Clinical Outcomes of Treatment of Geographic Atrophy: A Narrative Review

In the Western world, age-related macular degeneration (AMD) is one of the leading causes of blindness and vision loss [1], which is associated with a loss of quality of life [2, 3]. AMD is classified into neovascular AMD (NVAMD) and non-neovascular AMD, also referred to as “wet” and “dry” AMD, respectively [4, 5]. Advanced non-neovascular AMD can progress to geographic atrophy (GA), a condition that severely affects visual acuity [5]. While the first treatment for NVAMD was approved by the U.S. Food and Drug Administration (FDA) in 2004, no treatment existed at that time for GA, leaving patients with dry AMD unable to prevent disease progression and the associated vision loss. Previously, the AREDS trials investigated the efficacy of specific vitamin supplements, documenting a reduction in the risk of progression to advanced AMD and a decreased likelihood of developing NVAMD [6]. In addition to vitamin supplementation, smoking cessation was among the few preventive measures recommended for patients at risk of AMD progression [7].

Two drugs are currently FDA-approved for the treatment of GA: pegcetacoplan (SYFOVRE) [8] and avacincaptad pegol (Izervay) [9, 10]. Both treatments involve intravitreal injections (IVI), a method that may cause apprehension among some patients due to its invasive nature. Pegcetacoplan, a drug targeting complement component 3 (C3), was the first treatment for GA to receive FDA approval in February of 2023. Avacincaptad pegol (ACP), targeting complement component C5, was approved in August of 2023, making it the second drug available for the treatment of GA.

The complement pathway has been shown to play a role in the development and progression of AMD and GA, making its components potential therapeutic targets [11, 12]. Elevated plasma levels of C3 and C5 subtypes have been detected in AMD patients [13, 14]. An overly active complement system is implicated in the pathological process of AMD and GA, but the complement system also plays an important role in the innate immunological protection of the retina. Therefore, the goal in complement inhibition is to eliminate the negative complement overactivation while still preserving the overall protective immunological properties of the complement pathways. Pegcetacoplan targets the C3 complement protein, which is essential in multiple complement pathways. ACP targets the more downstream complement component C5.

The introduction of these new therapies may aid in preventing blindness in patients with GA, and numerous other potential treatments are currently under investigation. This article aims to give an overview of the clinical outcomes of GA treatment and to discuss which patient groups may benefit most from these therapies.

PubMed, Cochrane, and clinicaltrials.gov databases were searched for publications and protocols. Conference abstracts were not deemed eligible for inclusion. Inclusion criteria were randomized controlled trials or meta-analyses of randomized controlled trials; and outcomes were measured either by GA lesion growth or best-corrected visual acuity (BCVA). Six articles were deemed relevant for inclusion and selected to address the scope of this narrative review. The primary outcome evaluated in this study was the reduction of GA growth. Secondary outcome included BCVA. Ethics compliance: This narrative review is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. According to Danish law, review articles do not require institutional review board approval.

The results are summarized in Table 1.

Fu et al. [8] investigated the impact of pegcetacoplan IVIs on the progression of GA using optical coherence tomography (OCT). The study analyzed 11,614 spectral domain (SD)-OCT volumes collected from 936 out of a total of 1258 participants with GA in the OAKS and DERBY studies. Participants were randomized into four groups: monthly IVI (310 participants), IVI every other month (309 participants), sham monthly (157 participants), and sham every other month (160 participants). Data were collected from baseline to 24 months, revealing a significantly slower rate of GA progression in the treatment groups (p < 0.001). Specifically, the monthly IVI group demonstrated a reduction of − 0.86 mm² in atrophy growth compared to the pooled sham group, while the IVI every other month group showed a reduction of − 0.69 mm² (p < 0.001). However, no significant effect on best-corrected visual acuity (BCVA) was reported. With FAF, monthly IVI and every other month IVI were also associated with reduced GA lesion growth compared to sham treatment. The article does not address potential adverse effects, such as post-injection infections or the development of neovascular AMD (nAMD) among participants.

Patel et al. [10] evaluated the efficacy of ACP in reducing the progression of geographic atrophy (GA) and its impact on vision. In the GATHER1 trial, 286 participants were randomized to receive 1 mg (n = 26), 2 mg (n = 67), or 4 mg (n = 125) ACP or sham (n = 68) IVI monthly, while the GATHER2 trial randomized 448 participants to receive 2 mg ACP (n = 225) or sham (n = 223) IVI monthly. Over 18 months, ACP treatment significantly reduced GA growth compared to sham, with reductions of 28.1% for 2 mg (p = 0.0072) and 30.0% for 4 mg (p = 0.0051). However, rates of conversion to nAMD were higher in ACP-treated eyes (11.9% for 2 mg, 15.7% for 4 mg) compared to sham (2.7% and 2.4%, respectively). Danzig et al. [9] reported pooled 12-month data from GATHER1 and GATHER2, highlighting reduced vision loss in ACP-treated eyes. Fewer eyes lost ≥ 10, ≥ 15, or ≥ 20 BCVA ETDRS letters compared to sham. For example, 11.6% of ACP-treated eyes lost ≥ 10 letters versus 14.1% in sham (p = 0.03). Persistent vision loss (≥ 15 letters over two consecutive visits) occurred in 3.4% of ACP-treated eyes versus 7.8% in sham (p = 0.02) [9]. These findings suggest that ACP effectively slows GA progression and mitigates vision loss, though increased nAMD rates remain a concern.

