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Konrad Kauper, Michael Rivera, John Mills, Alline Lelis, Megan Billings, Cahil McGovern, Arne Nystuen, Sandy Sherman, Pam Heatherton, Rhett Schiffman; Design Considerations and Performance of a Next-Generation Encapsulated Cell Technology Intraocular Implant Delivering VEGF-Antagonist. Invest. Ophthalmol. Vis. Sci. 2014;55(13):441.
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Early generation ECT products delivering VEGF-antagonist (VEGF- α) for over a year have demonstrated clinically meaningful improvements in BCVA and reductions in macular thickening in patients with active neovascular AMD; higher dose levels are expected to achieve efficacy comparable or greater than standard-of-care treatments. A new ECT device, NT-503-3, incorporating multiple, optimized cell encapsulation chambers into a single cartridge implant was designed to substantially increase the dose of VEGF-α by increasing the total number of encapsulated cells, and by improving cell viability and protein expression efficiency. This design also supports combination therapy from a single device, by allowing discrete encapsulations of different therapeutic cell lines in a single intraocular implant product.
The performance of NT-503-3 was evaluated following encapsulation of a human RPE cell line transfected to produce VEGF-α. Dose levels of VEGF-α were characterized by ELISA; binding efficiency and affinity were quantified by a VEGF-inhibition and Bioacore assay, respectively. GLP toxicology studies, which include clinical examination, ERG, ocular histopathology, and detection of serum antibodies to VEGF-α and the encapsulated cell line, are ongoing.
A single NT-503-3 implant increased VEGF-α dose 5-fold compared to the previous ECT product (NT-503-2) which had demonstrated clinical efficacy in wet-AMD patients when implanted with two devices. VEGF-α produced by NT-503-3 results in high binding affinity to VEGF with a Kd of 0.7 pM and inhibits VEGF with an IC50 of 20-30 pM. Intraocular implants in rabbits and mini-pigs demonstrate that the NT-503-3 product is safe and well tolerated.
Clinically relevant VEGF-α expression and an excellent toxicology profile has been achieved with the novel NT-503-3 design. A single, intraocular NT-503-3 implant is anticipated to provide equivalent or improved efficacy compared to standard-of-care therapy while eliminating the burden of frequent injections in patients with active neovascular AMD. Furthermore, the new ECT cartridge design also supports ongoing combination therapy development.
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