A Phase 3 Safety and Efficacy Study of Intravitreal Administration of Zimura (Complement C5 Inhibitor)

Participants were randomized in a 1:1 ratio to the following monthly treatment groups:

* Avacincaptad pegol 2 mg
* Sham

At Month 12, the participants in the avacincaptad pegol 2mg treatment group were re-randomized to receive the study drug either on a monthly basis or on an every other month basis

The participants initially randomized to sham treatment continued with monthly sham administration through Month 23

All participants had a final follow up visit at Month 24

• Avacincaptad Pegol (Drug), also known as Zimura (previous name), IZERVAY: Avacincaptad Pegol Intravitreal Injection
• Sham (Drug): Sham Administration (includes placement of the blunt opening of an empty, needleless syringe barrel on the conjunctiva in the inferotemporal quadrant of the eyeball to simulate the pressure of an injection)

Primary outcomes

• The Mean Rate of Growth (Slope) Estimated Based on GA Area Measured by Autofluorescence (FAF) at 3 Time Points: Baseline, Month 6, and Month 12 [Baseline to month 12]: GA was associated with age-related macular degeneration (AMD) and caused bilateral, progressive, and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, and choriocapillaris) leading to a permanent loss of visual function and blindness. The least squares mean used to determine mean rate of change in GA growth (slope) was measured by FAF. LS mean \& SE were based on square-root transformation.
• The Mean Rate of Growth (Slope) Estimated Based on GA Area Measured by FAF at 5 Timepoints: Baseline, Month 6, Month 12, Month 18, and Month 24 [Baseline to month 24]: GA was associated with AMD and caused bilateral, progressive, and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, and choriocapillaris) leading to a permanent loss of visual function and blindness. The least square mean rate of GA growth (slope) was measured by FAF. LS mean \& SE were based on untransformed data.

Secondary outcomes

• Change From Baseline in Best Corrected Visual Acuity (BCVA) Using Early Treatment Diabetic Retinopathy Study (ETDRS) Letters at 24 Months [Baseline and month 24]: BCVA was assessed using ETDRS visual acuity testing charts. The ETDRS Visual Acuity Score (VAS) is defined as the number of letters read on the ETDRS chart. Minimum and maximum possible scores are 0-100. A higher score represented better visual functioning. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening.
• Change From Baseline in Low Luminance (LL) BCVA Using ETDRS Letters at 24 Months [Baseline and month 24]: BCVA was assessed using ETDRS visual acuity testing charts. The ETDRS VAS is defined as the number of letters read on the ETDRS chart. Minimum and maximum possible scores are 0-100. A higher score represented better visual functioning. A positive change from baseline indicates an improvement and a negative change from baseline indicates a worsening. LL BCVA was measured by placing a 2.0 log unit neutral density filter over the best correction for that eye and having the participant read the normally illuminated ETDRS chart.
• Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 6, 12 and 18 Months [Baseline, months 6, 12, and 18]: The National Eye Institute Visual Function Questionnaire-25 (VFQ-25) measured the influence of visual disability and visual symptoms on general health domains. The VFQ-25 consisted of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. A higher score represented better visual functioning. Each item was then converted to a 0 to 100 scale so that the lowest and highest possible scores were set at 0 and 100 points, respectively. Each subscale score had a range of 0 to 100 inclusive and were calculated from the re-scaled raw data. A composite score was derived based on the average of the 11 vision-related subscales.
• Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 24 Months [Baseline and month 24]: The National Eye Institute Visual Function Questionnaire-25 (VFQ-25) measured the influence of visual disability and visual symptoms on general health domains. The VFQ-25 consisted of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. A higher score represented better visual functioning. Each item was then converted to a 0 to 100 scale so that the lowest and highest possible scores were set at 0 and 100 points, respectively. Each subscale score had a range of 0 to 100 inclusive and were calculated from the re-scaled raw data. A composite score was derived based on the average of the 11 vision-related subscales.
• Number of Participants With Categorical One-level Loss in VFQ-25 Subscale [Baseline up to month 24]: The National Eye Institute VFQ-25 measured the influence of visual disability and visual symptoms on general health domains. The VFQ-25 consisted of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. A higher score represented better visual functioning. Each item was then converted to a 0 to 100 scale so that the lowest and highest possible scores were set at 0 and 100 points, respectively.Categorical one-level loss in each item was defined as decline of one or more levels at Month 24 on the original scale from Baseline (equivalently 20 points for general vision and 25 points for other vision items in a 0 to 100 scale).
• Time to Persistent Vision Loss [Baseline up to month 24]: Vision loss event was defined as a loss of ≥ 15 letters (equivalent to a loss of 3 lines on the ETDRS chart) in BCVA from Baseline measured at any two or more consecutive visits up to Month 24. These parameters were chosen as a 3-line BCVA loss (equivalent to doubling of visual angle) is widely recognized as a significant deterioration in vision and a minimum of two consecutive visits was representative of persistent disease progression. BCVA was assessed using ETDRS visual acuity testing charts. The ETDRS VAS was defined as the number of letters read on the ETDRS chart. Min and max possible scores are 0-100. A higher score represents better visual functioning. Kaplan-Meier method was used for analysis. Participants with an event were reported and not the median time to event.