Keenan et al. [15] performed a post hoc analysis of data from the AREDS and AREDS2 trials to determine whether dietary supplements reduced GA progression. The AREDS trial included 3640 participants with early or advanced AMD, randomized to antioxidants, zinc, antioxidants plus zinc, or placebo, with a follow-up over 5 years. AREDS2 included 4203 participants randomized to lutein/zeaxanthin, DHA/EPA, lutein/zeaxanthin plus DHA/EPA, or placebo, also with 5 years of follow-up. In AREDS, antioxidant supplementation significantly slowed GA progression toward the central macula compared to placebo (50.7 μm/year vs. to 72.9 μm/year, p = 0.012). Antioxidants plus zinc supplementation showed no effect on GA progression. Lutein/zeaxanthin supplementation in AREDS2 significantly slowed GA progression compared to placebo (84.5 μm/year vs. 105.3 μm/year, p = 0.017). Slower GA progression was observed with b-carotene supplementation compared to no b-carotene (0.264 mm²/year vs. 0.301 mm²/year p = 0.009). The study concluded that the AREDS2 formulation may be effective in preventing GA growth toward the macula.

Franceschelli et al. [16] examined the safety and efficacy of low-fluence light stimulation (photobiomodulation (PBM)) delivered via a wearable device designed to emit extremely low irradiance LED light at a peak wavelength of 630 nm and a corneal irradiance of 15 μW. The study included 60 participants divided into a treatment group (n = 33) and a placebo group (n = 27). Participants in the treatment group used the device for 10 min daily across ten sessions, excluding weekends, while the placebo group wore the device without active LED light in the same time frame. The study found no significant differences between the treatment and the placebo group in terms of anatomical parameters. However, a statistically significant improvement in BCVA was observed in the treatment group, with BCVA at 40 cm improving from 0.58 logMAR at baseline to 0.44 logMAR after the tenth treatment (p < 0.001). In contrast, the placebo group showed minimal change (from 0.59 to 0.60 logMAR). Similar improvements were observed at 4 m, with the treatment group improving from 0.61 to 0.46 logMAR, while the placebo group experienced a slight decline (from 0.60 to 0.62 logMAR). Microperimetry results indicated an improvement in the treatment group from 12.20 to 13.9 dB (p < 0.001), while the placebo group showed no significant change (from 14.30 to 14.01 dB). The study did not investigate long-term effects or potential side effects, leaving uncertainties regarding the durability of the benefits and possible adverse outcomes.

Rassi et al. [17] conducted a meta-analysis of three randomized controlled trials (RCTs) evaluating the efficacy of PBM in managing dry age-related macular degeneration (AMD). The study included a total of 247 eyes (151 in the PBM group and 96 in the sham group). PBM demonstrated a statistically significant improvement in BCVA with a mean difference (MD) of 1.76 ETDRS letters compared to sham (p = 0.04). However, the improvement did not meet the threshold for clinical relevance (MCID: 6.8 letters). PBM resulted in a significant reduction in drusen volume (MD: − 0.12 mm³, p = 0.02). Despite statistical significance, this change did not reach clinical relevance (MCID: 0.39 mm³). No significant difference was observed between PBM and sham groups in terms of GA area progression (MD: − 0.53 mm², p = 0.25). A trial sequential analysis revealed that the current sample size was insufficient for definitive statistical conclusions, as the required information size was not met for any outcome. All included studies were found to have a high risk of bias, particularly in measuring outcomes and missing data. While PBM showed statistically significant improvements in BCVA and drusen volume, these results did not translate into clinically meaningful benefits. Larger, higher-quality RCTs with longer follow-up periods are needed to validate PBM’s efficacy and assess its impact on GA progression.

This narrative review highlights various treatment options for geographic atrophy (GA), emphasizing their potential benefits and associated challenges. Intravitreal therapies, such as pegcetacoplan and ACP, have emerged as promising approaches to slowing the progression of GA. Additionally, photobiomodulation therapy (PBM) and dietary supplementation have been explored as non-invasive alternatives, with some improvements in visual outcomes and slower disease progression, particularly in earlier stages.

The current evidence underscores significant advancements in GA treatment, particularly through complement inhibition. Pegcetacoplan, as examined by Fu et al. [8], significantly reduced GA growth; however, its lack of impact on best-corrected visual acuity (BCVA) raises questions about its functional benefit in the early stages of disease progression. Safety concerns, such as the potential development of nAMD and post-injection complications, remain critical areas that require further long-term monitoring [18]. There have been reported cases of retinal vasculitis after intravitreal pegcetacoplan injection, raising concerns about the safety of this treatment [19]. There is currently no known etiology for vasculitis in pegcetacoplan treatment, and further studies are warranted to explore the risk of retinal vasculitis related to treatment.

