Study of Pegcetacoplan (APL-2) Therapy in Patients With Geographic Atrophy

Conditions

Geographic Atrophy

Brief summary

The primary objectives of the study are to assess the safety, tolerability and evidence of activity of multiple intravitreal (IVT) injections of pegcetacoplan in subjects with Geographic Atrophy associated with Age-Related Macular Degeneration (AMD).

Detailed description

This is a Phase II, prospective, multicenter, randomized, single-masked, sham-controlled study to assess the safety, tolerability and evidence of activity of multiple IVT injections of pegcetacoplan in subjects with GA secondary to Age-Related Macular Degeneration. The study will randomize approximately 240 subjects to obtain at least 200 evaluable subjects across 40 multinational sites. Subjects will be randomized in a 2:2:1:1 manner to receive pegcetacoplan Monthly (AM), pegcetacoplan Every-Other-Month (AEOM), Sham injection Monthly (SM) or Sham injection Every-Other-Month (SEOM), respectively. All subjects will return to the clinical site on Day 7 to assess acute safety after the first injection. After that, subjects in the monthly groups will return to the clinical site for additional pegcetacoplan (or Sham) injections and study procedures every month until Month 12. Subjects in the Every-Other-Month groups will return to the clinical site for additional pegcetacoplan (or Sham) injections and study procedures every two months until Month 12. All subjects will return for follow-up visits on Months 15 and 18 (3 and 6 months after last injection, respectively).

Sadda S, Hatcher KA, Shah BK, Kondapalli SS, Li C, Baumal CR.

2025-05-19

10.1007/s40123-025-01156-5

A Novel Management Challenge in Age-Related Macular Degeneration: Artificial Intelligence and Expert Prediction of Geographic Atrophy.

Reiter GS, Lachinov D, Bühl W, Weigert G, Grechenig C, Mai J, Bogunović H, Schmidt-Erfurth U.

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Evaluating the Effects of C3 Inhibition on Geographic Atrophy Progression from Deep-Learning OCT Quantification: A Split-Person Study.

Fu DJ, Lipkova V, Liefers B, Glinton S, Faes L, McKeown A, Scheibler L, Pontikos N, Patel PJ, Zhang G, Keane PA, Balaskas K.

2023-09-16

10.1007/s40123-023-00798-7

Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy

Maximilian Pfau, Steffen Schmitz-Valckenberg, Ramiro Ribeiro, Reza Safaei, Alex McKeown et al. (7 authors)

Scientific Reports2022-10-2536 citations

10.1038/s41598-022-22404-9

Predicting Topographic Disease Progression and Treatment Response of Pegcetacoplan in Geographic Atrophy Quantified by Deep Learning.

Vogl WD, Riedl S, Mai J, Reiter GS, Lachinov D, Bogunović H, Schmidt-Erfurth U.

2022-08-0757 citations

10.1016/j.oret.2022.08.003

Pegcetacoplan treatment for geographic atrophy due to age-related macular degeneration: a plain language summary of the FILLY study.

Liao DS, Metlapally R, Joshi P.

2022-07-2112 citations

10.2217/imt-2022-0078

Association of Pegcetacoplan With Progression of Incomplete Retinal Pigment Epithelium and Outer Retinal Atrophy in Age-Related Macular Degeneration

Muneeswar Gupta Nittala, Ravi Metlapally, Michael S. Ip, Usha Chakravarthy, Frank G. Holz et al. (13 authors)