Sex: All, ages: 50 Years to any

Inclusion Criteria:

* Subjects of either gender aged ≥ 50 years
* Diagnosis of Non-foveal GA secondary to dry AMD

Exclusion Criteria:

* Any prior treatment for AMD (dry or wet) or any prior intravitreal treatment for any indication in either eye, except oral supplements of vitamins and minerals
* Any intraocular surgery or thermal laser within 3 months of trial entry.
* Any prior thermal laser in the macular region, regardless of indication
* Any ocular or periocular infection (including blepharitis), or ocular surface inflammation in the past 12 weeks.
* Previous therapeutic radiation in the region of the study eye
* Any sign of diabetic retinopathy in either eye

Participant flow

Outcome results

• The Mean Rate of Growth (Slope) Estimated Based on GA Area Measured by Autofluorescence (FAF) at 3 Time Points: Baseline, Month 6, and Month 12 (Primary), Least squares mean, millimeters (mm)/year: Avacincaptad Pegol 0.336 +/- 0.032; Sham 0.392 +/- 0.033 (p 0.0064)
• The Mean Rate of Growth (Slope) Estimated Based on GA Area Measured by FAF at 5 Timepoints: Baseline, Month 6, Month 12, Month 18, and Month 24 (Primary), Least squares mean, mm^2/year: Avacincaptad Pegol 2.23 +/- 0.124; Avacincaptad Pegol and Sham 2.10 +/- 0.126; Sham 2.59 +/- 0.085 (p 0.0165)
• Change From Baseline in Best Corrected Visual Acuity (BCVA) Using Early Treatment Diabetic Retinopathy Study (ETDRS) Letters at 24 Months (Secondary), Least squares mean, score on a scale: Avacincaptad Pegol -7.31 +/- 1.07; Sham -6.48 +/- 1.05 (p 0.58)
• Change From Baseline in Low Luminance (LL) BCVA Using ETDRS Letters at 24 Months (Secondary), Least squares mean, score on a scale: Avacincaptad Pegol -10.58 +/- 1.20; Sham -9.1 +/- 1.18 (p 0.38)
• Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 6, 12 and 18 Months (Secondary), Mean, score on a scale: Avacincaptad Pegol -1.2 +/- 10.56; Sham -1.6 +/- 9.98
• Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Scores at 24 Months (Secondary), Least squares mean, score on a scale: Avacincaptad Pegol -7.735 +/- 0.950; Sham -7.023 +/- 0.931 (p 0.5929)
• Number of Participants With Categorical One-level Loss in VFQ-25 Subscale (Secondary), Number, participants: Avacincaptad Pegol 45; Sham 35
• Time to Persistent Vision Loss (Secondary), Median, months: Avacincaptad Pegol 17.02 (2.8 to 23.0); Sham 13.93 (1.3 to 23.2) (p 0.6424)

Adverse events

Time frame: All-cause mortality (ACM): From randomization up to 24 months Serious Adverse events (SAEs) and non-SAEs: From first dose up to 24 months

Serious adverse events by term

57 more terms not shown.

Other adverse events by term

105 more sites not listed.

• Results publication: Khanani AM, Danzig CJ, Heier JS, Jaffe GJ, Kaiser PK, Lally DR, Patel SS, Vajzovic L, Weng CY, Patel H, Clark J, Desai D, Luo D, Henry E, Holz FG; GATHER2 Trial Investigators. Avacincaptad Pegol for Geographic Atrophy Secondary to Age-Related Macular Degeneration: Two-Year Efficacy and Safety Results from the GATHER2 Phase 3 Trial. Ophthalmology. 2026 Apr;133(4):451-465. doi: 10.1016/j.ophtha.2025.12.011. Epub 2025 Dec 15. PMID 41407269
• Results publication: Khanani AM, Patel SS, Staurenghi G, Tadayoni R, Danzig CJ, Eichenbaum DA, Hsu J, Wykoff CC, Heier JS, Lally DR, Mones J, Nielsen JS, Sheth VS, Kaiser PK, Clark J, Zhu L, Patel H, Tang J, Desai D, Jaffe GJ; GATHER2 trial investigators. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1449-1458. doi: 10.1016/S0140-6736(23)01583-0. Epub 2023 Sep 8. PMID 37696275
• Results publication: Tzoumas N, Riding G, Williams MA, Steel DH. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst Rev. 2023 Jun 14;6(6):CD009300. doi: 10.1002/14651858.CD009300.pub3. PMID 37314061

• Study Protocol (PDF, 2021-05-24)
• Statistical Analysis Plan (PDF, 2022-04-07)