Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy

Charles C. Wykoff; Philip J. Rosenfeld; Nadia K. Waheed; Rishi P. Singh; Nick Ronca; Jason S. Slakter; Giovanni Staurenghi; Jordi Monés; Caroline R. Baumal; Namrata Saroj; Ravi Metlapally; Ramiro Ribeiro

doi:10.1016/j.ophtha.2021.02.025

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy

Charles C. Wykoff, Philip J. Rosenfeld, Nadia K. Waheed, Rishi P. Singh, Nick Ronca, Jason S. Slakter, Giovanni Staurenghi, Jordi Monés, Caroline R. Baumal, Namrata Saroj, Ravi Metlapally, Ramiro Ribeiro

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.

DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).

SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246.

INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.

MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.

RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.

CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

Original language	English (US)
Pages (from-to)	1325-1336
Number of pages	12
Journal	Ophthalmology
Volume	128
Issue number	9
DOIs	https://doi.org/10.1016/j.ophtha.2021.02.025
State	Published - Sep 2021

Keywords

Age-related macular degeneration
Complement
Double-layer sign
Exudation
Geographic atrophy
Macular neovascularization
Single-Blind Method
Complement C3/antagonists & inhibitors
Prospective Studies
Intravitreal Injections
Humans
Middle Aged
Male
Peptides, Cyclic/administration & dosage
Visual Acuity/physiology
Geographic Atrophy/diagnosis
Wet Macular Degeneration/chemically induced
Time Factors
Aged, 80 and over
Female
Fluorescein Angiography
Tomography, Optical Coherence
Subretinal Fluid
Complement Inactivating Agents/administration & dosage
Aged
Exudates and Transudates

ASJC Scopus subject areas

Ophthalmology

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10.1016/j.ophtha.2021.02.025

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Wykoff, C. C., Rosenfeld, P. J., Waheed, N. K., Singh, R. P., Ronca, N., Slakter, J. S., Staurenghi, G., Monés, J., Baumal, C. R., Saroj, N., Metlapally, R., & Ribeiro, R. (2021). Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy. Ophthalmology, 128(9), 1325-1336. https://doi.org/10.1016/j.ophtha.2021.02.025

Wykoff, CC, Rosenfeld, PJ, Waheed, NK, Singh, RP, Ronca, N, Slakter, JS, Staurenghi, G, Monés, J, Baumal, CR, Saroj, N, Metlapally, R & Ribeiro, R 2021, 'Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy', Ophthalmology, vol. 128, no. 9, pp. 1325-1336. https://doi.org/10.1016/j.ophtha.2021.02.025

@article{bf2e8b8b275f4228abf38cf0e3fe0de4,

title = "Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy",

abstract = "OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246.INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.",

keywords = "Age-related macular degeneration, Complement, Double-layer sign, Exudation, Geographic atrophy, Macular neovascularization, Single-Blind Method, Complement C3/antagonists & inhibitors, Prospective Studies, Intravitreal Injections, Humans, Middle Aged, Male, Peptides, Cyclic/administration & dosage, Visual Acuity/physiology, Geographic Atrophy/diagnosis, Wet Macular Degeneration/chemically induced, Time Factors, Aged, 80 and over, Female, Fluorescein Angiography, Tomography, Optical Coherence, Subretinal Fluid, Complement Inactivating Agents/administration & dosage, Aged, Exudates and Transudates",

author = "Wykoff, {Charles C.} and Rosenfeld, {Philip J.} and Waheed, {Nadia K.} and Singh, {Rishi P.} and Nick Ronca and Slakter, {Jason S.} and Giovanni Staurenghi and Jordi Mon{\'e}s and Baumal, {Caroline R.} and Namrata Saroj and Ravi Metlapally and Ramiro Ribeiro",