ACP, another complement inhibitor, demonstrates similar benefits in slowing GA progression in the GATHER1 and GATHER2 trials [9, 10]. Furthermore, it offers some protective effects against vision loss [9, 10]. A recent study by Corradetti et al. [20], a post hoc analysis of the GATHER1 trial, found a significant reduction in progression rates from drusen to retinal epithelium and outer retinal atrophy among the ACP treatment group, emphasizing the importance of early intervention. Nonetheless, increased rates of nAMD among treated eyes highlights a critical limitation of current pharmacological treatments: while they slow anatomical progression, they may introduce complications that could significantly compromise visual outcome.

Non-invasive approaches, such as PBM therapy, have garnered interest as alternatives to frequent intravitreal injections. PBM has demonstrated improvements in visual function, including best-corrected visual acuity and microperimetry outcomes, which may stem from its ability to enhance mitochondrial function and reduce oxidative stress [21, 22]. However, current studies reveal no significant impact on GA lesion growth, and the observed benefits in visual function remain modest and inconsistent across trials. The lack of meaningful changes in GA lesion size suggests that PBM’s role may be limited to symptomatic improvement rather than disease modification. Small sample sizes and limited follow-up periods further restrict the generalizability of these findings.

Dietary supplementation, particularly formulations including lutein, zeaxanthin, and beta-carotene, offers a low-risk strategy for managing early and intermediate AMD. The findings from the AREDS and AREDS2 trials highlight the potential of nutritional interventions to slow GA progression, particularly toward the central macula [15]. While antioxidant therapies are unlikely to reverse advanced GA, they remain an important preventive measure in earlier stages of the disease.

Thus far, it seems that the only non-invasive treatment options available are reserved for patients with only mild disease, in which the treatment goal is delaying progression rather than disease modification. In these patients, the risk associated with IVI therapy might surpass the potential treatment benefit. In patients with more severe GA, intravitreal injections with ACP or pegcetacoplan are the only available treatment options at this point. Aside from GA severity, patient ethnicity may be an important factor to consider in treatment decisions. Studies have shown GA characteristics in Asian populations to differ from those in Western populations [23]. Future studies are warranted to clarify whether the new complement modifying GA treatments, ACP and pegcetacoplan, will yield similar efficacy in this population specifically.

In addition to complement inhibition, as in ACP and pegcetacoplan, gene therapy is emerging as a promising avenue for GA treatment. For instance, GT005 is an AAV-based gene therapy designed to rebalance an overactive complement system by increasing the expression of complement factor I, a natural inhibitor of the complement pathway [24]. Similarly, JNJ-81201887 (formerly HMR59) is under investigation for its potential to slow GA progression by enhancing the eye’s ability to regulate complement activation [25]. These gene therapies aim to provide sustained treatment effects with a single administration, potentially mitigating the risks associated with repeated intravitreal injections.

While these innovative approaches offer hope, they also underscore the complexity of GA management. The interplay between therapeutic efficacy and potential adverse effects, such as the development of neovascular complications, necessitates a cautious and well-monitored application of these treatments. Continued research is essential to optimize these therapies, ensuring they provide meaningful clinical benefits while minimizing patient risks.

Both pegcetacoplan and avacincaptad pegol are high-cost treatments. Recent studies have conducted cost-effectiveness analyses of these drugs in the treatment of geographic atrophy [26, 27]. Treatment of GA with pegcetacoplan every other month has been found to be more cost-effective than at every month. As atrophy progression increases, the marginal cost–benefit ratio was found to increase as well [26], indicating that this treatment may not be made available for all disease stages in a real-life clinical setting. In the treatment of extrafoveal lesions, ACP has been found to be less cost-effective than pegcetacoplan for both monthly and every-other-month treatment regimens [27].

The heterogeneity of GA progression highlights the importance of personalized treatment approaches. Combining therapies, such as complement inhibition with photobiomodulation or dietary supplementation, may offer synergistic benefits that warrant further exploration. Patient adherence remains a key challenge, particularly for treatments requiring frequent intravitreal injections. Non-invasive options, though less robust in their efficacy, may provide an acceptable alternative for patients seeking lower treatment burdens.

The management of geographic atrophy has advanced significantly, with complement inhibition therapies like pegcetacoplan and ACP demonstrating clear benefits in slowing lesion progression. However, safety concerns, particularly the risk of neovascular complications, must be addressed through long-term studies. Photobiomodulation and dietary supplementation provide alternative strategies, offering modest benefits in visual function and disease progression, particularly in earlier stages. Moving forward, larger, high-quality trials are essential to establish the long-term safety, efficacy, and optimal integration of these therapies into clinical practice. Combining treatments and improving patient adherence will be critical to achieving meaningful outcomes for patients with GA.