Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration

Abstract

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.

Anti–Vascular Endothelial Growth Factor Use and Atrophy in Neovascular Age-Related Macular Degeneration

“…First, as individuals age, physiologic changes at the cellular level lead to RPE cell apoptosis (reviewed in Ehrlich et al 42 ), suggesting that patients with AMD may be destined to demonstrate atrophy. Phase 3 clinical trial data from patients with GA and no evidence of MNV demonstrated increased GA lesion size over time 43,44 ; such increases in the absence of VEGF inhibition support atrophy as part of the natural history of AMD. Recent evidence suggests that atrophy can arise de novo in areas of pre-existing subretinal lesions or in areas with outer retinal atrophy alone or with RPE loss.…”

Intravenous indocyanine green dye is insufficient for robust immune cell labelling in the human retina

“…Several examples of unique patterns only seen by DNIRA identify additional or complementary information for monitoring RPE health versus traditional 488 nm autofluorescence imaging. These data highlight an opportunity for superior stratification and earlier detection of pathology such as reversible RPE dysfunction, critical to identifying therapeutic response signals, as has remained problematic for example in studies of geographic atrophy (19).…”

Microperimetry for geographic atrophy secondary to age-related macular degeneration

“…Microperimetry data were collected as a secondary endpoint in a subset of patients in the lampalizumab clinical program, including the Proxima A (NCT02479386) and Proxima B (NCT02399072) natural history studies of patients with GA, as well as the phase 3 Chroma (NCT02247479) and Spectri (NCT02247531) interventional studies assessing the efficacy and safety of lampalizumab for reducing the rate of GA enlargement. 19 In these clinical trials, predefined study endpoints assessing longitudinal GA progression were the number of absolute scotomatous points and the mean retinal sensitivity.…”