Retina Today - Ocular Drug Delivery Systems for the Posterior Segment: A Review (May 2012)

摘要

Editora??s note: To follow is a review of ocular drug delivery systems for the posterior segment currently in development. Because of the sheer volume of technologies, we chose to narrow this review by eliminating discussion of those that have US Food and Drug Administration or European Union approval for at least 1 indication. Figure 1 and Table 1 provide supplementary information for this article. Nonbiodegradable polymeric drug delivery systems a?￠ I-vation. Sustained delivery of triamcinolone acetonide (TA) to the vitreous using I-vation (Surmodics Inc.) is in development for diabetic macular edema (DME). The I-vation intravitreal implant is a titanium helical coil coated with TA (925 ??g) and the nonbiodegradable polymers poly(methyl methacrylate) and ethylene-vinyl acetate. It is predicted that this implant will have an in vivo sustained delivery of at least 2 years. A phase 1 clinical trial in patients with DME has been completed and 24-month interim results have been reported.1 At 24 months, 25 of 31 patients remained in the study; 11 patients (11 eyes) in the slowrelease group, 14 patients (14 eyes) in the fast-release group. The proportion of patients demonstrating improved visual acuity (greater than 0 ETDRS letter gain from baseline) was 64% in the slow-release group and 72% in the fast-release group; 28.6% of patients in the fast-release group gained greater than 15 letters. The mean macular thickness, measured by optical coherence tomography (OCT), decreased in the slow group from 529 ??m at baseline to 328 ??m, and in the fast-release group from 376 ??m at baseline to 268 ??m. No further clinical trial has commenced.2 a?￠ Renexus. Encapsulated cell technology provides extracellular delivery of ciliary neurotrophic factor (CNTF) with long-term and stable intraocular release at constant doses through a device (Renexus [formerly NT-501], Neurotech) implanted in the vitreous. It contains human cell line of retinal pigment epithelium (RPE), NTC-200, genetically modified to secrete recombinant human CNTF. Renexus consists of a sealed semipermeable hollow fiber membrane capsule surrounding a scaffold of 6 strands of polyethylene terephthalate yarn, which can be loaded with cells. The device is surgically implanted in the vitreous through a tiny scleral incision and is anchored by a single suture through a titanium loop at one end of the device. The semipermeable hollow fiber membrane allows the outward diffusion of CNTF and other cellular metabolites and the inward diffusion of nutrients necessary to support the cell survival in the vitreous cavity while protecting the contents from host cellular immunologic attack. Data from a phase 1 clinical trial showed that Renexus was well tolerated in patients with late-stage retinitis pigmentosa (RP) for 6 months.3 A phase 2 study in patients with geographic atrophy (GA) associated with atrophic age-related macular degeneration (AMD) randomized patients in a 2:1:1 ratio to receive high- (20 ng/day) or low-dose (5 ng/day) Renexus, or to sham surgery, respectively. Among eyes with baseline BCVA of 20/63, the mean BCVA in the high dose group was 10.5 and 10.0 letters greater than the low dose/ sham group at 12 months (P = .03) and 18 months, respectively.4,5 Stabilized visual acuity was accompanied by corresponding structural changes that were dose dependent (P < .001). The growth rate of GA area was reduced in treated eyes compared with fellow eyes at 12 and 18 months. In addition, Renexus prevented secondary cone degeneration in patients with RP.6 At present, a phase 2 clinical trial for early-stage RP or Usher syndrome (type 2 or 3) and a phase 1 study for macular telangiectasia are under way. a?￠ NT-503. Neurotech has been developing another device (NT-503) encapsulating VEGF receptor Fc-fusion protein (VEGFR-Fc)-releasing cells.7 This VEGFR-Fc is 20-fold more efficient in neutralizing VEGF compared