Age-related macular degeneration (ARMD) is the leading cause of visual loss in the elderly population in the United States. Although there are many available therapies for neovascular ARMD including thermal laser, photodynamic therapy, and intravitreal steroid (sustained release form available), anti-vascular endothelial growth factor (anti-VEGF) therapy is the current standard of treatment for most patients with neovascular ARMD. Due to the risks and logistical burden associated with intravitreal injections, research to prolong the interval between injections while keeping the disease under control has been of paramount interest. One such effort was aflibercept. Through the VIEW 1 and 2 trials, bimonthly aflibercept injections after three monthly induction injections were shown to be non-inferior to monthly ranibizumab.1 However, efforts to increase the injection interval continue, and several other strategies are currently under development. This article will provide a brief update on the current status of sustained release forms of anti-VEGF therapy for neovascular ARMD.
One strategy to provide sustained intraocular release of drug is to utilize a non-biodegradable implant inside the eye. Encapsulated cell technique (ECT) harnesses immunologically isolated cells that produce anti-VEGF in capsules, which are implanted inside the eye through a pars plana approach.2 The capsules deliver the protein in a controlled fashion, and may be explanted if needed.3 NT-503 (Neurotech pharmaceuticals) is such a device currently in phase I clinical trial investigation for the treatment of neovascular ARMD.4 The major concerns with ECT are the long-term safety and efficacy of the device and the need for surgical implantation.
Another strategy involves an intracapsular ring that elutes bevacizumab. Capsule Drug Ring (CDR) is a polycarbonate urethane ring that is designed for placement inside the capsular bag during cataract extraction surgery. Preliminary biocompatibility and pharmacokinetic studies have been performed in rabbits in vivo, but no clinical trials are currently pending.5
A refillable port delivery system (PDS) with ranibizumab (Genentech and ForsightVision6) has also been investigated. A PDS is implanted into the vitreous cavity through a pars plana approach, and can be refilled with ranibizumab through transconjunctival injection. A phase I clinical trial for the implant was posted on clinicaltrials.gov in 2010, but was withdrawn prior to patient enrollment.6
Another method to achieve sustained intraocular release of drug is to utilize biodegradable vehicles. Pan et al. reported formulating bevacizumab in two ways: one with bevacizumab conjugated to poly(ethylene-glycol) (PEG) and the other with bevacizumab encapsulated in poly(lactic-co-glycolic acid) (PLGA).7 The authors reported that both formulations were able to retain the anti-angiogenic property of bevacizumab successfully, but further study is needed to evaluate long-term efficacy and safety.
Extended intraocular release of drug may also be achieved through thermoresponsive hydrogel, which maintains liquid form at room temperature, but converts to gel form at body temperature. Kang et al reported formulating a hydrogel to release bevacizumab and ranibizumab; the hydrogel showed a high rate of drug release within the first 48 hours, then more sustained release for up to 3 weeks.8 Wang et al reported a hydrogel that releases bevacizumab at a constant rate (80% release at 20 days) without an initial burst of high rate release in rabbit eyes.9
Genetic therapy to produce anti-VEGF molecules inside the eye is on the horizon. Marano et al studied the use of a lipophilic amino acid dendrimer to deliver an anti-VEGF oligonucleotide in a rat model of laser-induced choroidal neovascularization (CNV).10 The authors reported successful CNV suppression for up to 6 months in treated compared to control rats. Another genetic therapy approach utilizes an adeno-associated virus vector (AAV2) to transfect intraocular cells so that they express soluble VEGF receptor-1 (sFlt-1).11,12 It has been reported that, if delivered intravitreally, the AAV2 vector results in transduction of ganglion cells and cells in the inner nuclear layer, whereas subretinal delivery of the AAV2 vector results in transduction of photoreceptors and retinal pigment epithelial cells.13,14 In a 12-month safety study of intravitreal injection of AAV2-sFlt-1 in cynomolgus monkeys, Maclachlan et al reported the therapy to be well tolerated, localized, and capable of long-term expression, although occasional intravitreal inflammation was reported in the high dose group.12 AAV2-sFlt-1 is currently being investigated, through intravitreal injection administration, in a phase 1 clinical trial (Genzyme, a Sanofi Company) in patients with neovascular ARMD.15 Since inflammation from persistent viral capsids is associated with safety concerns, El Sanharawi et al. investigated non-viral gene transduction of ciliary muscle cells via electrotransfer to produce sFlt-1 variants for up to 6 months with successful inhibition of CNV in a laser-induced CNV rat model.16 This non-viral gene transduction method addresses the safety concerns associated with viral vectors persisting in retinal cells.
