Nonclinical evaluation of CTx001, a gene therapy for the treatment of geographic atrophy in age-related macular degeneration

Abstract

Purpose : Age-related macular degeneration (AMD) is strongly associated with genes that regulate the alternative complement pathway. Complement Therapeutics is developing CTx001, an AAV gene therapy expressing a soluble, truncated form of the complement regulatory protein complement receptor 1 (mini-CR1) for the treatment of geographic atrophy (GA).

Methods : CTx001, a self complementary AAV2 gene therapy, was produced via triple transfection methodology in HEK293 cells. In vivo activity of CTx001 was verified in the rat laser CNV model before progressing to NHP studies. Tolerability of CTx001 in NHP was assessed following a single, bilateral administration of drug into the subretinal space of cynomolgus macaques at low (2.5x10⁹ vg/eye), mid (5.0x10⁹ vg/eye) and high (2.65x10¹⁰ vg/eye) dose, followed by an eight week observation period. Volume matched vehicle control delivered via the same route of adminstration was used as comparator. Study endpoints included clinical observations, clincial pathology, biomicroscopic and funduscopic ophthalmic exams, tonometry, SD-OCT and fluorescein angiography.

Results : CTx001 displayed bioactivity in vivo, attenuating activation of the terminal complement pathway in the rat laser CNV model, which corroborates previous studies conducted in the mouse laser CNV model (Keefe, et al. IOVS 2023). CTx001 was well tolerated in NHP up to and inclusive of the high dose of 2.65x10¹⁰ vg/eye. All animals progressed to scheduled euthanasia, and there were no gross lesions apparent upon necropsy. There were no test item related clinical observations reported throughout the study, and animals gained and maintained weight consistent with vehicle controls. No remarkable findings linked to test item were seen in clinical chemistry, hematology or coagulation parameters. Mild inflammation secondary to the dosing procedure and test item was correlated with increased severity in the high-dose group. Ophthalmic findings such as pigment variation, anterior flare, vitreous and retinal hemorrhage were all reported as very slight to slight. There were no signs of retintis in any dose groups.

Conclusions : In this eight week, non-GLP dose range finding study, CTx001 was well tolerated following subretinal adminstration in NHP up to 2.65x10¹⁰ vg/eye. These results support inititation of IND enabling GLP toxicology studies for CTx001.

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