{"id":60657,"date":"2024-06-10T16:36:38","date_gmt":"2024-06-10T15:36:38","guid":{"rendered":"https:\/\/www.touchophthalmology.com\/?p=60657"},"modified":"2024-06-13T16:47:41","modified_gmt":"2024-06-13T15:47:41","slug":"review-and-appraisal-of-current-and-investigational-complement-system-inhibitory-therapy-for-geographic-atrophy-secondary-to-age-related-macular-degeneration","status":"publish","type":"post","link":"https:\/\/www.touchophthalmology.com\/macular-degeneration\/journal-articles\/review-and-appraisal-of-current-and-investigational-complement-system-inhibitory-therapy-for-geographic-atrophy-secondary-to-age-related-macular-degeneration\/","title":{"rendered":"Review and Appraisal of Current and Investigational Complement System Inhibitory Therapy for Geographic Atrophy Secondary to Age-related Macular Degeneration"},"content":{"rendered":"
Age-related macular degeneration (AMD) is a chronic deterioration and dysfunction of the outer retinal tissue and Bruch\u2019s membrane (BrM). It is the leading cause of vision loss in people older than 60 years and is estimated to affect 288 million people by 2040 with 39 million new cases by 2050.1,2<\/sup><\/span>\u00a0AMD has the highest economic burden among vision-impairing diseases.3<\/sup><\/span>\u00a0There are two distinct types of AMD, described as either non-exudative (\u2018dry\u2019 AMD) or exudative\/neovascular (\u2018wet\u2019 AMD\/nAMD). Notably, these two types are not mutually exclusive, as dry AMD, at any stage, can eventually develop into wet AMD.4<\/sup><\/span><\/p>\n Dry AMD is clinically recognized first by the presence of drusen, which are collections of extracellular debris consisting of lipids and proteins beneath the retinal pigmented epithelium (RPE) and in BrM.5<\/sup><\/span>\u00a0While subretinal deposits can be a benign finding in normal ageing (i.e. laminar deposits), pathological studies using electron microscopy are more specific for the location of these deposits and the correlation with definitive diseases (i.e. linear deposits and drusen).6,7<\/sup><\/span>\u00a0Specific clinical classifications, including age, size of the deposits and pigment abnormalities, are used to determine the severity of drusen and their risk of progression to nAMD.8,9<\/sup><\/span>\u00a0Dry AMD is further divided into three stages: early, intermediate and advanced, each involving increasing alterations to the outer retina and subsequent vision loss. During the earliest stages of AMD, symptoms may not be present. Signs of central vision loss progress slowly, manifesting as mild blurriness and progressing to metamorphopsia as AMD worsens into later stages. Risk factors for AMD include age older than 60 years, smoking, previous cataract surgery, family history of AMD, increased\u00a0body mass index (<\/span>BMI), hypertension, cardiovascular disease and genetic predisposition involving complement system-related genes.10<\/sup><\/span>\u00a0As no U.S.\u00a0Food and Drug Administration (<\/span>FDA)-approved treatments for early and intermediate stages of AMD exist, modifiable risk factors, such as smoking, hypertension, and increased BMI, must be identified and addressed.11<\/sup><\/span>\u00a0In high-risk individuals with advanced AMD, the benefits of vitamin supplementation proposed by the Age-Related Eye Disease Study (AREDS; ClinicalTrials.gov identifier:\u00a0NCT00000145<\/span>) have significantly reduced the odds of progression to nAMD.12<\/sup><\/span>\u00a0nAMD is managed by the long-term administration of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents under the treat-and-extend protocol.13,14<\/sup><\/span><\/p>\n The most severe form of late dry AMD is geographic atrophy (GA). GA occurs when photoreceptor cells in the outer retina in the macula gradually deteriorate and die, leading to well-defined, enlarging atrophic lesions and depigmented regions. It has been seen that these lesions grow at the same rate in both eyes in bilateral GA.15<\/sup><\/span>\u00a0Most recent data compilation states that nearly 20 million individuals in the USA have AMD.16<\/sup><\/span>\u00a0Recent literature also suggests that approximately 20\u201330% of eyes with AMD will develop GA in the advanced stage.17<\/sup><\/span>\u00a0GA can also develop in wet AMD as seen in a cohort analysis of participants with nAMD in the CATT study (Comparison of Age-related macular degeneration Treatments Trials<\/span>;\u00a0ClinicalTrials.gov identifier:<\/span>\u00a0NCT00593450), which showed that GA occurred in approximately 18% of their participants