A Phase 1b Multi-Center, Open Label, Single-Arm Safety Study of Intravitreal Pegcetacoplan Supporting the Phase 3 DERBY and OAKS Studies for Geographic Atrophy: A Solution to “Tarmac Delay"

Abstract

Purpose : Describe the origin and interim results of a phase 1b safety study, APL2-103, supporting two large phase 3 studies of intravitreal pegcetacoplan for geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Methods : In December 2018, the phase 3 DERBY and OAKS studies of intravitreal pegcetacoplan for GA were voluntarily paused due to transient intraocular inflammation (IOI, n=4) after dosing with a new formulation developed for phase 3 trials. An investigation to determine the exact cause was conducted. Quality review of the manufacturing process revealed an impurity in the active pharmaceutical ingredient introduced during scale up. Additional manufacturing steps to eliminate the impurity were implemented, and the resulting product was tested in several animal studies. APL2-103, a 24-month phase 1b, open-label, single-arm safety study of monthly pegcetacoplan was initiated in GA subjects with low vision (Snellen 20/200 to 20/800) before further dosing in phase 3 trials.

Results : All four patients with IOI in the phase 3 studies recovered fully (mean BCVA before: 47.5 letters [range 38-67] and after: 45.5 letters [29-68]). Phase 3 studies were re-initiated in March 2019 after a drug product lot without the impurity revealed no signs of investigator-assessed IOI in 10 subjects who completed a 7-day follow-up evaluation in APL2-103 across 4 clinical sites. APL2-103 continues supporting drug product lot evaluation before use in DERBY/OAKS. Safety findings in APL2-103 after phase 3 re-initiation were consistent with all previous and ongoing intravitreal pegcetacoplan programs. In APL2-103, one patient developed new-onset exudation, and no cases of IOI were observed with the phase 3 formulation. An exploratory interim efficacy analysis of APL2-103 in bilateral GA patients with 12 (n=9) and 18 (n=7) months of follow up revealed that the GA growth rate in pegcetacoplan-treated eyes was slower than untreated fellow eyes by 31% at month 12 and 52% at month 18.

Conclusions : The likely root cause of intraocular inflammation was identified and eliminated. These findings highlight the value of ensuring safety following manufacturing or formulation changes. APL2-103 continues to support the fully enrolled phase 3 studies, with an acceptable safety profile.

This is a 2021 ARVO Annual Meeting abstract.