The roadmap to geographic atrophy treatment: A journey of trials and promise

This review covers advancements in geographic atrophy (GA) research. It discusses genetic contributions to AMD, explores treatment strategies, including complement inhibition, and highlights recent FDA approvals, safety concerns and promising future directions.


| COM PL ET E D T R I A L S
Over the past decade, a multitude of clinical trials have been conducted, each contributing significantly to our understanding of geographic atrophy (GA) and its potential therapeutic interventions (Loewenstein & Trivizki, 2023).
Genetic association studies revealed that genetic polymorphisms associated with AMD have been localized within or in proximity to genes which encode complement proteins (Gehrs et al., 2010).
Protective alleles associated with the complement pathway also have been reported.Genetic variations in a regulator of the alternative complement pathway are considered protective against AMD (Hageman et al., 2005).These insights led to the treatment approach to inhibit complement activation by targeting effector molecules, such as C3 and C5, and D.
In 2014, the COMPLETE trial evaluated the efficacy of eculizumab, a humanized monoclonal antibody which acts by inhibiting C5 and preventing terminal complement activation and formation of membrane attack complex (Table 1).The intravenous medication did not lead to significant reduction in the GA growth rate at 26 or 52 weeks (Yehoshua et al., 2014).Complement factor D is considered a pivotal regulator of the alternative complement pathway and acts early in the alternative complement pathway.The MAHALO trial in 2017 was a phase 2 clinical trial and investigated intravitreal lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against CFD (Table 1; Yaspan et al., 2017).Results indicated a 20% reduction in GA growth rate, with a more pronounced 44% reduction in CFI risk-allele carriers.Subsequently, the CHROMA and SPECTRI studies in 2018 were two identical phase 3 trials that aimed to evaluate the efficacy and safety of intravitreal lampalizumab (Table 1) (Edmonds et al., 2023a;Edmonds et al., 2023b;Heier et al., 2020;Holz et al., 2018).Disappointingly, they did not meet their primary endpoint, and there was no significant difference in GA lesion growth between the lampalizumab and sham groups, including across prespecified subgroups by complement factor I-profile biomarker, leading to the discontinuation of lampalizumab for GA.
Pegcetacoplan (Syfovre; Apellis Pharmaceuticals) inhibits the C3 complement pathway and its efficacy and safety have been shown in the randomized, double-masked, sham-controlled phase 2 FILLY trial in 2020 (NCT02503332; Table 1; Liao et al., 2020).Pegcetacoplan was administered monthly or every other month (EOM) by intravitreal injection and reduced GA growth rate by 29% in the monthly, and 20% with EOM administration, compared to sham treatment.Post hoc analysis showed a reduction in the progression rate from incomplete to complete retinal RPE and outer retinal atrophy in regions outside the GA area (Nittala et al., 2022).Furthermore, the drug seems to have a protective effect on the retina surrounding the GA lesion, as shown by thicker photoreceptor inner segment layers and thicker outer nuclear layer, in treated eyes compared with sham (Riedl et al., 2022).Subsequently, two large phase 3 randomized controlled clinical trials OAKS and DERBY (NCT03525600 and NCT03525613) confirmed the efficacy of pegcetacoplan in reducing GA expansion (Table 1; Goldberg et al., 2022).While the DERBY trial reported a non-significant reduction in GA growth of 12% with monthly dosing and of 11% with EOM dosing, the OAKS trial observed a significant reduction in GA growth of 22% over 12 months with monthly dosing and of 16% with EOM dosing.The combined 18-month results from the DERBY and OAKS showed that pegcetacoplan reduced the rate of GA lesion growth by 23% and 18%, respectively, compared with the sham groups.In February 2023, these data have led to a breakthrough approval by the FDA of pegcetacoplan as the first treatment for GA in.
GALE (NCT04770545) is a phase 3, open-label, multicentre, extension study to evaluate the long-term safety and efficacy of pegcetacoplan, aiming to evaluate the long-term incidence and severity of ocular and systemic treatment emergent adverse events as well as change in the total area of GA lesions, as measured by fundus autofluorescence (Table 2).The study includes more than 80% of participants who completed the phase 3 OAKS and DERBY studies, as well as few patients from the phase 1b trial.All patients-those who were in the treatment and in the sham arms-are receiving monthly or EOM treatment for up to 36 months.The recently released 6-months GALE study results (i.e. between 24 and 30 months follow-up in total) demonstrated reduced GA lesion growth of 39% and 32% with monthly and EOM treatment, respectively, compared with the projected sham arm.Specifically, the treatment reduced non subfoveal GA lesion growth by 45% and 33% with monthly and EOM, respectively, compared with the projected sham arm (Meeting & https:// inves tors.apell is.com/ news-relea ses/ news-relea se-detai ls/ apell is-annou nces-seven -abstr acts-accep ted-oralprese ntation 2023a).