JAMA Ophthalmology2022-02-0361 citations

10.1001/jamaophthalmol.2021.6067

Interventions

DRUGPegcetacoplan

OTHERSham Procedure

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

50 Years to No maximum

Healthy volunteers

No

Inclusion criteria

Unless specified otherwise, ocular specific inclusion criteria apply to the study eye only. 1. Male or Female. 2. Age greater than or equal to 50 years. 3. BCVA of 20/320 (Snellen equivalent) or better using ETDRS charts. 4. Diagnosis of GA of the macula secondary to age-related macular degeneration, confirmed within 14 days prior to randomization by the central reading center (CRC) using Fundus Autofluorescence (FAF) images, as well as the following criteria: 1. Total GA area must be ≥ 2.5 and ≤ 17.5 mm2 (1 and 7 disk areas \[DA\] respectively), determined by screening images of FAF. 2. If GA is multifocal, at least one focal lesion must be ≥ 1.25 mm2 (0.5 DA). 3. GA can be completely visualized on the macula centered image. 4. GA must be able to be photographed in its entirety. 5. GA must be able to be measured separately from any areas of peripapillary atrophy as assessed by the CRC. 6. Presence of any pattern of hyperautofluorescence in the junctional zone of GA. Absence of hyperautoflouorescence (i.e. pattern = none) is exclusionary. See Holz et al. 2007.1 5. Female subjects must be: 1. Women of non-child-bearing potential (WONCBP), or 2. Women of child-bearing potential (WOCBP) with a negative pregnancy test at screening and must agree to use protocol defined methods of contraception for the duration of the study. 6. Males with female partners of child-bearing potential must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study. 7. Willing and able to give informed consent.

Exclusion criteria

Unless specified otherwise, ocular specific inclusion criteria apply to the study eye only. 1. GA due to causes other than AMD such as Stargardt disease, cone rod dystrophy or toxic maculopathies like plaquenil maculopathy. 2. Spherical equivalent of the refractive error demonstrating \> 6 diopters of myopia or an axial length \>26 mm. 3. Any history or current evidence of exudative (wet) AMD including any evidence of retinal pigment epithelium rips or evidence of neovascularization anywhere in the retina based on fluorescein angiogram as assessed by the CRC. 4. Retinal disease other than AMD; however, benign conditions of the vitreous or peripheral retina are not exclusionary (i.e. pavingstone degeneration). 5. Any ophthalmologic condition that reduces the clarity of the media and that, in the opinion of the Investigator interferes with ophthalmologic examination (e.g. advanced cataract or corneal abnormalities). 6. Any ophthalmologic condition that prevents adequate imaging of the retina judged by the site or CRC. 7. Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization. 8. Aphakia or absence of the posterior capsule. Previous violation of the posterior capsule is also excluded unless it occurred as a result of yttrium aluminum garnet (YAG) laser posterior capsulotomy in association with prior posterior chamber intraocular lens implantation and at least 60 days prior to Day 0. 9. Any ophthalmic condition that may require surgery during the study period. 10. Any contraindication to IVT injection including current ocular or periocular infection. 11. History of uveitis or endophthalmitis. 12. History of IVT injection at any time. 13. Participation in another interventional clinical study, or use of any experimental treatment for AMD or any other investigational new drug within 6 weeks or 5 half-lives of the active (whichever is longer) prior to the start of study treatment. Note: clinical trials solely involving observation, over-the-counter vitamins, supplements, or diets are not exclusionary. 14. Medical or psychiatric conditions that, in the opinion of the investigator, make consistent follow-up over the treatment period unlikely, or in general a poor medical risk because of other systemic diseases or active uncontrolled infections. 15. Any screening laboratory value (hematology, serum chemistry or urinalysis) that in the opinion of the Investigator is clinically significant and not suitable for study participation. 16. Hypersensitivity to fluorescein.

Design outcomes

Primary

Measure	Time frame	Description
Least Square (LS) Mean Change From Baseline in Square Root GA Lesion Size in the Study Eye at Month 12	Baseline (screening) and Month 12.	The square root GA lesion size (i.e. transformed area of GA) was measured by FAF photographs. Baseline was defined as the last available, non-missing observation prior to first study drug administration.
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	From the time of first study drug administration (Day 1) up to Month 12 (Data cut-off date).	A TEAE was defined as any adverse event (AE) that commenced or worsened on or after time of first study drug administration up to 60 days beyond last dose of study drug. A treatment-related TEAE was defined as a TEAE with a relationship to study drug of possibly related or probably related or not reported. Severity of TEAEs were categorized as mild; moderate; severe; life-threatening or death related to TEAE, according to Common Terminology Criteria for AEs v4.03. A TEAE of special interest (TEAESI) was defined as a TEAE of scientific and medical concern specific to pegcetacoplan, whether serious or non-serious.

