Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial

Monés, Jordi; Kaiser, Peter K.; Clark, Julie; Zhu, Lei; Patel, Hersh; Tang, Justin; Desai, Dhaval; Jaffe, Glenn J.; Alezzandrini, Arturo; Francone, A; Bafalluy, Joaquín; Bainttein, Silvina; Pinto, Jose Luna; Saravia, Mario; Vidosevich, Matko; Zeolite, Carlos; Sola, Federico Furno; Chang, Andrew; Cornish, Elisa E; Nguyen, Thanh N.; Findl, Oliver; Haas, Anton; Kralinger, Martina; Sacu, Stefan; Postelmans, Laurence; Farah, Michel Eid; Maia, Maurício; Nehemy, Márcio Bittar; Ali, Fareed; Brent, Michael H.; Dollin, Michael; Gonder, John R.; Kherani, Amin; Merkur, Andrew; Tuli, Raman; Lopera, Maria J.; Rodriguez, Francisco J.; Bradvica, Mario; Ernest, Jan; Kalijurand, Kuldar; Noor, Khaled; Cohen, Yves; Creuzot‐Garcher, Catherine; Bats, Flore De; Devin, François; Français-Maury, C.; Kodjikian, Laurent; Korobelnik, J.-F.; Mer, Y. Le; Maftouhi, M. Quaranta El; Razavi, Sam; Souied, Eric H.; Tadayoni, Ramin; Weber, Michel; Eter, Nicole; Feltgen, Nicolas; Grisanti, Salvatore; Walter, Peter; Liegl, Raffael; Lorenz, Katrin; Spital, Georg; Priglinger, Siegfried; Spitzer, Martin S.; Völker, Michael; Krohne, Tim U.; Jochmann, Claudia; Lohmann, Chris P.; Framme, Carsten; Kerényi, Ágnes; Papp, András; Seres, András; Tóth-Molnár, Edit; Tsorbatzoglou, Alexis; Vajas, Attila; Varsányi, Balázs; Vogt, Gábor; Bar, Asaf; Eting, Eva; Hauser, David; Levy, Jamie; Mathalone, Nurit; Morori-Katz, Haia; Rosenblatt, Irit; Soudry-Zayit, Shiri; Trivizky, Omert; Bandello, Francesco; Ciardella, Antonio P.; Figus, Michele; Giansanti, Fabrizio; Lanzetta, Paolo; Mariotti, Cesare; Mastropasqua, Leonardo; Midena, Edoardo; Parmeggiani, Francesco; Ricci, Federico; Simonelli, Francesca; Staurenghi, Giovanni; Viola, Francesco; Varano, Monica; Laganovska, Guna; Cisiecki, Sławomir; Jedrzejewski, Wojciech; Kałuz̊ny, Jakub J.; Misiuk-Hojło, Marta; Abengoechea, Santiago; Iribarren, Javier Araiz; Ascaso, Fj; Cubero, Juan José; Gallego-Pinazo, Roberto; Irazazábal, Francisco Gómez-Ulla De; Mestre, I; Carilla, Jordi Manel Mones I; Moreno, Javier Montero; Moreno, José María Ruiz; Ramsay, Laura Sararols; Layana, Alfredo García; Downey, Louise; Abraham, Prema; Alfaro, D. Virgil; Bagheri, Nika; Barbazetto, Irene; Benevento, Joseph; Bernstein, Paul S.; Bertolucci, George; Bhavsar, Abdhish R.; Bridges, William Z.; Brooks, Harold L.; Brown, Jamin S.; Brucker, Alexander J.; Calvo, Charles M.; Capone, Antonio; Carlson, John R.; Chan, Clement W N; Chang, Emmanuel; Chan-Kai, Brian T.; Chaudhry, Nauman; Chen, Sanford; Csaky, Karl G.; Cummings, Howard; Danzig, Carl J; Dessouki, Amr; Dyer, David S.; Eaton, Alexander M.; Eichenbaum, David; Faber, David; Feldman, Robert L.; Finnen, Neil; Freeman, William R.; Frenkel, Ronald E. P.; Gonzales, Christine R.; González, Víctor H.; Gross, John B.; Gupta, Sunil; Hall, Edward F.; Han, Minkyu; Heier, Jeffrey S.; Hershberger, Vrinda; Higgins, Patrick M.; Hsu, Jason; Ip, Michael S.; Jablon, Eric P.; Jewart, Brian; John, Vishak J.; Jonisch, Jonathan; Joondeph, Brian C.; Kay, Christine N.; Khanani, Arshad M.; Kokame, Gregg T.; Kwun, Robert; Lai, Michael M.; Lally, David R.; Laud, Ketan; Lavina, Adrian; Lee, Michael; Lin, Phoebe; Lin, Haijiang; Manoharan, Niranjan; Marcus, Dennis M.; Martidis, Adam; McCabe, Frank; Nielsen, Jared S.; Osher, James M.; Palmer, James D.; Patel, Sunil; Pearlman, Joel; Perkins, Stephen J.; Pirouz, Ashkan; Qureshi, Jawad; Randolph, John; Piri, Niloofar; Rosenfeld, P; Saperstein, David; Scartozzi, Richard; Schwartz, Steven D.; Sharma, Ashish; Sharma, Atul; Sheth, Veeral; Singer, Michael; Spinak, David J.; Suan, Eric; Tabandeh, Homayoun; Tabassian, Ali; Uchiyama, Eduardo; Varenhorst, Michael P.; Wagner, Alan; Warrow, David; Wells, John A.; Wong, Robert; Wong, Keye L.; Wykoff, Charles C.; Xavier, Samantha; Ysasaga, Edward