The current overview highlights a few of the techniques for delivering anti-VEGF therapy into the vitreous cavity in a sustained fashion. Myriad other therapies are currently being investigated, including but not limited to other anti-angiogenic drugs (SU541617 and TG-005418 ), iontophoresis,19 macroesis,20 and hydrogel contact lenses.21
Schwartz et al expressed that, in order for sustained release intraocular drug delivery to be utilized in a practical setting, it needs to be more advantageous than conventional therapy in terms of efficacy, safety, convenience or cost. Sustained release intraocular drug therapy may be a more plausible strategy when utilized as maintenance therapy after initial loading treatment with anti-VEGF injections.22
1. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537-48.
2. 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. Proceedings of the National Academy of Sciences of the United States of America 2006;103:3896-901.
3. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2008;13:135-43.
4. Guerrero-Naranjo JL Q-MH, Sanchez-Bermudez G, et al. "Safety of implantation of the NT-503 device in patients with Choroidal Neovascularization secondary to Age-related Macular Degeeration". Proceedings of the Association for Research in Vision and Ophthalmology Annual Meeting, Seattle, Wash, USA; 2013.
5. Gooch N, Burr R, Holt D, Gale B, Ambati B. Design and in Vitro Biocompatibility of a Novel Ocular Drug Delivery Device. J Funct Biomater. 2013;4:14-26.
6. ClinicalTrials.gov. Safety and Preliminary Efficacy Study of PDS-1.0 in Patients With Neovascular AMD; NCT01177644. Available at: http://clinicaltrials.gov/ct2/show/NCT01177644; Accessed January 2014.
7. Pan CK, Durairaj C, Kompella UB, et al. Comparison of long-acting bevacizumab formulations in the treatment of choroidal neovascularization in a rat model. J Ocul Pharmacol Ther. 2011;27:219-24.
8. Kang Derwent JJ, Mieler WF. Thermoresponsive hydrogels as a new ocular drug delivery platform to the posterior segment of the eye. Transactions of the American Ophthalmological Society 2008;106:206-13; discussion 13-4.
9. Wang CH, Hwang YS, Chiang PR, Shen CR, Hong WH, Hsiue GH. Extended release of bevacizumab by thermosensitive biodegradable and biocompatible hydrogel. Biomacromolecules. 2012;13:40-8.
10. Marano RJ, Toth I, Wimmer N, Brankov M, Rakoczy PE. Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity. Gene Ther. 2005;12:1544-50.
11. Campochiaro PA. Gene transfer for ocular neovascularization and macular edema. Gene Ther. 2012;19:121-6.
12. Maclachlan TK, Lukason M, Collins M, et al. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration. Mol Ther. 2011;19:326-34.
13. Ali RR, Reichel MB, De Alwis M, et al. Adeno-associated virus gene transfer to mouse retina. Hum Gene Ther. 1998;9:81-6.
14. Lai CM, Shen WY, Brankov M, et al. Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys. Mol Ther. 2005;12:659-68.
15. ClinicalTrials.gov. Safety and Tolerability Study of AAV2-sFLT01 in Patients With Neovascular Age-Related Macular Degeneration (AMD). Available at: http://clinicaltrials.gov/ct2/show/NCT01024998?term=nct01024998; Accessed January 2014.
16. El Sanharawi M, Touchard E, Benard R, et al. Long-term efficacy of ciliary muscle gene transfer of three sFlt-1 variants in a rat model of laser-induced choroidal neovascularization. Gene Ther. 2013;20:1093-103.
17. Honda M, Asai T, Umemoto T, Araki Y, Oku N, Tanaka M. Suppression of choroidal neovascularization by intravitreal injection of liposomal SU5416. Arch Ophthal. 2011;129:317-21.
18. Shelke NB, Kadam R, Tyagi P, Rao VR, Kompella UB. Intravitreal Poly(L-lactide) Microparticles Sustain Retinal and Choroidal Delivery of TG-0054, a Hydrophilic Drug Intended for Neovascular Diseases. Drug Deliv Transl Res. 2011;1:76-90.
19. Pescina S, Ferrari G, Govoni P, et al. In-vitro permeation of bevacizumab through human sclera: effect of iontophoresis application. J Pharm Pharmacol. 2010;62:1189-94.
20. Singh RP, Mathews ME, Kaufman M, Riga A. Transcleral delivery of triamcinolone acetonide and ranibizumab to retinal tissues using macroesis. Br J Ophthalmol. 2010;94:170-3.
21. Schultz C, Breaux J, Schentag J, Morck D. Drug delivery to the posterior segment of the eye through hydrogel contact lenses. Clin Exp Optom. 2011;94:212-8.
22. Schwartz SG, Scott IU, Flynn HW, Jr., Stewart MW. Drug delivery techniques for treating age-related macular degeneration. Expert Opin Drug Deliv. 2014;11:61-8.
About our author(s):
Samuel Yun, MD
Department of Ophthalmology and Visual Sciences
Yale School of Medicine
New Haven, CT
Ron A. Adelman, MD, MPH, MBA
Professor of Ophthalmology and Visual Sciences
Yale School of Medicine
New Haven, CT