Implantable Anti-VEGF “Biofactory” in Development for AMD

Questions regarding the efficacy, tolerability, and best practices for long-term VEGF suppression in AMD patients continue to plague conventional bolus injection-based approaches to wet AMD treatment. A well-tolerated, implantable, encapsulated cell line engineered to generate and release therapeutic molecules into the vitreous would change all that, and its advent may be closer than many think.

by Quinton Oswald, President/CEO Neurotech Pharmaceuticals, Inc.

The aging of the baby boom generation is already having, and will continue to have, a staggering impact on the incidence of age-related diseases of the eye. Rising rates of age-related macular degeneration (AMD), which already affects more than 2 million Americans, will impact patients, offices, and all aspects of healthcare delivery.1,2 Anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to stall the progression of wet AMD and sometimes improve vision, yet questions regarding optimal administration remain.3,4 For example, are indefinite anti-VEGF injections sustainable or effective over the long-term? Are bolus injections of anti-VEGF optimal to keep vessel growth and leakage in check? Can eyecare providers handle the volume of procedures required for regular injections?

Regarding ongoing therapy after the initial 3 months, it remains unclear whether continuous monthly or bimonthly injection is superior to alternative, less intensive regimens such as “treat and extend” or “prn treat and observe.”5 Whichever regimen one chooses, disadvantages exist, including: inconvenience, discomfort, and the complication risk that accompanies repeated injections, not to mention the financial costs of multiple visits and procedures. Furthermore, without a predictable endpoint, patients may lose motivation to undergo repeated intraocular injections. Indeed, several large database analyses indicate that most patients do not receive an adequate number of injections to maintain visual acuity.6-8 It is tragic when treatment fatigue leads patients to discontinue therapy and lose their initial gains.

Sustainable Drug Delivery

How, then, can we deliver VEGF inhibition on a continuous basis without having to subject patients to monthly injections? One answer is an implantable, sustained drug delivery system for local, long-term delivery of anti-VEGF medication that is currently in phase 2 clinical trials and could conceivably enter the market within the next several years. This is an encapsulated cell therapy (ECT) platform in development at my company, Neurotech Pharmaceuticals (Cumberland, RI).

ECT can be thought of as an implantable “biofactory” with three essential components: a protein product; a cell line that synthesizes the protein; and a surrounding semipermeable membrane that permits both elution of the protein out of the device and entry of oxygen and nutrients into the device while protecting the cell line from immune recognition.

Not only does ECT technology hold enormous potential for sustained delivery of one or more biologics, it can be removed if a need arises. This relative ease of reversibility is a big advantage over some other paradigm-changing innovations, including gene therapy.

The specific ECT product in development for treating AMD, NT-503, manufactures a unique anti-VEGF molecule via retinal pigment epithelial (RPE) cells housed in the device. It is inserted via a simple outpatient procedure through a small incision and sutured to the scleral wall, where it floats tethered out of the field of vision; it has been shown to elute protein for more than 2 years. Similar ECT devices have been shown to elute a therapeutic molecule for 5 to 7 years.

Research and Development

ECT was initially investigated by scientists at Brown University as a way to target pain, an application that was ultimately not successful. But as a way to pump a continuous supply of a biologic into a small space, it made sense for ophthalmologic applications and was tried for sustained delivery of ciliary-derived neurotrophic factor (CNTF) in the treatment of retinitis pigmentosa.9 These studies yielded years of valuable safety data, laying the groundwork for use of the technology with different protein products, including VEGF inhibitors.

Phase 1 dose-escalation trials conducted using an earlier version of NT-503 showed that delivering between 0.3 and 5 μg per day of anti-VEGF in drug-naïve patients slowed AMD progression in a dose-dependent manner and led to the ultimate evolution of the latest generation device, which produces 10-12 μg of this novel anti-VEGF protein per day. The current proof-of-concept trial has begun and will aim to enroll 150 previously treated patients. The trial will look at vision preservation among anti-VEGF responsive patients, comparing the latest ECT platform with repeated injections of aflibercept (every 8 weeks). One-year interim results are expected by the first half of 2017.

Beyond AMD

As basic science research advances and more disease mediators are uncovered, more biologics targeting these mediators will be engineered and tested. A few will make it to market. Packaging these agents for sustained, long-term delivery at the site of disease will be an important step towards meeting treatment aims and providing high-quality patient care.

In situ anti-VEGF is likely to be the first application of ECT technology, and we expect others will follow. Diabetic macular edema (DME), like AMD, is to some extent a VEGF-mediated disease, and anti-VEGF therapy has been shown to be effective against DME.10 Ciliary-derived neurotrophic factor may be a mediator of optic nerve damage in glaucoma and other neurodegenerative diseases.9,11 A novel CNTF-eluting ECT is currently in testing for neuroprotective treatment of glaucoma.

Quinton Oswald is the CEO of Neurotech. Prior to joining Neurotech, he served as the CEO of SARcode Bioscience, a biotech that developed lifitegrast, for dry eye disease; and Vice President & Business Unit Head for Genentech’s Tissue Growth and Repair Business, where he directed the highly successful commercial launch of Lucentis® (ranibizumab) for the treatment of wet AMD.


  1. Congdon N, O’Colmain B, Klaver CCW, et al. for the Eye Disease Prevalence Research Group. Arch Ophthalmol. 2004;122:477-85.

  2. National Eye Institute: Age-Related Macular Degeneration. Accessed July 31, 2015:

  3. Brown DM, Michels M, Kaiser PK, et al; ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116:57-65.

  4. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age related macular degeneration. N Engl J Med. 2006;355:1419-31.

  5. Agarwal A, Rhoades WR, Hanout M, et al. Management of neovascular age-related macular degeneration: current state-of-the-art care for optimizing visual outcomes and therapies in development. Clin Ophthalmol. 2015;9:1001-15.

  6. Lad EM, Hammill BG, Qualls LG, et al. Anti-VEGF treatment patterns for neovascular age-related macular degeneration among medicare beneficiaries. Am J Ophthalmol. 2014;158(3):537-43.

  7. Holekamp NM, Liu Y, Yeh W, et al. Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration. Am J Ophthalmol. 2014;157:825-33.

  8. Kiss S, Liu Y, Brown J, et al. Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab. Ophthalmic Surg Lasers Imaging Retina. 2014;45(4):285-91.

  9. Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA. 2006;103:3896-901.

  10. Boyer DS, Hopkins JJ, Sorof J, et al. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrinol Metab. 2013;4:151-69.

  11. Pease ME, Zack DJ, Berlinicke C, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50:2194-200.