Abstract
Purpose :
Geographic Atrophy (GA) is an advanced stage of age-related macular degeneration (AMD); a major cause of blindness affecting almost 1 million people in the US alone. GA is characterized by a loss of RPE, photoreceptors, and atrophy of the choriocapillaris. Dysregulation of the complement system is a contributor to the pathogenesis of AMD. Polymorphisms in C3, factor H and factor B are associated with risk of AMD and upregulation of the complement pathway leads to C3 opsonization of photoreceptors and RPE. Since C3 is the central component of all three complement pathways, inhibition of C3 represents a promising approach to treat GA. Pegcetacoplan (APL-2), a PEGylated cyclic peptide inhibitor of C3, slowed GA lesion growth in a Phase II (FILLY) study and is being investigated in ongoing Phase III trials (DERBY and OAKS). Intravitreal (IVT) injection remains the most efficient route to reach the diseased tissues in the posterior section of the eye. However, therapeutics delivered from the vitreous to the retina must traverse multiple biological barriers; including the inner limiting membrane (ILM) which is considered the main filtration barrier between the retina and vitreous.
Methods :
An ocular distribution study of pegcetacoplan in New Zealand white rabbits was conducted to measure concentrations in aqueous humor (AH), iris-ciliary body, vitreous humor (VH) and the retina/RPE/choroid. Pegcetacoplan was administered as a single IVT dose of 12 mg and animals were euthanized for tissue/fluid compartment collection on Days 1, 3, 7, 14 and 28. Isolated tissues were analyzed by LC-MS/MS methods specific for each matrix.
Results :
Peak concentrations in each ocular compartment were reached 24 hours with the exception of VH which plateaued between 24 and 96 hours. Exposure in the retina/RPE/choroid and AH was generally 3- and 6-fold lower than VH, respectively. Elimination half-life was ~5 days in each ocular compartment in rabbits compared to 3 days in cynomolgus monkeys.
Conclusions :
Pegcetacoplan has rabbit vitreal kinetics in the range of marketed anti-VEGF biologics and does traverse the ILM in adequate concentrations supporting the posology in the clinical studies.
This is a 2021 ARVO Annual Meeting abstract.