Secondary

Measure	Time frame	Description
LS Mean Change From Baseline in Low Luminance BCVA (LL-BCVA) Score in the Study Eye at Month 12	Baseline (Day 1) and Month 12.	The LL-BCVA was measured by placing a 2.0-log-unit neutral density filter over the best correction and having the participant read the normally illuminated ETDRS chart. The score ranges from 0 to 100 letters, lower number indicating worse vision; a positive value of change from baseline indicates visual acuity gain and a negative value indicates visual acuity loss.
LS Mean Change From Baseline in Low Luminance VA (LL-VA) Deficit Score in the Study Eye at Month 12	Baseline (Day 1) and Month 12.	The LL-VA deficit score is calculated as BCVA score minus LL-BCVA score. The LL-VA deficit score ranges from 0 to 100 letters, lower number indicating worse deficit.
LS Mean Change From Baseline in Untransformed GA Lesion Size in the Study Eye at Month 12	Baseline (Day 1) and Month 12.	The untransformed area of GA was measured by FAF. Baseline is defined as the last available, non-missing observation prior to first study drug administration.
Number of Subjects With Any Macular Neovascularization (MNV) TEAEs in the Study Eye	From the time of first study drug administration (Day 1) up to Month 12 (Data cut-off date).	The number of subjects with any MNV TEAEs in the study eye was identified via clinical review of all ocular TEAEs.
LS Mean Change From Baseline in Distance of GA Lesion From the Fovea (Foveal Encroachment) in the Study Eye at Month 12	Baseline (Day 1) and Month 12.	The foveal encroachment in the study eye was measured by FAF. Baseline is defined as the last available, non-missing observation prior to first study drug administration.
LS Mean Change From Baseline in Best-Corrected Visual Acuity (BCVA) Score of the Study Eye at Month 12	Baseline (Day 1) and Month 12.	The BCVA letter score was determined using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. The score ranges from 0 to 100 letters, lower number indicating reduced visual acuity; a positive value of change from baseline indicates visual acuity gain and a negative value indicates visual acuity loss.

Countries

Australia, New Zealand, United States

Participant flow

Recruitment details

This Phase II, randomized, single-masked, sham injection-controlled study in subjects with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) was conducted at 47 sites (46 active) in 3 countries between 24 September 2015 and 14 July 2017 (Data cut-off date, Month 12).

Pre-assignment details

Subjects were randomized in a 2:2:1:1 manner to receive treatment with pegcetacoplan monthly, pegcetacoplan every-other-month (EOM), sham monthly or sham EOM, respectively. A total of 246 subjects were randomized in the study.

Participants by arm

Arm	Count
Pegcetacoplan Monthly Subjects received IVT injections of pegcetacoplan 15 mg/100 μL once monthly for 12 months.	86
Pegcetacoplan EOM Subjects received IVT injections of pegcetacoplan 15 mg/100 μL EOM for 12 months.	79
Sham Pooled Sham Monthly: Subjects received sham injections once monthly for 12 months. Sham EOM: Subjects received sham injections EOM for 12 months. The procedure for sham injection was the same as that used for IVT injection until the actual injection but no actual injection occurred.	81
Total	246

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	17	5	3	1
Overall Study	Death	0	2	2	0
Overall Study	Investigator's Decision	5	1	0	0
Overall Study	Other	5	6	1	1
Overall Study	Sponsor's Decision	1	0	0	1
Overall Study	Subject Request	6	5	2	1

Baseline characteristics

Characteristic	Total	Sham Pooled	Pegcetacoplan Monthly	Pegcetacoplan EOM
Age, Continuous	79.7 years STANDARD_DEVIATION 7.54	78.4 years STANDARD_DEVIATION 7.43	79.6 years STANDARD_DEVIATION 7.51	81.0 years STANDARD_DEVIATION 7.55
GA Lesion Size (fundus autofluorescence [FAF]) in the Study Eye	8.4 millimeter square (mm^2) STANDARD_DEVIATION 4.12	8.2 millimeter square (mm^2) STANDARD_DEVIATION 4.05	8.0 millimeter square (mm^2) STANDARD_DEVIATION 3.84	8.9 millimeter square (mm^2) STANDARD_DEVIATION 4.47
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	1 Participants	0 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Black or African American	2 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Hispanic or Latino	5 Participants	2 Participants	2 Participants	1 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	234 Participants	77 Participants	81 Participants	76 Participants
Race/Ethnicity, Customized Not Reported	2 Participants	0 Participants	2 Participants	0 Participants
Race/Ethnicity, Customized Other	2 Participants	0 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Unknown	5 Participants	2 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized White	241 Participants	81 Participants	84 Participants	76 Participants
Region of Enrollment Australia	35 Participants	12 Participants	12 Participants	11 Participants
Region of Enrollment New Zealand	10 Participants	4 Participants	3 Participants	3 Participants
Region of Enrollment United States	201 Participants	65 Participants	71 Participants	65 Participants
Sex: Female, Male Female	154 Participants	49 Participants	55 Participants	50 Participants
Sex: Female, Male Male	92 Participants	32 Participants	31 Participants	29 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk
deaths Total, all-cause mortality	0 / 86	0 / 79	0 / 81	0 / 86	0 / 79	0 / 81	0 / 86	2 / 79	2 / 81
other Total, other adverse events	51 / 86	35 / 79	25 / 81	12 / 86	8 / 79	10 / 81	23 / 86	18 / 79	23 / 81
serious Total, serious adverse events	4 / 86	2 / 79	1 / 81	0 / 86	0 / 79	1 / 81	12 / 86	23 / 79	16 / 81