doi:10.1016/s0140-6736(23)01583-0

Cited by 93 publications

(43 citation statements)

References 23 publications

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“…In the GATHER2 phase 3 trial, 448 patients were randomized 1:1 to receive 2-mg avacincaptad pegol injections monthly or sham injections for 12 months . Avacincaptad pegol reduced geographic atrophy growth, with a rate of 0.336 mm/y compared with 0.392 mm/y for sham.…”

Section: Discussion and Observationsmentioning

confidence: 91%

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Age-Related Macular Degeneration

Fleckenstein,

Schmitz-Valckenberg,

Chakravarthy

2024

JAMA

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ImportanceAge-related macular degeneration (AMD) affects approximately 20 million people in the US and 196 million people worldwide. AMD is a leading cause of severe vision impairment in older people and is expected to affect approximately 288 million people worldwide by 2040.ObservationsOlder age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD. AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older. The estimated heritability of late-stage AMD is approximately 71% (95% CI, 18%-88%). Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked. AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil. Exudative neovascular AMD is best identified using angiography and by optical coherence tomography. Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo. In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti–vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment.Conclusions and RelevanceThe prevalence of AMD is anticipated to increase worldwide to 288 million individuals by 2040. Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD.

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Section: Discussion and Observationsmentioning

confidence: 91%

“…Throughout the reported study periods, neither pegcetacoplan nor avacincaptad pegol demonstrated statistically significant differences in prespecified visual function end points compared with corresponding sham groups in their respective studies …”

Section: Discussion and Observationsmentioning

confidence: 99%

Age-Related Macular Degeneration

Fleckenstein,

Schmitz-Valckenberg,

Chakravarthy

2024

JAMA

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“…Pegcetacoplan, an inhibitor of complement C3, has demonstrated effectiveness in reducing GA lesion growth (Goldberg et al, 2022;Khan et al, 2023). Additionally, Avacincaptad pegol is an emerging therapy that shows promise, with potential benefits on anatomical endpoints in GA as well (Khan et al, 2023;Khanani et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial damage and clearance in retinal pigment epithelial cells

