I-vation Implant Technology

DANTE J. PIERAMICI, MD

The number of diabetes-related eye complications such as diabetic macular edema (DME) is expected to increase substantially in the next 20 years, driven by the increasing incidence of diabetes mellitus and aging of the population of the United States.^1,2 The standard treatment for DME continues to be focal or grid laser photocoagulation. This treatment, though effective at reducing the rates of moderate vision loss, less commonly results in significant visual improvement for many patients.^3-5 Newer treatment modalities, such as intravitreal injections of bevacizumab (Avastin, Genentech), ranibizumab (Lucentis, Genentech), and corticosteroids, have shown promising results.^6-9 However, there are several important shortcomings with these treatment options, such as these drugs requiring administration by intravitreal injection. Since the half-life of these drugs in the vitreous is days, frequent repeat injections (sometimes monthly) are necessary to maintain therapeutic drug levels.¹⁰ Repeat injections carry the risk of endophthalmitis and other less-common ocular side effects such as cataract or retinal detachment. With intraocular steroids, there is a significant risk of elevated intraocular pressure (IOP), glaucoma, and cataract formation.^11-12 Current therapies offer a sufficient short-term solution to these retinal diseases; however, with the number of cases of vision loss associated with DME expected to increase, a better long-term method of drug delivery is necessary to treat these patients.

Surmodics, Inc. (Irvine, CA) has developed the I-vation Intravitreal Implant and Sustained Drug Delivery System to provide controlled long-term drug delivery into the posterior chamber of the eye. The I-vation Intravitreal Implant is comprised of a nonferrous metal alloy, MP35N. The narrow wire diameter of the implant allows for minimally invasive placement through a 25-g to 30-g needlestick. The unique helical shape of the device maximizes the surface area available for the drug-eluting portion of the implant and enables secure, sutureless anchoring of the device against the surface of the sclera. (Figure) The thin scleral cap resides under the conjunctival membrane to minimize foreign-body sensation and the design parameters allow the implant to remain outside the visual field and safely away from the lens.

The patented technology driving the I-vation Sustained Drug Delivery System facilitates targeted drug delivery with minimal systemic drug exposure (SurModics' BRAVO coating). Varying combinations of nonbiodegradable polymers and drug allow for compatibility with a range of therapeutic molecules from small hydrophobic drugs to larger macromolecules and proteins. The I-vation Sustained Drug Delivery System can be set to deliver a constant rate of drug for up to 2 years, thereby simplifying the drug regimen and improving patient compliance.

Figure. The I-vation sustained drug delivery system by Surmodics, Inc.

FIGURE APPEARS COURTESY OF SURMODICS.

The I-vation Sustained Drug Delivery System was engineered with ease of surgical implantation and removal in mind. Implantation is currently performed under local anesthesia in the operating room setting and is expected to take less than 15 minutes. The procedure begins with a 2-mm to 3-mm circumferential dissection of the conjunctiva and Tenon's capsule, followed by a sclerotomy using a 25-g to 30-g needle. With the insertion instrument, the I-vation implant is inserted through the sclerotomy into the vitreous cavity and rotated clockwise until the cap of the implant abuts the sclera. Once the insertion instrument is removed, biodegradable sutures are used to close the conjunctival tissue.

The first clinical application of the I-vation Sustained Drug Delivery System was in a phase 2 study to evaluate the safety and tolerability of the implant coated with triamcinolone acetonide (TA) in patients with DME. In this prospective study conducted at multiple study centers across the United States, 31 subjects were randomized to receive a slow-release (1 μg/day) or fast-release (3 μg/day) formulation containing 925 μg of TA. Participants in the study are to be monitored for 3 years.

A preliminary safety and efficacy review of data at 9 months postimplantation was reported on 27 of the 31 patients enrolled in the study. Four patients were no longer enrolled and were excluded from data analysis at 9 months postimplant: 2 patients were early explants, 1 patient missed the postoperative visit, and 1 patient was deceased (cause of death unrelated to study drug). At 9 months, the mean change in central retinal thickness was 100.2 μm (±158.9) from baseline (N = 27) and best-corrected visual acuity (BCVA) improved to 20/80 or better (Early Treatment Diabetic Retinopathy Study Snellen equivalent) in 18 of 27 patients (67%). There was an increase in the mean IOP of 4 mm Hg at 9 months compared to baseline and IOP-lowering medications were prescribed to 4 patients. All patients were evaluated for cataract formation and/or progression. One phakic patient underwent cataract surgery within 9 months of implantation and had improved BCVA after cataract extraction.

The implant was well tolerated in a majority of patients and required explantation in only 2 cases. One possible reason for explantation was exposure of the cap through the conjunctivae. Newer designs will incorporate features to minimize this problem. Surmodics has partnered with Merck (Whitehouse Station, NJ) in a license and research collaboration agreement to develop and commercialize the I-vation TA system. A phase 2 or phase 3 study for the treatment of DME is scheduled to begin in late 2008. RP

REFERENCES

1. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122:552-563.
2. de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355:1474-1485.
3. Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse diabetic macular edema. Long-term visual results. Ophthalmology. 1991;98:1594-1602
4. Early Treatment of Diabetic Retinopathy Study Group. Photocoagulation for diabetic macular edema. Early Treatment of Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796-1806.
5. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
6. Avery RL, Pieramici D, Rabena M, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:363-372.
7. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006 Apr;113:642.e1-4. Epub 2006 Feb 14.
8. Martidis A, Duker JS, Greenberg PD, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920-927.
9. Jonas JB, Kreissig I, Sofker A, Degenring RF. Intravitreal injection triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol. 2003;121:57-61.
10. Audren F, Tod M, Massin P, et al. Pharmacokinetic-pharmacodynamic modeling of the effect of triamcinolone acetonide on central macular thickness in patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2004;45:3435-3441.
11. Scott IU, Flynn HW Jr. Reducing the risk of endophthalmitis following intravitreal injections. Retina. 2007;27:10-12.
12. Gibran SK, Cullinane A, Jungkim S, et al. Intravitreal triamcinolone for diffuse diabetic macular oedema. Eye. 2006 Jun;20:720-724.