Pharmacokinetic/pharmacodynamic analysis of geographic atrophy lesion area in patients receiving pegcetacoplan treatment or sham

Abstract

Pegcetacoplan is a complement C3/C3b inhibitor indicated for the treatment of geographic atrophy (GA). A population pharmacokinetic (PK)/pharmacodynamic (PD) analysis of pegcetacoplan used GA lesion area measurements from three clinical studies to determine the effect of pegcetacoplan exposure on GA progression. A base disease progression model was developed using data from sham-treated eyes and untreated fellow eyes, followed by treatment effect assessment in dose-response and PK/PD models. In total, 1501 patients from FILLY (NCT02503332), OAKS (NCT03525613), and DERBY (NCT03525600) received intravitreal pegcetacoplan 15 mg monthly or every other month (EOM) or sham treatment monthly or EOM and were included in the population analysis of lesion area. Disease progression over time was adequately described as linear-with-time over the 24-month maximal study duration. Disease-specific covariates associated with slower lesion growth were unilateral, unifocal, and subfoveal GA lesions and >20 intermediate or large drusen groups (≥63 μm) at baseline. The dose-response model estimated 0.80-fold (95% CI: 0.75, 0.84) and 0.83-fold (95% CI: 0.78, 0.87) reductions in GA lesion growth rate with pegcetacoplan monthly and EOM, respectively, versus sham. A relationship between vitreous humor concentration and GA lesion growth rate was quantified as 2.6% per unit of log-transformed vitreous pegcetacoplan concentration in the PK/PD model. PK/PD predictions of treatment effect based on exposure (pegcetacoplan monthly: 0.80 [90% CI: 0.77, 0.84]; pegcetacoplan EOM: 0.83 [90% CI: 0.80, 0.86]) were consistent with predictions based on dose response. These results support the benefit of pegcetacoplan administered monthly or EOM in slowing GA lesion growth.

FIGURE 1

Flowchart of model development. VPC, visual predictive check.

FIGURE 2

Influence of covariates on change in GA lesion area ratio at month 24. CI, confidence interval; GA, geographic atrophy.

FIGURE 3

Influence of treatment effect on change in GA lesion area ratio at month 24. CI, confidence interval; GA, geographic atrophy; PEOM, pegcetacoplan every other month; PM, pegcetacoplan monthly.

FIGURE 4

Typical predicted treatment effect on GA lesion area disease progression. The continuous PK/PD relationship is illustrated using fixed‐effect parameter final estimates without uncertainty in estimation or interindividual variability and overlaid on the 90% prediction interval of individual patient vitreous average concentration for each dosing regimen. Horizontal reference lines are included for estimated effects on lesion area from the dose–response models. C _avg,ss, average concentration at steady state; DR, dose–response; ER, exposure–response; GA, geographic atrophy; PD, pharmacodynamics; PEOM, pegcetacoplan every other month; PI, prediction interval; PK, pharmacokinetics; PM, pegcetacoplan monthly.

FIGURE 5

Influence of concomitant anti‐VEGF medication on change in GA lesion area ratio at month 24. CI, confidence interval; GA, geographic atrophy; PEOM, pegcetacoplan every other month; PM, pegcetacoplan monthly; VEGF, vascular endothelial growth factor.

FIGURE 6

Influence of anti–polyethylene glycol antibodies on change in GA lesion area ratio at month 24. CI, confidence interval; GA, geographic atrophy; PEG, polyethylene glycol; PEOM, pegcetacoplan every other month; PM, pegcetacoplan monthly.