Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials

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 mm2 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 mm2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were -0.02 mm2 (95% CI, -0.21 to 0.16 mm2; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm2 (95% CI, 0.00-0.31 mm2; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm2 (95% CI, -0.13 to 0.24 mm2; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm2 (95% CI, -0.07 to 0.24 mm2; 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 mm2 per year.

Trial registration: ClinicalTrials.gov Identifier: NCT02247479 and NCT02247531.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Holz reported receiving consulting fees from Acucela, Allergan, Bayer, Genentech/Roche, GSK, Heidelberg Engineering, Merck, Novartis, and Thrombogenics. Dr Sadda reported serving as a consultant for Allergan, Carl Zeiss Meditec Inc, Centervue, F. Hoffmann–La Roche Ltd, Genentech Inc, Heidelberg Engineering, Iconic, Novartis, Optos PLC, and Thrombogenics; and receiving research support from Allergan, Carl Zeiss Meditec Inc, Genentech Inc, and Optos PLC. Dr Busbee reported serving as a consultant for Aerpio, Genentech Inc, and Valeant; and receiving royalties from Akorn. Dr Mitchell reported serving as a consultant for Abbott, Allergan, Bayer, Novartis, and Roche. Dr Tufail reported serving as a consultant for Allergan, Bayer, Genentech Inc, Genentech/Roche, GSK, Heidelberg Engineering, Novartis, and Thrombogenics; and receiving research support from Bayer and Novartis. Drs Brittain, Ferrara, Gray, Honigberg, Martin, and Ehrlich are employees of Genentech Inc. Dr Tong reported being a former employee of Genentech Inc, and was an employee of Genentech Inc at the time of manuscript development. Dr Bressler reported serving as principal investigator of grants at Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Bayer, Genentech Inc, Novartis, and Samsung. The Department of Ophthalmology, University of Bonn, has received nonfinancial support for supply of technical equipment by several imaging device manufacturers, including Centervue, Heidelberg Engineering, Optos, and Zeiss Meditec and has received research grants from Acucela, Alcon, Allergan, Bayer, Formycon, Genentech/Roche, Heidelberg Engineering, and Novartis. No other conflicts were reported.

Figures

Figure 1.. CONSORT Flow Diagram for Chroma and Spectri Randomized Clinical Trials

GA indicates geographic atrophy; q4w, every 4 weeks; and q6w, every 6 weeks.

Figure 2.. Adjusted Mean Change From Baseline in Geographic Atrophy (GA) Area Over Time From Baseline to 48 Weeks in Chroma and Spectri Pooled as Measured on Fundus Autofluorescence Imaging

A, Overall intent-to-treat population. B, Complement factor I (CFI)–positive population. C, CFI-negative population. The mixed effects model repeated-measures analysis was adjusted for baseline GA area, baseline GA lesion location, baseline GA lesion contiguity, baseline best-corrected visual acuity category, sex, biomarker status (overall population only), and study. Error bars indicate 95% CIs. q4w Indicates every 4 weeks; q6w, every 6 weeks.