s role in monitoring geographic atrophy with the availability of new geographic atrophy drugs.

Avacincaptad pegol treatment may yet open a new treatment possibility for patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). With few therapeutic options available to slow disease progression, patients with GA remain at risk of experiencing central vision loss. Data from 2 clinical trials, the GATHER 1 (ClinicalTrials.gov Identifier: NCT02686658) and GATHER 2 (ClinicalTrials.gov Identifier: NCT04435366), suggest that avacincaptad pegol may be able to limit GA progression while providing a tolerable safety profile.1,2 

In the GATHER 1 clinical trial, researchers performed a 2-part investigation. In part 1, the team randomly assigned participants (n=77) 1:1:1 to treatment with 1 mg avacincaptad pegol, 2 mg avacincaptad pegol or sham treatment. The second part of the study, which was conducted simultaneously, involved a 1:2:2 random assignment to treatment with 2 mg avacincaptad pegol (100 µl injection plus 1 sham administration), 4 mg avacincaptad pegol (2 separate 2 mg injections) or sham treatment. The team examined the drug’s safety profile and assessed GA change rates using fundus autofluorescence during the 18-month study duration.1 

The treatment demonstrated an ability to reduce GA lesion growth by 28.1% among individuals treated with 2 mg avacincaptad pegol compared with sham treatment (least squares mean values, 0.60 vs 0.43 mm) and by 30% among individuals treated with 4 mg of the drug compared with sham treatment (least squares mean values, 0.56 vs 0.39).1 

Visual outcomes were also better in individuals treated with avacincaptad pegol — participants treated with 2 and 4 mg of the drug experienced a 12.7 and 4.27 Early Treatment Diabetic Retinopathy Study (ETDRS) letter loss compared with 15.1 and 7.07 of individuals undergoing sham treatment, respectively. A total of 2 participants experienced adverse events (optic ischemic neuropathy and retinal detachment), but these were not determined to be related to treatment, according to the report.1 

On February 16, 2023, the US Food and Drug Administration (FDA) completed a filing review and accepted a new drug application (NDA) for avacincaptad pegol. A Prescription Drug User Fee Act (PDUFA) target date of August 19, 2023 has been assigned to this application. Previously, the FDA granted the drug Fast Track and Breakthrough Therapy designations.3

This new treatment option shows promise for improving outcomes in individuals with GA, but how will it affect the way optometrists advise, manage, and refer patients? Carolyn Majcher, OD, an associate professor at Northeastern State University Oklahoma, College of Optometry, who presented a review of the GATHER trials at the American Optometric Association’s ePoster Sessions, explains how this novel treatment may affect the way optometrists manage patients with GA.4 

Credit: Carolyn Majcher, OD

Q: With new geographic atrophy drugs becoming available, how does the optometrist’s role in early disease management change? Should optometrists be referring earlier?

Dr Majcher: Detect early and refer early. Because there were no treatment options available before February 2023, I think most optometric physicians were monitoring and observing patients with GA internally. In addition, the primary focus of retinal imaging was identifying exudative features that would warrant referral for anti-vascular endothelial growth factor (VEGF) therapy, with less emphasis paid to GA development. Equal emphasis must now be placed on utilizing multimodal retinal imaging technologies to identify early extrafoveal GA, since studies show that there is particular benefit in treating noncentral, rather than center-involved, GA with complement inhibition. Post hoc analysis of combined data from the GATHER 1 and GATHER 2 trials, in which all patients had noncentral GA at enrollment, found that there was a 56% reduction in the risk of vision loss with avacincaptad pegol (ACP) 2 mg compared with sham over the first 12 months of treatment. 

Relying on visual acuity decline to refer will undoubtedly result in delayed treatment and irreversible central vision loss, since acuity is often spared until the fovea becomes involved, at which point the patient notices a rather sudden and severe decrease in vision. OCT [optical coherence tomography] and fundus autofluorescence [FAF] are the primary and most sensitive imaging methods to identify GA (not color fundus photography) and these tests should be performed staring at intermediate stage of AMD in order to screen for early GA and also identify high-risk biomarkers that increase the risk of future GA development. OCT assessment provides powerful prognostic value because it provides high-resolution, detailed images of the individual retinal layers that allows us to detect the earliest atrophic lesions before they become clinically apparent with ophthalmoscopic exam or FAF. There are also high-risk OCT biomarkers for GA development, such as subretinal drusenoid deposits (reticular pseudodrusen), loss of the ellipsoid zone, subsidence or sinking of the of the OPL [outer plexiform layer], hyporeflective wedges, and hyperreflective sub-RPE [retinal pigment epithelium] crystalline deposits. Optometric physicians need to be on the lookout for such features and when identified, patients should be monitored more closely and frequently for GA development.