after 2 years.18<\/sup><\/span>\u00a0In a UK study, the median time for progression to legal blindness in patients with GA was reported to be 6.2 years.19<\/sup><\/span>\u00a0Demographic investigations into GA reveal a noteworthy association with advanced age, which often accompanies a myriad of concurrent health challenges in afflicted individuals.20,21<\/sup><\/span>\u00a0These challenges manifest in various aspects of daily life, including the ability to operate a vehicle, engage in routine activities and manage the financial burdens of increased healthcare costs. The specific underlying disease process of GA has yet to be fully uncovered. However, the aberrant complement system activation has been indicated as a cause in past investigations.22,23<\/sup><\/span><\/p>\n Findings of GA are typically characterized and documented by lesion size, location, growth rate, best corrected visual acuity (BCVA) loss and low-luminance visual acuity (LLVA) loss.24<\/sup><\/span>\u00a0GA typically appears in the extrafoveal region, later progressing to the foveal centre with a median timespan of 1.4\u20132.5 years.25<\/sup><\/span>\u00a0In cases of subfoveal GA (affecting the foveal centre), vision loss is typically more pronounced and directly affects central vision. Patients may experience blurred or distorted central vision. Nonsubfoveal GA, while not directly affecting central vision, may lead to disturbances in peripheral or paracentral vision. Patients with nonsubfoveal GA have preserved visual acuity but may experience difficulties in up-close activities due to paracentral scotomas. Fleckenstein et al. state in a review article that the median GA lesion growth rate is 1.78 mm2<\/sup>\/year.24<\/sup><\/span>\u00a0Sunness et al. reported the median GA lesion growth rate to be 2.1 mm2<\/sup>\/year, with similar rates seen in both eyes.26<\/sup><\/span>\u00a0Both the National Eye Institute and the FDA have accepted the decrease in atrophic lesion growth as a primary endpoint for clinical trials.4,27<\/sup><\/span>\u00a0Although the diagnosis of GA is clinical, a multimodal approach with fundus autofluorescence (FAF) and optical coherence tomography (OCT) is highly useful to help diagnose and monitor progression.28<\/sup><\/span>\u00a0FAF can reveal hypoautofluorescent RPE tissue as dark areas, indicating the absence of healthy lipofuscin-producing cells. FAF can also show hyperautofluorescence in the junction between atrophic and healthy tissue, indicating the expulsion of lipofuscin from RPE cells during the process of dying.29,30<\/sup><\/span>\u00a0The absence of hyperautofluorescence at the borders of atrophic areas generally indicates that the atrophy is due to retinal diseases other than AMD. Recent consensus suggests using OCT to record baseline and to track disease progression with evidence that OCT is more sensitive to detecting GA in patients being treated for nAMD.31\u201334<\/sup><\/span>\u00a0OCT produces high-definition images, which can be used to identify and characterize morphological changes in GA, such as tissue loss in RPE and outer retinal layers, photoreceptor loss, intraretinal fluid, hypertransmission of\u00a0<\/span>BrM<\/span><\/span>\u00a0and choroidal capillaries, and splitting of the RPE and BrM. Apart from imaging, visual function tests are an important tool to assess real-world consequences on patients. Vision charts may not be adequate, as diseased areas and scotomas are located outside the fovea and the retinal dysfunction can be missed to identify. Instead, specialized reading charts that can measure reading speed are more favourable in testing for deficits. Macula stimulation in multiple areas using a microperimeter and patient feedback can better evaluate vision as well as test for LLVA and contrast sensitivity.35<\/sup><\/span><\/p>\n Prior to 2023, management options for GA were primarily supportive, as there were no specific treatments available for this advanced stage of dry AMD. Regular monitoring is a key part of managing GA, with patients undergoing frequent check-ups to assess disease progression. In February 2023, the FDA approved pegcetacoplan (SYFOVRE<\/span>\u2122, Apellis Pharmaceuticals, Waltham, MA, USA) as the first-ever medication for the treatment of GA associated with dry AMD. The DERBY (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT03525613) and OAKS (ClinicalTrials.gov identifier:<\/span>\u00a0NCT03525600) trials are phase III studies that assessed the efficacy of pegcetacoplan and have substantiated its ability to decelerate the