note = "Funding Information: The author(s) have made the following disclosure(s): C.C.W.: Consultant ? Acucela, Adverum, Aerpio, Alcon, Alimera Sciences, Allegro, Allergan, Alnylam, Apellis Pharmaceuticals, Arctic Vision, Bausch + Lomb, Bayer, Chengdu Kanghong Biotech, Clearside Biomedical, Corcept Therapeutics, DORC, EyePoint Pharmaceuticals, Genentech, Gyroscope, Iveric Bio, Kodiak Sciences, Merck, NGM Biopharmaceticals, Notal Vision, Novartis, ONL Therapeutics, Opthea, Oxurion, Palatin, Polyphotnix, RecensMedical, Regeneron, RegenXBio, Roche, Santen, Takeda, Thea Open Innovation, Verana Health, and Bionic Vision Technologies; Financial support ? Adverum, Aerie, Aldeyra, Allergan, Apellis Pharmaceuticals, Chengdu Kanghong Biotech, Clearside Biomedical, Gemini Therapeutics, Genentech, Graybug, Gyroscope, IONIS Pharmaceutical, Iveric Bio, Kodiak Sciences, LMRI, Mylan, Neurotech Pharmaceuticals, NGM Biopharmaceticals, Novartis, Opthea, Outlook Therapeutics, RecensMedical, Regeneron, RegenXBio, Roche, Samsung Bioepis, Santen, Senju, Taiwan Liposome Company, Xbrane BioPharma P.J.R.: Consultant ? Apellis Pharmaceuticals, Biogen, Boehringer-Ingelheim, Zeiss, Chengdu Kanghong Biotech, EyePoint, Ocunexus Therapeutics, Ocudyne, Regeneron, Unity Biotechnology; Financial support ? Zeiss, Stealth BioTherapeutics; Equity owner ? Apellis, Ocudyne, Valitor, Verana Health N.K.W.: Consultant ? Gyroscope Therapeutics, Nidek, Topcon; Nonfinancial support ? Zeiss, Heidelberg; Office holder ? Gyroscope Therapeutics R.P.S.: Consultant ? Alcon, Apellis, Bausch + Lomb, Genentech, Novartis, Regeneron, Zeiss; Financial support ? Aerie, Apellis Pharmaceuticals, Graybug J.S.S.: Consultant ? Apellis Pharmaceuticals; Financial support - Aerie, Amgen, Apellis Pharmaceuticals, Regeneron, Samsung; Equity owner - Apellis Pharmaceuticals G.S.: Consultant ? Heidelberg, Optos, Centervue, Apellis Pharmaceuticals, Allergan, Astrellas, Bayer, Boehringer Ingelheim, Genentech, Graybug, Novartis, Roche, Chengdu Kanghong Biotech, Kyoto Drug Discovery and Development, Biogen; Financial support ? Heidelberg, Optos, Centervue, Zeiss, Bayer; Patent ? Ocular Instruments J.M.: Consultant ? Apellis Pharmaceuticals, Cellcure, Iveric Bio, Lineage Cell Therapeutics, Maculogix, Novartis, ReNeuron, Roche; Financial support ? Apellis Pharmaceuticals, Iveric Bio, Kodiak Sciences, Novartis, ReNeuron, Roche; Equity owner ? Iveric Bio, Notal Vision N.S.: Consultant ? Allegro, Amgen, Apellis Pharmaceuticals, iRenex, RegenxBio, SamaCare; Financial support ? Allegro, Amgen, iRenix, RegenxBio, Retina Technologies, Placid0, Prev3nt, SamaCare Supported by Supported by Apellis Pharmaceuticals. Obtained funding: Wykoff, Singh, Slakter, Staurenghi, Mon?s, Saroj; Metlapally, Ribeiro, and Ronca are employees of Apellis Pharmaceuticals, and the study was performed as part of their regular employment duties. Publisher Copyright: {\textcopyright} 2021 American Academy of Ophthalmology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "10.1016/j.ophtha.2021.02.025",

language = "English (US)",

volume = "128",

pages = "1325--1336",

journal = "Ophthalmology",

issn = "0161-6420",

publisher = "Elsevier",

number = "9",

}

TY - JOUR

T1 - Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy

AU - Wykoff, Charles C.

AU - Rosenfeld, Philip J.

AU - Waheed, Nadia K.

AU - Singh, Rishi P.

AU - Ronca, Nick

AU - Slakter, Jason S.

AU - Staurenghi, Giovanni

AU - Monés, Jordi

AU - Baumal, Caroline R.