Sending documentation of GA progression to the retinal specialist when referring is also important. Retinal specialists may consider the rate of expansion when deciding whether or not to treat and how frequent to treat (monthly or bimonthly), and proof of a reduced growth rate will likely be required by some insurance payers.

Q: How should clinicians monitor disease regression for patients being treated with a C5 inhibitor?

Dr Majcher: This is a great question because GA will not regress; rather, it will progress at a slower rate than if treatment was withheld. Therefore, educating patients on realistic treatment expectations (vision will continue to decline but at a slower rate) is critical to prevent treatment drop-out and promote compliance. Patient education should also include a discussion of the chronic nature of this treatment and how a significant benefit is usually not seen until about 1 year of therapy.

Right now, I can quantitatively track GA progression using the advanced RPE analysis sub-RPE slab. The subRPE slab allows you to visualize areas of choroidal hyper transmission that occur following RPE atrophy within GA lesions. This analysis automatically delineates areas of GA and graphs over time and quantitative GA area measures, as well as the closest distance to the foveal center. I’d expect with successful treatment over at least 1 year’s time to see a change in the slopes for these graphs (slower GA enlargement rate and less quickly approaching the foveal center). Of course, it may be more simplistic to consider any treated eye in which the GA is still extrafoveal (prevented central invasion) to be a more qualitative success. To compare this to the GATHER 1 and GATHER 2 trials, change in GA area was assessed using FAF imaging. As far as I am aware, there is no commonly used, commercially available review software that will automatically delineate and measure GA size from FAF images.

I think optometric physicians can think about GA much like glaucoma since there are so many similarities between these diseases, such as the progressive course they both take and the fact that both conditions often spare central vision until end stage disease. Glaucoma causes progressive “atrophy” or irreversible tissue loss of the optic nerve axons, and similarly, GA causes progressive irreversible loss of the RPE and photoreceptors. Available treatments for both conditions slow progression rather than restore and improve vision. Eye care providers routinely and diligently screen for glaucoma, making an effort to detect it early, and I believe GA should be considered with similar regard. In the future, will there be legal ramifications if patients with progressing extrafoveal GA are not offered an option of referral for consideration of complement inhibition?

Q: What about the optometrist’s responsibilities during the course of treatment? What kinds of adverse reactions should optometrists be monitoring for and how likely are they? 

Dr Majcher: Optometric physicians should continue to be aware that endophthalmitis is a potential vision threatening complication of any intravitreal injection and is related to the procedure. However, when looking at the [avacincaptad pegol] 2 mg treated group from combined GATHER 1 and GATHER 2 data at 12 months, no cases of endophthalmitis were reported.

Higher rates of macular neovascularization were found with [avacincaptad pegol] 2 mg treatment compared with sham in both GATHER 1 and GATHER 2 trials (over 12 months 9% treated with [avacincaptad pegol] 2 mg compared with 2.7% with sham in GATHER 1, and 6.7% treated with [avacincaptad pegol] 2 mg compared with 4.1% with sham in GATHER 2). A similar increase in macular neovascularization conversion rates were also found in the OAKS and DERBY trials and is likely related to complement inhibition in general.

It is therefore prudent for optometric physicians to diligently monitor for exudative features (such as OCT fluid and hemorrhage) in patients undergoing complement inhibition therapy for GA and to alert the treating retinal specialist should they occur. Patients should also be educated on the risks of macular neovascularization and be encouraged to self-screen at home frequently.

That being said, exudative conversion can be effectively treated with anti-VEGF therapy, which can be done in combination with complement inhibition. The fact that neovascular or exudative AMD and GA are not mutually exclusive and can occur in combination (as well as be treated in combination) is important for optometric physicians to recognize and understand.


  1. Patel SS, Lally DR, Hsu J. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye (Lond). Published online March 24, 2023. doi:10.1038/s41433-023-02497-w
  2. Iveric Bio Announces Positive Topline Data from Zimura® GATHER2 Phase 3 Clinical Trial in Geographic Atrophy. News release. Iveric Bio. Published September 6, 2022. Accessed June 14, 2023. https://investors.ivericbio.com/news-releases/news-release-details/iveric-bio-announces-positive-topline-data-zimurar-gather2-phase
  3. Iveric Bio announces FDA accepts New Drug Application and grants Priority Review for avacincaptad pegol for the treatment of geographic atrophy. News release. Iveric Bio. Published February 16, 2023. Accessed June 14, 2023. https://www.businesswire.com/news/home/20230216005773/en/Iveric-Bio-Announces-FDA-Accepts-New-Drug-Application-and-Grants-Priority-Review-for-Avacincaptad-Pegol-for-the-Treatment-of-Geographic-Atrophy.
  4. Majcher C, Khanani A, Danzig C, et al. Avacincaptad pegol for geographic atrophy: a review of the GATHER1 and GATHER2 clinical trials. Poster presented at: American Optometric Association 2023 ePosters Virtual Event; June 13-14, 2023; Washington, DC. ePoster 790