Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration

Abstract

Inhibition of vascular endothelial growth factor, a key contributor to the choroidal neovascularization associated with wet age-related macular degeneration, is the mode of action of several approved therapies, including aflibercept, which requires frequent intravitreal injections to provide clinical benefit. Lack of compliance with the dosing schedule may result in recurrence of active wet macular degeneration, leading to irreversible vision impairment. Gene therapy providing sustained anti-vascular endothelial growth factor levels in the retina following a single injection could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, is optimized for intravitreal delivery and strong protein expression. Here, we report the long-term expression and efficacy of ADVM-022-derived aflibercept in a laser-induced choroidal neovascularization model in non-human primates. Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels. In addition, ADVM-022 administration 13 months before lasering prevented the occurrence of clinically relevant choroidal neovascularization lesions, similar to animals that received a bolus of intravitreal aflibercept (standard of care) at the time of lesioning. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for wet macular degeneration and may ultimately improve patients’ visual outcomes.

Analysis of Aflibercept Expression in NHPs following Intravitreal Administration of ADVM-022, a Potential Gene Therapy for nAMD

“…The ADVM-022-induced aflibercept expression measured 56 days post-dose reported here was within the range we previously reported in our long-term study, in which aflibercept levels were monitored over a 16-month period post-ADVM-022 administration. 20 In this study, aflibercept expression was detected in all ocular tissues sampled (aqueous humor, vitreous humor, choroid, and retina) following ADVM-022 administration.…”

“…We previously reported that ADVM-022, an adeno-associated virus (AAV) vector optimized for IVT injection encoding aflibercept, demonstrated sustained expression of the protein out to 16 months in nonhuman primates (NHPs), and in a laser-induced choroidal neovascularization (CNV) animal model of nAMD, ADVM-022 provided the same degree of protection as an IVT bolus of aflibercept recombinant protein delivered at the time of laser treatment. 20 …”

“… 21 , 22 , 23 It is known that IVT administration of AAV vectors with various transgenes can induce intraocular inflammation. 20 , 24 , 25 Several studies have used concomitant anti-inflammatory interventions as an approach for mitigating or eliminating the inflammatory responses following administration of AAV vectors. 24 , 25 , 26 Consequently, we measured parameters of ocular inflammation as a function of ADVM-022 dose.…”

Soluble ligands as drug targets

“…However, there are six investigational therapies in our dataset for which the mode of action involves the delivery of a gene to express a protein that targets a ligand. The two currently active gene therapies are both in phase I trials; one is an AAV vector which encodes the anti-VEGF agent aflibercept and has been optimized for intravitreal delivery and strong protein expression 58 , while the other is an AAV vector that carries a gene that encodes a soluble anti-VEGF protein 59 . Eye disorders have been one of the areas in which gene therapies in general have been successful in recent years, and in the case of VEGFA-targeted agents for treatment of AMD, such agents could circumvent the need for repeated intravitreal injections, which is a limitation of current therapies 60 .…”

Suprachoroidal and Subretinal Injections of AAV Using Transscleral Microneedles for Retinal Gene Delivery in Nonhuman Primates

“…3,4 The first US Food and Drug Administra-tion (FDA)-approved gene therapy for the eye employs AAV2 to express the RPE65 gene encoding a retinal isomerase to treat patients with biallelic RPE65 mutation-associated retinal dystrophy, a rare retinal condition characterized by severe visual impairment that begins during infancy. [5][6][7][8][9][10] Similar gene therapy strategies have also been developed for retinitis pigmentosa, [11][12][13] achromatopsia, 14,15 X-linked retinoschisis, 16,17 and neovascular forms of age-related macular degeneration (AMD), [18][19][20] with many ongoing clinical trials underway.…”