Alternative Complement Pathway Inhibition by Lampalizumab: Analysis of Data from Chroma and Spectri Phase 3 Clinical Trials

• Published in: Ophthalmology science (Online) p. 100286
• Main Authors: Edmonds, Rose, MS, Steffen, Verena, MSc, Honigberg, Lee A., PhD, Chang, Michael C., PhD
• Format: Journal Article
• Language: English
• Published: 2023
• Subjects: Ophthalmology; complement component 2; CFD; Ab; complement component 4; complement component 3; antigen-binding fragment; below lower limit of quantification; CFI; glycoprotein D; Alternative complement pathway; complement component 5; C2; C3; C4; C5; every 4 weeks; Chroma and Spectri trials; AMD; GA; age-related macular degeneration; BLLOQ; complement factor D; antibody; complement factor B; Lampalizumab; Fab; percent coefficient of variation; FAF; Antibody conjugate assay; CV; Q6W; Q4W; fundus autofluorescence; Geographic atrophy; every 6 weeks; complement factor I; gD; CFB
• ISSN: 2666-9145; 2666-9145
• DOI: 10.1016/j.xops.2023.100286

AbstractObjectiveLampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in phase 3 Chroma/Spectri trials, we investigated the impact of lampalizumab on the complement system in vivo. We developed 6 novel assays to measure changes in complement pathway activities in aqueous humor samples collected from patients enrolled in these trials. DesignChroma/Spectri were double-masked, sham-controlled, 96-week trials. ParticipantsAqueous humor samples from 97 patients with bilateral GA across all groups (ie, intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested. MethodsNovel antibody capture assays were developed on the Simoa platform for complement factor B (CFB), the Bb fragment of CFB, intact complement component 3 (C3), processed C3, intact complement component 4 (C4), and processed C4. Main Outcome MeasuresThe ratio of processed versus intact complement factors (ie, complement activity) in aqueous humor were assessed. ResultsPatients treated with either of the lampalizumab regimens demonstrated an increase in CFD level at week 24 compared with baseline, along with a corresponding median reduction in the Bb:CFB ratio of 41% to 43%. There were no strong correlations between lampalizumab concentrations in aqueous humor and change in CFD levels or Bb:CFB ratio over time. No change in downstream C3 processing was observed with lampalizumab treatment. Additionally, there was no change in C4 processing. ConclusionsThe collection of aqueous humor samples from patients in Chroma and Spectri trials provided key insights on the effects of lampalizumab, a novel complement inhibitor, on local ocular complement activation. Lampalizumab inhibited the alternative complement pathway in the eyes of patients with GA; however, this did not translate into a measurable reduction in either classical or total complement activity, based on absence of changes in C4 and C3 processing, respectively.