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

• Published in: Molecular therapy. Methods & clinical development 2020-09, Vol.18, p.345-353
• Main Authors: Kiss, Szilárd, Grishanin, Ruslan, Nguyen, Aivan, Rosario, Romeo, Greengard, Judith S., Nieves, Julio, Gelfman, Claire M., Gasmi, Mehdi
• Format: Article
• Language: English
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2020.06.007

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. [Display omitted] Current treatments of nAMD require frequent intravitreal injections of VEGF inhibitors. ADVM-022 is a one-time intravitreal gene therapy designed to express aflibercept. Kiss et al. demonstrated a range of ADVM-022 doses in non-human primates that resulted in safe ocular expression of aflibercept in the therapeutic range, without systemic exposure.