Outcome results

Primary

Least Square (LS) Mean Change From Baseline in Square Root GA Lesion Size in the Study Eye at Month 12

The square root GA lesion size (i.e. transformed area of GA) was measured by FAF photographs. Baseline was defined as the last available, non-missing observation prior to first study drug administration.

Time frame: Baseline (screening) and Month 12.

Population: The modified ITT (mITT) population included all randomized subjects who received at least one injection of study drug and had at least one visit at or after Month 2 where primary efficacy data was collected. Subjects were included in their randomized treatment group even if they received the wrong study drug.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pegcetacoplan Monthly	Least Square (LS) Mean Change From Baseline in Square Root GA Lesion Size in the Study Eye at Month 12	0.26 mm	Standard Error 0.025
Pegcetacoplan EOM	Least Square (LS) Mean Change From Baseline in Square Root GA Lesion Size in the Study Eye at Month 12	0.28 mm	Standard Error 0.026
Sham Pooled	Least Square (LS) Mean Change From Baseline in Square Root GA Lesion Size in the Study Eye at Month 12	0.35 mm	Standard Error 0.025

Primary

Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity

A TEAE was defined as any adverse event (AE) that commenced or worsened on or after time of first study drug administration up to 60 days beyond last dose of study drug. A treatment-related TEAE was defined as a TEAE with a relationship to study drug of possibly related or probably related or not reported. Severity of TEAEs were categorized as mild; moderate; severe; life-threatening or death related to TEAE, according to Common Terminology Criteria for AEs v4.03. A TEAE of special interest (TEAESI) was defined as a TEAE of scientific and medical concern specific to pegcetacoplan, whether serious or non-serious.

Time frame: From the time of first study drug administration (Day 1) up to Month 12 (Data cut-off date).

Population: The safety population included all randomized subjects who received at least one injection of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with life-threatening intensity	0 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Serious TEAEs	4 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAESIs	5 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs	65 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs leading to study/treatment discontinuation	19 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with mild intensity	36 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Death related to TEAEs	0 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with moderate intensity	23 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Treatment-related TEAEs	21 Participants
Pegcetacoplan Monthly	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with severe intensity	6 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Treatment-related TEAEs	11 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with mild intensity	30 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Death related to TEAEs	0 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Serious TEAEs	2 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with life-threatening intensity	0 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAESIs	4 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with severe intensity	3 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with moderate intensity	14 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs leading to study/treatment discontinuation	5 Participants
Pegcetacoplan EOM	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs	47 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs leading to study/treatment discontinuation	3 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Treatment-related TEAEs	0 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs	42 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Serious TEAEs	1 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with mild intensity	28 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with moderate intensity	11 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with severe intensity	3 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAEs with life-threatening intensity	0 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	Death related to TEAEs	0 Participants
Sham Pooled	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) in the Study Eye, Including by Severity	TEAESIs	0 Participants

Secondary

LS Mean Change From Baseline in Best-Corrected Visual Acuity (BCVA) Score of the Study Eye at Month 12

The BCVA letter score was determined using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. The score ranges from 0 to 100 letters, lower number indicating reduced visual acuity; a positive value of change from baseline indicates visual acuity gain and a negative value indicates visual acuity loss.