Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm/year (median, ∼1.78 mm/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.

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IMPORTANCE Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. OBJECTIVE To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. DESIGN, SETTING, AND PARTICIPANTS Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm 2 with diffuse or banded fundus autofluorescence patterns. INTERVENTIONS Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. MAIN OUTCOMES AND MEASURES Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I-profile genetic biomarker. RESULTS A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm 2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were −0.02 mm 2 (95% CI, −0.21 to 0.16 mm 2 ; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm 2 (95% CI, 0.00-0.31 mm 2 ; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm 2 (95% CI, −0.13 to 0.24 mm 2 ; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm 2 (95% CI, −0.07 to 0.24 mm 2 ; P = .27) for lampalizumab every 6 weeks in Spectri. No benefit of lampalizumab was observed across prespecified subgroups, including by complement factor I-profile biomarker. Endophthalmitis occurred after 5 of 12 447 injections (0.04%) or in 5 of 1252 treated participants (0.4%) through week 48. CONCLUSIONS AND RELEVANCE In Chroma and Spectri, the largest studies of GA conducted to date, lampalizumab did not reduce GA enlargement vs sham during 48 weeks of treatment. Results highlight the substantial and consistent enlargement of GA, at a mean of approximately 2 mm 2 per year.

Geographic atrophy is an advanced form of age-related macular degeneration that can significantly impact visual function, but has no approved treatment. This review focuses on the pathophysiology of geographic atrophy, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade.

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