advancement of dry AMD, with the recommended dose being 15 mg intravitreal injections every 25\u201360 days.36<\/sup><\/span>\u00a0More recently in August 2023, avacincaptad pegol (IZERVAY<\/span>\u2122, Astellas Pharma, Inc., Tokyo, Japan) was also approved for the treatment of GA after supportive findings from the GATHER1 trial (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT02686658) and the GATHER2 trial (<\/span><\/span>ClinicalTrials.gov identifier: <\/span>NCT04435366). The current recommended dose for avacincaptad pegol is 2 mg via intravitreal injection to each affected eye approximately every 28 \u00b1 7 days for up to 12 months.37<\/sup><\/span><\/p>\n We conducted a database search from 2005 to 2024 for publications related to AMD and GA by selecting open-access publications primarily from the PubMed\/PMC\/MEDLINE databases, the IOVS.org database, the WithPower.com database and ClinicalTrials.gov. Key terms searched included a combination of \u2018macular degeneration\u2019, \u2018treatment\u2019, \u2018management\u2019, \u2018geographic atrophy\u2019, \u2018pegcetacoplan\u2019, \u2018avacincaptad pegol\u2019, \u2018complement\u2019, \u2018study\u2019, and \u2018trial\u2019. Various presentations from physicians, researchers, pharmaceutical companies and conferences (hosted by the American Academy of Ophthalmology, American Society of Retina Specialists, The Retina Society and The Macula Society) were also included in the literature search. This review compiles and provides a summary of current and recent complement system-based therapeutic approaches for GA.<\/p>\n It is essential to acknowledge the inherent limitations stemming from the sources we have referenced as some are cited works drawn from retinal conference abstracts and presentations by pharmaceutical companies. These sources might present preliminary or truncated findings and usually have a less rigorous peer-review process than that which typically characterizes full research publications, potentially impacting the depth and reliability of the data presented. Furthermore, as the topic of GA management continues to evolve, it is possible that future long-term studies could yield findings that differ from the current observations. Our review aims to provide a comprehensive overview of the existing knowledge while recognizing the potential for forthcoming research to provide more nuanced insights into the effectiveness and safety of the discussed therapies.<\/p>\n The complement system works to eliminate pathogens and damaged cells within an organism by supporting the functions of antibodies and phagocytic cells. The eyes are immune privileged, with the dominant immune defence being only the complement system and innate immune systems. A combination of complement system, perivascular macrophages and microglia plays a crucial role in retinal vascular homeostasis, retinal tissue integrity and clearance of waste.38\u201340<\/sup><\/span>\u00a0In the context of AMD, a substantial proportion of genetic risk variants are concentrated within genes associated with the alternative pathway of the complement system.41<\/sup><\/span>\u00a0Notable elevations in complement activation products, specifically C3d\/C3 ratio, are seen in individuals afflicted by AMD.23<\/sup><\/span>\u00a0A clear consensus has not been reached regarding which complement pathway dysregulation is predominantly responsible for AMD and GA. Evidence also indicates that the accumulation of C1q aligns with its established role in synapse elimination and the neurodegenerative processes seen in other neurodegenerative disorders.42 <\/sup><\/span>Consequently, targeting complement factors has surfaced as a promising strategy for addressing GA. The currently approved complement inhibitors show strong efficacy in decreasing the growth rate of atrophic lesions in severe AMD. Challenges with this group of medications, as seen in clinical trials, include conversion into choroidal neovascularization (CNV) in eyes without CNV at baseline, less efficacy in more severe and later disease stages and pharmacokinetic limitations with intravitreal injections.43<\/sup><\/span><\/p>\n <\/sup>Pegcetacoplan injection secured FDA approval on 17 February 2023,44<\/sup><\/span>\u00a0which was supported by positive findings from the phase III, double-masked DERBY (n=621) and OAKS (n=637) trials, with a primary endpoint being changes in the total area of GA lesions (calculated from the slope value) at 24 months from baseline as measured with autofluorescence.45<\/sup><\/span>\u00a0Pegcetacoplan