Another interesting point is the perseveration of the photoreceptors.Pegcetacoplan demonstrated its efficacy in preserving photoreceptors beyond the regions of retinal pigment epithelium (RPE) atrophy, a pivotal goal in managing eyes with geographic atrophy (GA) to mitigate vision deterioration.Post hoc analysis, on both monthly and bi-monthly regimens, exhibited a pronounced thickness in the outer nuclear layer (ONL) relative to the control group as well as a thicker photoreceptor inner segment layer was observed in pegcetacoplan-treated eyes by Month 12 (Pfau et al., 2022).Even though were no safety reports on retinal vasculitis during the trial period, recently rare events of intraocular inflammation and severe occlusive vasculitis have been reported in real-world treatment.This topic is still under investigation.In the phase 3 programme, the rate of intraocular inflammation was found to be 0.26% per injection among all patients treated with pegcetacoplan, and there were no cases of retinal vasculitis after more than 23 000 injections to date (Committee 2023).
In August 2023, the US Food and Drug Administration (FDA) granted approval for the use of another drug, Zervay (avacincaptad pegol intravitreal solution) for GA, without any specific limitations (Table 2).Functionally analogous to pegcetacoplan, avacincaptad pegol acts on the complement system by targeting and inhibiting the C5 component.
This approval was substantiated by the compelling outcomes observed in the GATHER1 and GATHER2 phase 3 clinical trials (Table 2).Specifically, the GATHER1 trial, conducted within the same year, evaluated the efficacy of avacincaptad pegol and documented a notable 27.4% reduction in GA growth rate over a span of 12 months with a 2 mg monthly dosage, and a 27.8% reduction with a 4 mg monthly dosage (Patel et al., 2023).
Subsequently, the GATHER2 phase 3 trial in 2022 further assessed avacincaptad pegol and reported a 14.3% decline in GA growth rate over a 12-month duration.Of significant mention is the fact that patients administered with avacincaptad pegol exhibited a remarkable 56% reduction in the risk of enduring vision loss over a year (15-letter loss), in comparison with the control group.The safety profile of avacincaptad pegol, as evidenced by the GATHER programme, was commendable, with no significant instances of intraocular inflammation or retinal vasculitis being reported (Jaffe et al., 2021).
The Phase 2 ARCHER trial results (NCT04656561) released by Annexon Inc., indicated that their complement therapy, ANX007, significantly helped in maintaining visual acuity and preventing vision loss over a 12-month timeframe (Table 1).(Meeting & https:// ir.annex onbio.com/ news-relea ses/ news-relea se-detai ls/ annex on-repor t-arche r-phase -2-trial -resul ts-geogr aphic -atrophy 2023b) This was measured by changes from the initial levels in the best corrected visual acuity (BCVA) for both foveal and non-foveal patients.In the group receiving monthly treatment, there was a 72% reduction in the risk of losing 15 letters (n = 89, p = 0.006).The group treated every other month experienced a 48% reduction in the risk of a 15-letter loss (n = 92, p = 0.064).Additionally, the combined treatment group demonstrated a 59% reduction in the risk of losing more than 15 letters (n = 181, p = 0.008).However, there was no statistically significant change in the rate of geographic atrophy lesion growth.Despite that limitation, the ARCHER results lend support to ANX007's ability to protect photoreceptor cells, synapses and function.Annexon Inc. is planning to consult with regulatory bodies to decide the best next steps for ANX007. of procedurerelated adverse events at 3 months -Most pts showed an improvement or maintenance of baseline in the OpRegen-treated eye -Improvement was most apparent in the 5 pts with extensive OpRegen coverage, resulting in maintenance and improvement of outer retina structure in treated eyes vs worsening in fellow eyes (mm 2 ; RPE 2.6 ± 2.5 gain vs 1.2 ± 1.5 loss; ELM 0.2 ± 0.6 gain vs. 1.3 ± 0.8 loss) An elevated of new-onset macular neovashas been observed with the use of intravitreal complement inhibitors.In the GATHER1 study, the conversion rate to MNV was reported as 11.9% and 15.7% for avacincaptad pegol treatment with doses of 2 and 4 mg, respectively, at Month 12 (Patel et al., 2023).In the FILLY trial, the MNV conversion rate exhibited a dose-dependent rise by the 18-month point, reaching 20.9% for monthly injections and 8.9% for EOM pegcetacoplan, in comparison to 1.2% with sham treatment.When the OAKS and DERBY trials were jointly analysed, the MNV conversion rate at 24 months stood at 12% for monthly injections and 7% for EOM pegcetacoplan, compared with 3% in the sham group (Goldberg et al., 2022).The higher rate observed in the FILLY trial could potentially be attributed to the relatively greater proportion of patients with a history of exudative AMD in the fellow eye who were enrolled in the study (Nittala et al., 2022).

