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

Abstract

Several standard-of-care therapies for the treatment of retinal disease, including aflibercept, inhibit vascular endothelial growth factor (VEGFA). The main shortcoming of these therapies is potential undertreatment due to a lack of compliance resulting from the need for repeated injections. Gene therapy may provide sustained levels of anti-VEGFA proteins in the retina following a single injection. In this nonhuman primate study, we explored whether ADVM-022, a recombinant adeno-associated virus (AAV) vector designed to express aflibercept, could induce anti-VEGFA protein levels comparable with those observed following a single-bolus intravitreal (IVT) injection of the standard-of-care aflibercept recombinant protein. The results demonstrated that intraocular levels of aflibercept measured at 56 days after a single IVT injection of ADVM-022 were equivalent to those in the aflibercept recombinant protein-injected animals measured 21–32 days post-administration. ADVM-022-injected animals exhibited signs of an initial self-limiting inflammatory response, but overall all doses were well tolerated. ADVM-022 administration did not result in systemic exposure to aflibercept at any dose evaluated. These results demonstrated that a single IVT injection of ADVM-022 resulted in safe and efficacious aflibercept levels in the therapeutic range, suggesting the potential of a gene therapy approach for long-term treatment of retinal disease with anti-VEGF therapy.

Long-Term Safety Evaluation of Continuous Intraocular Delivery of Aflibercept by the Intravitreal Gene Therapy Candidate ADVM-022 in Nonhuman Primates

“…Together with previous reports on the efficacy and pharmacokinetics of ADVM-022–derived aflibercept, 33 , 34 the long-term safety results presented herein support the exploration of ADVM-022 safety and efficacy in clinical trials. ADVM-022 is currently being evaluated in two early human studies: (1) in a multicenter phase I clinical trial in patients with nAMD who have been previously treated with a high number of anti-VEGF IVIs (OPTIC trial NCT03748784), and (2) in a prospective, randomized, double-masked phase II clinical trial in patients with DME (INFINITY, NCT 04418427).…”

“…Nevertheless, theoretical risks of VEGF suppression based on the nonpathologic role of VEGF in maintaining a normal ocular structure and function remain. As such, in this study, we show that the expression of therapeutic levels of biologically active aflibercept at concentrations within the range of the current bi-monthly regimen indicated in the aflibercept label for the treatment of nAMD, 33 do not appear to lead to any adverse effects, even when VEGF levels are suppressed in eyes without elevated pathologic VEGF.…”

“…However, the theoretical risks of VEGF suppression center around the nonpathologic role of VEGF in maintaining normal ocular structure and function. As such, in this study, we show that the expression of therapeutic levels of aflibercept (at concentrations within the range of the current every 2-month FDA-approved IVT injection-delivered aflibercept in nAMD 26 ) do not appear to lead to any apparent adverse effects, even when VEGF levels are suppressed in eyes without elevated pathologic VEGF. The lack of any evidence of retinal damage from frequent anti-VEGF injections in patients with DME or RVO suggests that the suppression of VEGF does not directly damage retinal neurons and that any new-onset macular atrophy in patients with nAMD treated with anti-VEGF agents is likely to be owing to an interaction between the disease process and VEGF suppression.…”

“…These levels were previously shown to be pharmacologically active 20 and therapeutically meaningful. 26 Aqueous humor aflibercept protein levels, although generally lower than those measured in the vitreous, remained stable throughout the course of the study ( Supplementary Fig. S1 ).…”

“…The gradient of aflibercept concentration with highest levels observed in the retina and decreasing toward the front and back of the eye is consistent with what was observed in the previously reported efficacy and pharmacokinetics study. 20 , 26 One outlier was observed with respect to the level of aflibercept in the choroidal tissue in the OD of animal A055 that was below the limit of quantification, although the same eye showed high sustained levels of aflibercept in the other ocular compartments. Overall, the results of the analysis of long-term ADVM-022–mediated expression of aflibercept indicate robust sustained levels of the protein in the ocular compartments for the duration of the long-term study.…”