AU - Saroj, Namrata

AU - Metlapally, Ravi

AU - Ribeiro, Ramiro

N1 - Funding Information: The author(s) have made the following disclosure(s): C.C.W.: Consultant ? Acucela, Adverum, Aerpio, Alcon, Alimera Sciences, Allegro, Allergan, Alnylam, Apellis Pharmaceuticals, Arctic Vision, Bausch + Lomb, Bayer, Chengdu Kanghong Biotech, Clearside Biomedical, Corcept Therapeutics, DORC, EyePoint Pharmaceuticals, Genentech, Gyroscope, Iveric Bio, Kodiak Sciences, Merck, NGM Biopharmaceticals, Notal Vision, Novartis, ONL Therapeutics, Opthea, Oxurion, Palatin, Polyphotnix, RecensMedical, Regeneron, RegenXBio, Roche, Santen, Takeda, Thea Open Innovation, Verana Health, and Bionic Vision Technologies; Financial support ? Adverum, Aerie, Aldeyra, Allergan, Apellis Pharmaceuticals, Chengdu Kanghong Biotech, Clearside Biomedical, Gemini Therapeutics, Genentech, Graybug, Gyroscope, IONIS Pharmaceutical, Iveric Bio, Kodiak Sciences, LMRI, Mylan, Neurotech Pharmaceuticals, NGM Biopharmaceticals, Novartis, Opthea, Outlook Therapeutics, RecensMedical, Regeneron, RegenXBio, Roche, Samsung Bioepis, Santen, Senju, Taiwan Liposome Company, Xbrane BioPharma P.J.R.: Consultant ? Apellis Pharmaceuticals, Biogen, Boehringer-Ingelheim, Zeiss, Chengdu Kanghong Biotech, EyePoint, Ocunexus Therapeutics, Ocudyne, Regeneron, Unity Biotechnology; Financial support ? Zeiss, Stealth BioTherapeutics; Equity owner ? Apellis, Ocudyne, Valitor, Verana Health N.K.W.: Consultant ? Gyroscope Therapeutics, Nidek, Topcon; Nonfinancial support ? Zeiss, Heidelberg; Office holder ? Gyroscope Therapeutics R.P.S.: Consultant ? Alcon, Apellis, Bausch + Lomb, Genentech, Novartis, Regeneron, Zeiss; Financial support ? Aerie, Apellis Pharmaceuticals, Graybug J.S.S.: Consultant ? Apellis Pharmaceuticals; Financial support - Aerie, Amgen, Apellis Pharmaceuticals, Regeneron, Samsung; Equity owner - Apellis Pharmaceuticals G.S.: Consultant ? Heidelberg, Optos, Centervue, Apellis Pharmaceuticals, Allergan, Astrellas, Bayer, Boehringer Ingelheim, Genentech, Graybug, Novartis, Roche, Chengdu Kanghong Biotech, Kyoto Drug Discovery and Development, Biogen; Financial support ? Heidelberg, Optos, Centervue, Zeiss, Bayer; Patent ? Ocular Instruments J.M.: Consultant ? Apellis Pharmaceuticals, Cellcure, Iveric Bio, Lineage Cell Therapeutics, Maculogix, Novartis, ReNeuron, Roche; Financial support ? Apellis Pharmaceuticals, Iveric Bio, Kodiak Sciences, Novartis, ReNeuron, Roche; Equity owner ? Iveric Bio, Notal Vision N.S.: Consultant ? Allegro, Amgen, Apellis Pharmaceuticals, iRenex, RegenxBio, SamaCare; Financial support ? Allegro, Amgen, iRenix, RegenxBio, Retina Technologies, Placid0, Prev3nt, SamaCare Supported by Supported by Apellis Pharmaceuticals. Obtained funding: Wykoff, Singh, Slakter, Staurenghi, Mon?s, Saroj; Metlapally, Ribeiro, and Ronca are employees of Apellis Pharmaceuticals, and the study was performed as part of their regular employment duties. Publisher Copyright: © 2021 American Academy of Ophthalmology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246.INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

AB - OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246.INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

KW - Age-related macular degeneration

KW - Complement

KW - Double-layer sign

KW - Exudation

KW - Geographic atrophy

KW - Macular neovascularization

KW - Single-Blind Method

KW - Complement C3/antagonists & inhibitors

KW - Prospective Studies

KW - Intravitreal Injections

KW - Humans

KW - Middle Aged

KW - Male

KW - Peptides, Cyclic/administration & dosage

KW - Visual Acuity/physiology

KW - Geographic Atrophy/diagnosis

KW - Wet Macular Degeneration/chemically induced

KW - Time Factors

KW - Aged, 80 and over

KW - Female

KW - Fluorescein Angiography

KW - Tomography, Optical Coherence

KW - Subretinal Fluid

KW - Complement Inactivating Agents/administration & dosage

KW - Aged

KW - Exudates and Transudates

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UR - http://www.scopus.com/inward/citedby.url?scp=85104365586&partnerID=8YFLogxK

U2 - 10.1016/j.ophtha.2021.02.025

DO - 10.1016/j.ophtha.2021.02.025

M3 - Article

C2 - 33711380

AN - SCOPUS:85104365586

SN - 0161-6420

VL - 128

SP - 1325

EP - 1336

JO - Ophthalmology

JF - Ophthalmology

IS - 9

ER -

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy

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