| ONGOING TRIALS
Numerous clinical trials are in progress at the moment.The GOLDEN trial is evaluating IONIS-FB-LRx, while a trial identified by NCT05019521 is examining Danicopan (Table 2).Three trials-FOCUS, EXPLORE and HORIZON-are all scrutinizing GT011, which is a subretinal gene therapy (Table 2).Ocular gene therapies like GT005 seek to balance the complement system by enhancing the production of complement factor I (CFI) protein, thereby mitigating inflammation.Another gene therapy, AAVCAGsCD59, boosts the soluble form of CD59, which functionally resembles naturally occurring CD59, and has demonstrated encouraging outcomes in slowing down GA progression (Table 2).
Stem cell therapy holds promise for regenerating retinal pigment epithelium (RPE) and damaged photoreceptors.Several clinical trials tested RPE cells derived from human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs)-derived RPE cells and mesenchymal stem cells (MSCs).In a Phase I/IIa trial (NCT02286089), OpRegen hESC-derived RPE showed favourable safety indicators in 12 patients (Table 2) (Banin et al., 2019).Cells were detected long-term in the subretinal space, with noted RPE layer improvements.Moreover, improvements of the ellipsoid zone and directional growth changes in the area of GA have been seen in single patients (Riemann et al., 2020).

| FUTURE PROSPECTS
The advancement in GA treatment appears optimistic, with numerous innovative drugs and therapeutic approaches on the horizon.Current research endeavours are anticipated to shed light on the effectiveness and safety of these emerging treatments.Furthermore, insights garnered from concluded studies, encompassing both their challenges and shortcomings, will indubitably shape subsequent investigations and innovations in this domain.A particularly promising direction is the exploration of neuroprotective agents.Preliminary research indicates encouraging outcomes, hinting that these agents might mitigate apoptosis and possibly decelerate GA progression in AMD.Notable examples of such medications encompass antiapoptotic compounds like tauroursodeoxycholic acid (TUDCA), therapies associated with dopamine and growth stimulants such as ciliary neurotrophic factor (CNTF; Lawson et al., 2016;Pardue & Allen, 2018).The emergence of gene therapies is notably exhilarating.Preliminary outcomes from clinical investigations are heartening, particularly in relation to the enduring expression of therapeutic proteins.Comprehensive studies are imperative prior to their mainstream adoption to circumvent unforeseen repercussions.Gene therapies herald a transformative approach in addressing age-related macular degeneration, geographic atrophy and other senescent ocular conditions.Their success could potentially offer a lasting remedy for GA, diminishing the frequency of treatment interventions.Nonetheless, extensive exploration is requisite to ascertain their safety and effectiveness.

R E F E R E NC E S
Completed trials.
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