Development of PAS-nomacopan for treatment of geographic atrophy and its efficacy in a blue light model comparing the relative contributions of C5 and LTB₄ inhibition to decreased retinal damage

Abstract

Purpose : Bispecific PASylated-nomacopan (66kDa) is in development for treatment of geographic atrophy (GA) by intravitreous (IVT) administration. PAS-nomacopan (66.5kDa) inhibits complement C5 and leukotriene B4 (LTB₄) as potently as its smaller (16.8kDa), Phase 3 ready, parent molecule nomacopan but is long acting with a vitreous half-life in rabbits of 7-8 days and good bioavailability in retina and choroid. Here, a model of GA has been used to investigate whether C5 and LTB₄ both contribute to retinal damage.

Methods : Vehicle or PAS-nomacopan and its engineered variants, which only bind either C5 or LTB₄ (assessed by surface plasmon resonance and fluorescence titration) were injected IVT into SD rats (n = 6-12/group) immediately before dark adaptation and 24 hours before induction of retinal damage by BL (2000lx ± 500lx for 9 hours). Electroretinograms (ERG), optical coherence tomography (OCT) and histological staining for terminal complement complex (C5b9) deposition and activated microglia were used to assess retinal damage and cellular infiltration. Measurements were made at baseline and 7 days after exposure to BL.

Results : Bispecific PAS-nomacopan used in the study is representative of material to be used in the clinic. The site directed mutant PAS-nomacopan variants were shown to bind either C5 or LTB₄ as potently as PAS-nomacopan. PAS-nomacopan decreased retinal damage assessed by ERG amplitude of A and B waves by up to 50% at day 7 after BL damage compared to vehicle. Quantification of C5b9 deposition, infiltrating macrophages and retinal thickness associated with dual inhibition, LTB₄ specific inhibition or C5 specific inhibition is ongoing. The relative contributions of C5 inhibition and LTB₄ inhibition to the reduction in BL induced retinal damage will be presented.

Conclusions : The reduction in retinal damage following IVT administration of PAS-nomacopan further supports the drug’s clinical development. The product profile supports an IVT dosing interval of 3 months or longer, efficacy equivalent to the C5 inhibitor approved for GA, and the possibility that inhibition of LTB₄, which can induce VEGF-A in preclinical models, may prevent elevated rates of choroidal neovascularization (CNV) seen with the approved complement-only inhibitors for GA.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.