Development of long-acting PAS-nomacopan for treatment of GA and other retinal diseases

Abstract

Purpose : Studies indicate that complement inhibitors slow the progression of geographic atrophy (GA) but may promote choroidal neovascularisation (CNV).[i] [ii] Treatments that slow the progression of GA whilst inhibiting CNV are needed.
Long-acting 68kda PASylated-nomacopan (PAS-nomacopan) inhibits complement C5 and leukotriene B4 (LTB₄), a potent leukotactic agent that increases retinal VEGF. The addition of a PAS polypeptide tail to nomacopan increases the effective MW to 580kda which may permit a dosing interval of up to 3 months. Inhibition of LTB4 may decrease the risk of CNV seen with avicincaptad and pegcetacoplan.
Here we report 1.) the effect of IVT administered PAS-nomacopan in a mouse model of laser-induced CNV, 2.) the pharmacokinetics (PK) of IVT administered PAS-nomacopan in rabbits.

[i] Liao DS, et al. Ophthalmology. 2020 Feb;127(2)

[ii] Jaffe GJ et al. Ophthalmology. 2021 Apr;128(4)

Methods : For the CNV study, 5 groups of C57BL/6 mice received single or repeat 3µL doses of saline, PAS-nomacopan (20mg/ml) or aflibercept (40mg/ml). CNV was induced by laser in the right eye on Day 0. Retinal angiography was undertaken on Days 7 and 14. CNV volume was measured on Day 16 from flat mount choroid preparations.
To examine PK, pigmented rabbits received a single IVT dose of 50µL PAS-nomacopan on Day 1 to the right eye. Vitreous (V), retina (R) and choroid (CH) were harvested on Days 3, 7, 14, 21, 28 and 56. PAS-nomacopan concentrations in eye tissue were measured using liquid chromatography mass spec to derive half-life and bioavailability.

Results : Single IVT PAS nomacopan significantly (p = 0.022) reduced CNV compared to saline and was as effective as multiple IVT aflibercept (p = 0.019). Single IVT PAS-nomacopan showed a trend towards reduced leakage on Day 14 (p = 0.097). Surprisingly, multiple IVT PAS-nomacopan did not reduce leakage or CNV.
The V and R half-life of PAS-nomacopan in rabbits was shown to be 5-6 days and the concentration of the drug in R was approximately 30% of the concentration in V indicating that PAS enters R.

Conclusions : VEGF is a key driver of CNV and LTB4 inhibition reduces VEGF and CNV.[1] We have shown that nomacopan inhibits retinal VEGF in a uveitis model.[2] Collectively, these data support ongoing development of PAS-nomacopan as therapy for GA and other retinal diseases.

[1] Sasaki F et al. JCI Insight. 2018 Sep 20;3(18)

[2] Eskandarpour M et al. Cells. 2021 Feb 15;10(2)

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.