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

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase II, Multicenter, Randomized, Single-Masked, Sham-Controlled Study of Safety, Tolerability and Evidence of Activity of Intravitreal APL-2 Therapy in Patients With Geographic Atrophy (GA)

Conditions
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Geographic Atrophy

Intervention / Treatment
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* Drug: Pegcetacoplan
* Other: Sham Procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unless specified otherwise, ocular specific inclusion criteria apply to the study eye only. Male or Female. Age greater than or equal to 50 years. BCVA of 20/320 (Snellen equivalent) or better using ETDRS charts. 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: Total GA area must be ≥ 2.5 and ≤ 17.5 mm2 (1 and 7 disk areas [DA] respectively), determined by screening images of FAF. If GA is multifocal, at least one focal lesion must be ≥ 1.25 mm2 (0.5 DA). GA can be completely visualized on the macula centered image. GA must be able to be photographed in its entirety. GA must be able to be measured separately from any areas of peripapillary atrophy as assessed by the CRC. 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 Female subjects must be: Women of non-child-bearing potential (WONCBP), or 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. 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. Willing and able to give informed consent. Exclusion Criteria: Unless specified otherwise, ocular specific inclusion criteria apply to the study eye only. GA due to causes other than AMD such as Stargardt disease, cone rod dystrophy or toxic maculopathies like plaquenil maculopathy. Spherical equivalent of the refractive error demonstrating > 6 diopters of myopia or an axial length >26 mm. 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. Retinal disease other than AMD; however, benign conditions of the vitreous or peripheral retina are not exclusionary (i.e. pavingstone degeneration). 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). Any ophthalmologic condition that prevents adequate imaging of the retina judged by the site or CRC. Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization. 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. Any ophthalmic condition that may require surgery during the study period. Any contraindication to IVT injection including current ocular or periocular infection. History of uveitis or endophthalmitis. History of IVT injection at any time. 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. 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. 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. Hypersensitivity to fluorescein.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pegcetacoplan 15 mg/100 µL Monthly for 12 months<br>A single dose of 15 mg pegcetacoplan/100 µL will be administered via intravitreal injection in this study. Subjects will receive an injection every month for 12 consecutive months. | Drug: Pegcetacoplan<br> <br> * Other names: APL-2;|
| Experimental: Pegcetacoplan 15 mg/100 µL EOM for 12 months<br>A single dose of 15 mg pegcetacoplan/100 µL will be administered via intravitreal injection in this study. Subjects will receive an injection every other month (EOM) for 12 consecutive months. | Drug: Pegcetacoplan<br> <br> * Other names: APL-2;|
| Sham Comparator: Sham Monthly for 12 months<br>Subjects will receive a Sham procedure every month for 12 consecutive months. | Other: Sham Procedure<br> <br> |
| Sham Comparator: Sham EOM for 12 months<br>Subjects will receive a Sham procedure every other month (EOM) for 12 consecutive months. | Other: Sham Procedure<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (screening) and Month 12. | 
| 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. | From the time of first study drug administration (Day 1) up to Month 12 (Data cut-off date). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LS Mean Change From Baseline in Untransformed GA Lesion Size in the Study Eye at 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. | Baseline (Day 1) and Month 12. | 
| 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. | Baseline (Day 1) and Month 12. | 
| LS Mean Change From Baseline in Low Luminance BCVA (LL-BCVA) Score in the Study Eye at 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. | Baseline (Day 1) and Month 12. | 
| LS Mean Change From Baseline in Low Luminance VA (LL-VA) Deficit Score in the Study Eye at 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. | Baseline (Day 1) and Month 12. | 
| LS Mean Change From Baseline in Distance of GA Lesion From the Fovea (Foveal Encroachment) in the Study Eye at 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. | Baseline (Day 1) and Month 12. | 
| Number of Subjects With Any Macular Neovascularization (MNV) TEAEs in the Study Eye | The number of subjects with any MNV TEAEs in the study eye was identified via clinical review of all ocular TEAEs. | From the time of first study drug administration (Day 1) up to Month 12 (Data cut-off date). |