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

Abstract

Purpose: Lampalizumab, 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 the phase III 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.

Design: Chroma/Spectri were double-masked, sham-controlled, 96-week trials.

Participants: Aqueous humor samples from 97 patients with bilateral GA across all groups (i.e., intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested.

Methods: Novel 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 measures: The ratio of processed vs. intact complement factors (i.e., complement activity) in aqueous humor were assessed.

Results: Patients 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.

Conclusions: The 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.

Financial disclosures: Proprietary or commercial disclosure may be found after the references.

Keywords: Alternative complement pathway; Antibody conjugate assay; Chroma and Spectri trials; Geographic atrophy; Lampalizumab.

Figure 1

Overview of the complement pathways. C2 = complement component 2; C3 = complement component 3; C4 = complement component 4; C5 = complement component 5; CFB = complement factor B; CFD = complement factor D.

Figure 4

A, Total complement factor D (CFD) levels (ng/ml) and (B) Bb:complement factor B (CFB) ratio. Plots on left show values at baseline and week 24; plots on right show percentage change from baseline to week 24. LQ4W = lampalizumab every 4 weeks; LQ6W = lampalizumab every 6 weeks.

Figure 9

A, Processed complement component 3 (C3):intact C3 ratio and (B) processed complement component 4 (C4):intact C4 ratio. Plots on left show values at baseline and week 24; plots on right show percentage change from baseline to week 24. LQ4W = lampalizumab every 4 weeks; LQ6W = lampalizumab every 6 weeks.

Figure 11

Schematic showing potential hypotheses for lower-than-expected reduction in complement factor B (CFB) cleavage with complement factor D (CFD) inhibition by lampalizumab.