works by inhibiting complement factor C3 (Figure 1<\/em><\/span>). Both trials consisted of eyes with subfoveal and nonsubfoveal lesions. At 24 months, the DERBY trial demonstrated that both monthly and once every other month (EOM) treatment arms showed a slower lesion growth of 19% (p<\/span><\/span><\/span><\/em>=0.0004) and 16% (p<\/span><\/span><\/span><\/span><\/span><\/em>=0.0030), respectively, compared with the sham group. Similarly, the OAKS trial also showed that the treatment decreases the growth rate of lesions compared with the sham: reduction of 22% (<\/em>p<0.0001) in those treated monthly and 18% (p<\/span><\/span>=0.0002) in those treated EOM. Notably, growth rates of GA lesions reduced the most in both treatment arms between months 18 and 24 in both DERBY and OAKS trials. Findings at 36 months are reported in the GALE extension trial (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT04770545), where at this timepoint, lesion size continues to show divergence with a growth rate reduction of 35 and 24% for monthly and EOM administered pegcetacoplan, compared with the projected growth rate of the control group. Additionally, nonsubfoveal lesions in treated eyes experienced greater reductions than those seen for subfoveal lesions.46<\/sup><\/span>\u00a0Furthermore, pegcetacoplan exhibited favourable impacts on visual function and quality of life of patients, especially in those with extrafoveal lesions. The treatment also demonstrated a significant reduction in the loss of photoreceptor and retinal RPE cells. As with many intraocular therapies, pegcetacoplan carries the potential for mild-to-severe side effects. At 18 months, nAMD developed in 12% (<\/em>p<0.01 versus monthly;\u00a0<\/em>p<0.0001 versus sham), 7% (<\/em>p<0.0214 versus sham) and 3% in the monthly, EOM and sham groups, respectively, indicating a statistically significant increased likelihood for conversion into CNV with the treatment (these specific p-values were not officially reported by Apellis but were calculated by the authors using Z-statistics, comparing two population proportions).45<\/sup><\/span>\u00a0In recent reports, a total of 10 real-world cases involving<\/sup>\u00a0pegcetacoplan injection treatment-developed retinal vasculitis have been verified as of October 2023. These patients experienced visual symptoms with a median onset occurring approximately 1\u20132 weeks after treatment. To date, over 24,000 injections have been administered, with the incidence of retinal vasculitis remaining exceptionally rare, estimated at 0.01% per injection.<\/p>\n Figure 1: <\/span>The mechanism of action of various complement inhibitors on the complement activation cascade<\/p>\n <\/p>\n Figure was generated by the author using\u00a0PathVisio<\/span>.<\/em><\/p>\n C = complement factor; FB = factor B; MAC = membrane attack complex; MBL =\u00a0mannose-binding lectin<\/span><\/span><\/span>; mRNA =\u00a0messenger ribonucleic acid<\/span>.<\/em><\/p>\n<\/div>\n <\/span><\/sup>Avacincaptad pegol is an intravitreally delivered inhibitor that targets complement factor C5 (Figure 1<\/em><\/span>). The approval of the drug by the FDA on 4 August 2023 was supported by findings from the GATHER1 and GATHER2 phase III clinical trials.47<\/sup><\/span>\u00a0The phase II\/III GATHER1 trial assessed the safety and efficacy of avacincaptad pegol at 12 months in patients with non-foveal GA lesions in part within 1.5 mm from the foveal centre point.34<\/sup><\/span>\u00a0The results revealed that monthly doses of 2 and 4 mg of avacincaptad pegol led to a reduction in GA growth rates by 27.4% (p<\/span><\/span>=0.0072) and 27.8% (p<\/span><\/span>=0.0051), respectively. Notably, both doses exhibited a noticeable divergence in growth curves from the sham group as early as month 6. This separation persisted and demonstrated a progressive increase in therapeutic efficacy for both dosages over the course of 18 months.48<\/sup><\/span>\u00a0Expanding upon these findings, the phase III GATHER2 trial aimed to assess the effects of avacincaptad pegol for 24 months.49<\/sup><\/span> The patients of the GATHER2 trial were randomly assigned to receive either avacincaptad pegol 2 mg (n=225) or a sham treatment (n=223). The primary endpoin t measured GA lesion size using FAF. From baseline to month 12, avacincaptad pegol 2 mg exhibited a mean lesion growth rate of 1.745 mm2<\/sup>\/year, while the sham group recorded 2.121 mm2<\/sup>\/year. This translated to a growth rate difference of 0.376 mm2<\/sup>\/year (p<\/span><\/span>=0.0027), indicating a statistically significant reduction of 18% in GA lesion progression compared with the sham group. Favourable results continue at 24 months after re-randomizing the treatment group into monthly and EOM injections.50<\/sup><\/span>\u00a0Monthly and EOM injections displayed a reduction in growth rate of 14 and 19%, respectively, compared with the sham group. The safety profile at 24 months continues to exhibit minimal concerns. CNV conversion at 24 months for the treatment pool was similar to sham, with the incidence of CNV in the EOM group being greater than sham.