8 Although early clinical trial results are encouraging 9 and a phase III program was recently completed in nAMD, the Port Delivery System is implanted in the operating room and requires at least two refills each year, which potentially limits its broad use owing to health care capacity constraints.Īlthough concerns of potential choriocapillaris thinning and RPE atrophy owing to long-term VEGF suppression remain, prolonged repeated IVT administration of anti-VEGF therapies in nAMD, DME, DR, and RVO appears to be safe and well-tolerated based on the real-world experience gained from millions of intraocular anti-VEGF injections over the past 20 years. The Port Delivery System (Genentech/Roche), for example, is an investigational approach that requires the surgical implantation of a transscleral device containing a reservoir that is refilled every 6 months to continuously release a special formulation of ranibizumab. 4 – 7 Prolonged suppression of pathologic VEGF activity without the requirement for repeated IVIs has thus become a focus of several drug development efforts. Despite commonly used treat-and-extend treatment regimens, patients still need at least six, and often times more, 3, 4 injections in the first year after a diagnosis of nAMD.Īs a direct consequence of the substantial treatment burden to the patient and their caregivers, numerous “real-world” studies indicate that patients receive considerably fewer anti-VEGF injections than what is recommended in product label or treatment guidelines, directly resulting in suboptimal anatomic and visual outcomes, especially when compared with the results noted in pivotal clinical trials. 2 However, there is a substantial treatment burden associated with this clinical outcome.
With repeated, frequent anti-VEGF IVIs, patients with previously blinding VEGF-driven retinal disorders can expect to maintain and even improve visual function. 1 In clinical practice, intraocular injections of anti-VEGF therapy are delivered as often as every 4 weeks, in many cases for the lifetime of the patient. The current standard of care for these conditions includes repeated intravitreal (IVT) administration of anti-VEGF therapeutics, including the US Food and Drug Administration–approved aflibercept (Eylea, Regeneron Pharmaceuticals, Tarrytown, NY), ranibizumab (Lucentis, Genentech/Roche, South San Francisco, CA), recently approved brolucizumab (Beovu, Novartis, Basel, Switzerland), and bevacizumab (Avastin, Genentech/Roche), which is used off label. Inhibitors of vascular endothelial growth factor (VEGF) have revolutionized the treatment of retinal and choroidal vascular disorders, including wet or neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), and macular edema associated with retinal vein occlusion (RVO). Together with the results from previous ADVM-022 preclinical studies, these data support the evaluation of this gene therapy candidate in clinical trials as a potential durable treatment for various VEGF-mediated ophthalmic disorders. In non-human primates, long-term, sustained aflibercept expression and the resulting continuous VEGF suppression by a single IVI of ADVM-022, appears to be safe, with no measurable adverse effects on normal retinal structure and function evaluated out to 2.5 years. RPE integrity was maintained throughout the study no histologic abnormalities were observed 2.5 years after ADVM-022 IVI. No abnormalities in retinal structure or function were observed, as measured by optical coherence tomography and electroretinography, respectively.
Mild to moderate inflammatory responses were observed, which trended toward spontaneous resolution without anti-inflammatory treatment. Sustained expression of aflibercept was noted out to the last time point evaluated. Histologic evaluation of the retina was performed at the longest time point measured (2.5 years after injection). The integrity of the retinal structure was analyzed by optical coherence tomography and blue light fundus autofluorescence and electroretinography was performed to determine retinal function. Ocular inflammation was assessed by slit lamp biomicroscopy and fundoscopy. Aflibercept levels from ocular fluids and tissues were measured. Non-human primates received bilateral IVI of ADVM-022, a gene therapy vector encoding aflibercept, a standard of care for the treatment of VEGF-based retinal disease. To evaluate the long-term safety of vascular endothelial growth factor (VEGF) suppression with sustained aflibercept expression after a single intravitreal injection (IVI) of ADVM-022, an anti-VEGF gene therapy, in non-human primates (NHPs).