Comprehensive Preclinical Assessment of ADVM-022, an Intravitreal Anti-VEGF Gene Therapy for the Treatment of Neovascular AMD and Diabetic Macular Edema.

Inhibition of vascular endothelial growth factor is the mode of action for several approved therapies, including aflibercept, for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Lack of compliance due to the frequent intravitreal dosing requirements may result in inadequately treated disease, leading to irreversible vision impairment. To date, the majority of gene therapy clinical trials providing sustained anti-VEGF levels in the retina have been limited to subretinal injections requiring a vitrectomy. A single intravitreal injection of a gene therapy product could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, has been optimized for intravitreal delivery and strong protein expression. Long-term expression and efficacy of ADVM-022-derived aflibercept were evaluated in a laser-induced choroidal neovascularization (CNV) model in non-human primates. Ocular safety was evaluated following long-term suppression of VEGF by clinical scoring (inflammatory parameters) as well as optical coherence tomography (OCT) and electroretinography (ERG). Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels in ocular tissues. In addition, ADVM-022 administration 13 months before laser-induced CNV prevented the occurrence of clinically relevant CNV lesions, to the same degree as a bolus of aflibercept delivered at the time of laser. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for nAMD and DME, and may ultimately improve patients' visual outcomes. Clinical trials are currently underway, evaluating safety and efficacy following a single intravitreal injection of ADVM-022.

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

Purpose: 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). Methods: 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. Aflibercept levels from ocular fluids and tissues were measured. Ocular inflammation was assessed by slit lamp biomicroscopy and fundoscopy. 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. Histologic evaluation of the retina was performed at the longest time point measured (2.5 years after injection). Results: Sustained expression of aflibercept was noted out to the last time point evaluated. Mild to moderate inflammatory responses were observed, which trended toward spontaneous resolution without anti-inflammatory treatment. No abnormalities in retinal structure or function were observed, as measured by optical coherence tomography and electroretinography, respectively. RPE integrity was maintained throughout the study; no histologic abnormalities were observed 2.5 years after ADVM-022 IVI. Conclusions: 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. Translational Relevance: 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.

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

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.

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

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.

Engineering goals for future thoracic endografts-how can we make them more effective?

Endovascular treatments for catastrophic aortic conditions have gained increasing popularity over the past 20 years. Originally developed for abdominal aortic aneurysms (EVAR), treatment has been modified for use in thoracic aortic repair (TEVAR). As expanding numbers of patients with increasingly intractable conditions and more hostile anatomies are treated, endovascular stent designs are maturing to be suitable for these more demanding situations. This article discusses the engineering considerations that apply to changing stent graft designs for current and evolving thoracic applications. The biological parameters that differentiate thoracic from abdominal aortic environments are outlined. Factors concerning materials, sealing mechanisms, deployment, stent frame architecture, and migration resistance are described, and eagerly awaited potential future developments are summarized.