<\/p>\n The discussion will focus on results from several recent and ongoing investigational complement inhibitor therapies (Table 1<\/span>), including, in order of their commencement, GOLDEN (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT03815825), CATALINA (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT04465955), ARCHER (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT04656561), GALE\u00a0extension trial (<\/span>ClinicalTrials.gov identifier:\u00a0NCT04770545)<\/span><\/span>, Danicopan (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT05019521) and SIGLEC (<\/span>ClinicalTrials.gov identifier:<\/span>\u00a0NCT05839041).44,47,51\u201357<\/sup><\/span><\/p>\n Table 1: <\/span>The current U.S.\u00a0Food and Drug Administration<\/span>-approved and investigational complement system inhibitors for geographic atrophy secondary to age-related macular degeneration<\/p>\n Drug<\/span><\/p>\n<\/td>\n Trial Number<\/b><\/p>\n<\/td>\n Sponsor<\/p>\n<\/td>\n Route\/mechanism<\/span><\/p>\n<\/td>\n Approval status<\/p>\n<\/td>\n<\/tr>\n<\/thead>\n Pegcetacoplan<\/p>\n<\/td>\n DERBY (NCT03525613)<\/span><\/span><\/span><\/p>\n OAKS (NCT03525600)<\/span><\/p>\n GALE\u00a0extension trial (<\/span>NCT04770545)<\/span><\/p>\n GARLAND<\/span>\u00a0(NCT06161584)<\/span><\/p>\n<\/td>\n Apellis Pharmaceuticals, Inc.<\/p>\n<\/td>\n Intravitreal C3 inhibitor<\/p>\n<\/td>\n Approved by the FDA as of 17 February 2023.44<\/sup><\/span>\u00a0Phase IV trial began September 2023 and is ongoing51<\/sup><\/span><\/span><\/p>\n<\/td>\n<\/tr>\n Avacincaptad pegol<\/p>\n<\/td>\n GATHER1 (NCT02686658)<\/span><\/p>\n GATHER2 (NCT04435366)<\/span><\/p>\n NCT05536297<\/span><\/p>\n<\/td>\n IVERIC Bio, Inc.<\/p>\n<\/td>\n Intravitreal C5 inhibitor<\/p>\n<\/td>\n Approved by the FDA as of 4 August 2023.47<\/sup><\/span>\u00a0Phase III extension trial began September 2022 and is ongoing52<\/sup><\/span><\/span><\/span><\/p>\n<\/td>\n<\/tr>\n ANX007<\/p>\n<\/td>\n ARCHER (NCT04656561)<\/span><\/p>\n \n<\/td>\n Alexion Pharmaceuticals, Inc.<\/p>\n<\/td>\n Intravitreal C1q complex inhibitor<\/p>\n<\/td>\n Phase III ARROW trial to initiate in mid-202453<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n Danicopan\/ALXN2040<\/p>\n<\/td>\n NCT05019521<\/span><\/p>\n<\/td>\n Alexion Pharmaceuticals, Inc.<\/p>\n<\/td>\n Oral factor D inhibitor<\/p>\n<\/td>\n Phase II in progress54<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n IONIS-FB-LRx<\/p>\n<\/td>\n GOLDEN (NCT03815825)<\/span><\/p>\n<\/td>\n lonis Pharmaceuticals, Inc.<\/p>\n<\/td>\n Subcutaneous ligand-conjugated antisense oligonucleotide against factor B mRNA<\/p>\n<\/td>\n Phase II in progress55<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n AVD-104<\/p>\n<\/td>\n SIGLEC (NCT05839041)<\/span><\/p>\n<\/td>\n Aviceda Therapeutics, Inc.<\/p>\n<\/td>\n Intravitreal factor H stimulus, macrophage modulator<\/p>\n<\/td>\n Phase II\/III; part 1 completed and part 2 in progress56<\/sup><\/span><\/p>\n<\/td>\n<\/tr>\n NGM621<\/p>\n<\/td>\n CATALINA (NCT04465955)<\/span><\/p>\n<\/td>\n NGM Biopharmaceuticals, Inc.<\/p>\n<\/td>\n Intravitreal C3 inhibitor<\/p>\n<\/td>\n Phase II results released on 17 October 2022.57<\/sup><\/span>\u00a0Drug development has ceased<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n C<\/span>\u00a0=\u00a0complement factor<\/span>; <\/span>FDA<\/span>\u00a0=\u00a0US Food and Drug Administration<\/span>; <\/span>mRNA<\/span>\u00a0=\u00a0messenger RNA<\/span>.<\/span><\/em><\/p>\n<\/div>\n<\/div>\n<\/div>\nMethods<\/h1>\n
Acknowledgement of\u00a0l<\/span>imitations<\/h1>\n
Role of the\u00a0c<\/span>omplement\u00a0s<\/span>ystem in geographic atrophy<\/h1>\n
Pegcetacoplan injection<\/sup><\/sup><\/h1>\n
Avacincaptad pegol<\/sup><\/sup><\/h1>\n
Investigation of\u00a0c<\/span>omplement\u00a0s<\/span>ystem\u00a0i<\/span>nhibitors in\u00a0c<\/span>linical\u00a0t<\/span>rials<\/h1>\n
\n\n
\n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n