Gurubaran

2024

Acta Ophthalmologica

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Age‐related macular degeneration (AMD) is a devastating eye disease that causes permanent vision loss in the central part of the retina, known as the macula. Patients with such severe visual loss face a reduced quality of life and are at a 1.5 times greater risk of death compared to the general population. Currently, there is no cure for or effective treatment for dry AMD. There are several mechanisms thought to underlie the disease, for example, ageing‐associated chronic oxidative stress, mitochondrial damage, harmful protein aggregation and inflammation. As a way of gaining a better understanding of the molecular mechanisms behind AMD and thus developing new therapies, we have created a peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha and nuclear factor erythroid 2‐related factor 2 (PGC1α/NFE2L2) double‐knockout (dKO) mouse model that mimics many of the clinical features of dry AMD, including elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen‐like structures in retinal pigment epithelial cells (RPE). In addition, a human RPE cell‐based model was established to examine the impact of non‐functional intracellular clearance systems on inflammasome activation. In this study, we found that there was a disturbance in the autolysosomal machinery responsible for clearing mitochondria in the RPE cells of one‐year‐old PGC1α/NFE2L2‐deficient mice. The confocal immunohistochemical analysis revealed an increase in autophagosome marker microtubule‐associated proteins 1A/1B light chain 3B (LC3B) as well as multiple mitophagy markers such as PTE‐induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN), along with signs of damaged mitochondria. However, no increase in autolysosome formation was detected, nor was there a colocalization of the lysosomal marker LAMP2 or the mitochondrial marker, ATP synthase β. There was an upregulation of late autolysosomal fusion Ras‐related protein (Rab7) in the perinuclear space of RPE cells, together with autofluorescent aggregates. Additionally, we observed an increase in the numbers of Toll‐like receptors 3 and 9, while those of NOD‐like receptor 3 were decreased in PGC1α/NFE2L2 dKO retinal specimens compared to wild‐type animals. There was a trend towards increased complement component C5a and increased involvement of the serine protease enzyme, thrombin, in enhancing the terminal pathway producing C5a, independent of C3. The levels of primary acute phase C‐reactive protein and receptor for advanced glycation end products were also increased in the PGC1α/NFE2L2 dKO retina. Furthermore, selective proteasome inhibition with epoxomicin promoted both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial‐mediated oxidative stress, leading to the release of mitochondrial DNA to the cytosol, resulting in potassium efflux‐dependent activation of the absent in melanoma 2 (AIM2) inflammasome and the subsequent secretion of interleukin‐1β in ARPE‐19 cells. In conclusion, the data suggest that there is at least a relative decrease in mitophagy, increases in the amounts of C5 and thrombin and decreased C3 levels in this dry AMD‐like model. Moreover, selective proteasome inhibition evoked mitochondrial damage and AIM2 inflammasome activation in ARPE‐19 cells.

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“…The US Food and Drug Administration has recently approved intravitreal pegcetacoplan and avacincaptad pegol for slowing GA progression. Despite slowing GA progression in fundus autofluorescence (FAF) imaging, both drugs yet failed to improve BCVA [6][7][8][9]. It is unclear whether this lack of concordance between the structure and function is attributable to the selection of visual function tests or the nonefficaciousness of the drugs.…”

Section: Introductionmentioning

confidence: 99%

“…It is unclear whether this lack of concordance between the structure and function is attributable to the selection of visual function tests or the nonefficaciousness of the drugs. The former possibility highlights the need for a more refined understanding of the ability to detect change of visual function tests in GA [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

The Optical Coherence Tomography and Microperimetry Biomarker Evaluation in Patients with Geographic Atrophy (OMEGA) Study: Design and Baseline Characteristics – OMEGA Report 1

Ansari,

Schärer,

Camenzind Zuche

et al. 2023

Ophthalmic Res

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Introduction: The aim of this study was to describe the design and the participants’ baseline characteristics of a prospective natural history study of geographic atrophy (GA) secondary to age-related macular degeneration. Methods: The optical coherence tomography (OCT) and microperimetry biomarker evaluation in patients with GA (OMEGA) study was conducted at a tertiary referral center (ClinicalTrials.gov identifier: NCT05963646). Participants were followed for 12 months during 4 visits (baseline and follow-up exams at weeks 12, 24, and 48) with best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity, low-luminance visual acuity (LLVA), and quick contrast sensitivity function testing. Further, participants underwent spectral-domain OCT, OCT angiography, fundus autofluorescence imaging, and mesopic microperimetry testing. Results: Thirty participants (median [IQR] age of 79 [77, 84] years) and 37 study eyes were included with a (median [IQR]) GA area of 1.40 mm2 (0.49, 5.24) at baseline. Out of 37 study eyes, six developed macular neovascularizations (16%). The study-eye best-corrected visual acuity was (median [IQR]) 0.18 logarithm of the minimum angle of resolution (logMAR) (0.06, 0.26), LLVA 0.66 logMAR (0.36, 0.88), and the microperimetry mean sensitivity 18.4 dB (9.21, 20.9). The highest correlation between square root GA area and a visual function test was evident for LLVA (R2 of 0.578), followed by area under the log contrast sensitivity function curve (0.519) and microperimetral retinal sensitivity (0.487). Conclusion: This report lays out the design and baseline characteristics of the OMEGA study, which aims to contribute to the understanding of the natural history of GA. The OMEGA study will provide estimates of the ability to detect change and retest reliability for a panel of structure and functional assessments.

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Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial

Cited by 93 publications

References 23 publications

Age-Related Macular Degeneration

Age-Related Macular Degeneration

Mitochondrial damage and clearance in retinal pigment epithelial cells

The Optical Coherence Tomography and Microperimetry Biomarker Evaluation in Patients with Geographic Atrophy (OMEGA) Study: Design and Baseline Characteristics – OMEGA Report 1

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