249. Preliminary Results of a Phase 1, Open-Label, Safety and Tolerability Study of a Single Intravitreal Injection of AAV2-sFLT01 in Patients with Neovascular Age-Related Macular Degeneration
Authors: Abraham Scaria, Annaig LeHalpere, Annie Purvis, Cheryl Delacono, Seng Cheng, Samuel Wadsworth, Peter Campochiaro, Jeff Heier, Ronald Buggage
Journal: Molecular Therapy (2016)

Clinical Trial: www.clinicaltrials.gov NCT01024998 Introduction: Vascular endothelial growth factor (VEGF) plays a critical role in the development of the neovascular AMD (wet AMD), the most common cause of new onset blindness in elderly adults. While intravitreal (IVT) administration of anti-VEGF agents are effective for improving vision in wet AMD patients, the need for repeated monthly IVT injections imposes a burden on patients and ophthalmologists which may limit the realization of the full benefits of VEGF inhibition. AAV2-sFLT01 is a replication defective, recombinant adeno-associated virus (serotype 2) vector (AAV2) that encodes sFLT01, a novel soluble chimeric protein composed of domain 2 of VEGF receptor 1 and the Fc region of human Immunoglobulin G type 1 (IgG1). We investigated the safety and tolerability of a single IVT administration of AAV2-sFLT01 in wet AMD patients. Methods: The study was a Phase 1, open-label,, dose-escalating, safety and tolerability study conducted in 4 sites in the USA. 5 cohorts of patients with BCVA of ≤20/100 in the study eye received a single IVT injection of one of four AAV2-sFLT01 doses (2×108, 2×109, 6×109, or 2×1010 vg). Patients in cohorts 1-4 had subfoveal disciform scarring, while cohort 5 patients had responsiveness to an anti-VEGF therapy within 12 months prior to enrollment. All patients were monitored for 52 weeks following the injection in the core study, and encouraged to participate in the extended follow-up program for up to 4 years. The primary safety endpoint was the occurrence of adverse events. Biological activity was evaluated by changes from baseline in sub/intraretinal fluid by optical coherence tomography (OCT), best corrected visual acuity (BCVA) and sFLT01 protein level detected in the aqueous fluid. Results: 19 patients with end-stage/advanced wet AMD (53% males, median age 77.0 years, median time since diagnosis of AMD of 5.4 years and median basal BCVA of 22.0 letters) were treated. All patients completed the 52-week study with 17 patients consenting to the 4 year extended follow-up study. Overall, the treatment was considered safe and tolerable with no dose-limiting toxicity observed in any dose level. 11/19 patients were expected to show an anti-VEGF response clinically. Of them, transient (2 patients) and sustained (4 patients) reduction in retinal thickness suggested a biological effect of the treatment. Aqueous sFLT01 protein expression was identified in 5 patients receiving 2×1010 vg. Post-treatment changes in BCVA did not correlate with other parameters of biological activity. Conclusion: Despite advanced disease state, a sustained reduction in retinal fluid in four patients provides evidence of biological activity supporting the concept that a sustained therapeutic anti-VEGF level can be achieved following a single intravitreal administration of an ocular gene therapy.