Implantable Posterior Segment Drug Delivery Devices

Intravitreal implants offer long-term pharmacotherapeutic exposure to the posterior segment. This has several obvious advantages, not the least of which is the fact that it removes the problem of patient adherence and compliance with topical drug regimens. The disadvantages include the inherent risks with implantation of these various devices (endophthalmitis, retinal detachment, inflammation, or cataract) as well as the fact that, once implanted, surgical explantation may be necessary to reduce the effects of some of the serious side-effects of these devices in rare circumstances. This article reviews the current status of various posterior segment intraocular drug delivery devices, both approved and in clinical development.

(ganciclovir 0.45mg intravitreal implant, Bausch and Lomb, Inc.)

Vitrasert was approved by the FDA in 1996 for the treatment of AIDS-associated CMV Retinitis. CMV retinitis is estimated to affect about 15-40% of AIDS patients. Retinal damage including retinal detachment can occur in about 15-29% of those with CMV retinitis resulting in permanent visual loss.

In a Phase III clinical trial of 188 AIDS patients with newly diagnosed CMV Retinitis, the time to disease progression was significantly longer for patients who received Vitrasert than those who received intravenous ganciclovir. Those who received Vitrasert had a median time to disease progression of 216 days versus 106 days for those who received intravenous ganciclovir. The implant is effective for five to eight months and can be replaced or removed after that time period.

As with any surgical procedure, surgical complications include retinal detachment, cataract formation, vitreous loss, vitreous hemorrhage, uveitis, endophthalmitis and decrease in visual acuity. Following Vitrasert implant, most patients are expected to experience an immediate and temporary decrease in visual acuity which last for two to four weeks post-operatively, most likely due to the surgical procedure. Since CMV is a systemic disease, care should be taken to monitor for disease in the other eye as well and systemic infection of the lungs and GI tract. Patients should be advised that ganciclovir decreased sperm production and may lead to infertility. It is also known to cause birth defect in animals and women of childbearing age should be advised of this effect. It has also been found to cause tumors in animals although there is no information from human studies. However its potential carcinogenic effect in humans should be recognized.

Retisert (fluocinolone 0.59mg intravitreal implant, Bausch and Lomb, Inc.)

Retisert is the first FDA approved intravitreal implant for the treatment of chronic posterior non-infectious uveitis. It is a sterile implant that releases fluocinolone initially at a rate of 0.6 micrograms per day to the posterior segment of the eye decreasing over the month to 0.3-0.4 micrograms per day over approximately 30 months.

By continuous delivery of therapy to a localized area, Retisert can reduce the rate of recurrence of uveitis. During the clinical trials leading up to the FDA approval, the rate of recurrence of uveitis decreased from 54% (before Retisert) to 7% (after Retisert) and 40% (before Retisert) to 14% (after Retisert) in 2 different trials.

It also stabilized or improved visual acuity in 80 percent of patients and reduced the need for systemic or local adjunctive therapy.

It also reduces the systemic side effects of systemic steroids and immunosuppressants which include mood changes, increased appetite, weight gain, osteoporosis, impaired wound healing and peptic ulcers. Many systemic immunosuppressive medications also require frequent blood tests to monitor the effect of the medication on the liver, kidney and bone marrow.

In terms of side effect profile, within 34 weeks of implant, 60% of patients will require intraocular pressure lowering medication. At an average post-implant period of 2 years, 32% of patients are expected to require filtering glaucoma procedure to lower their intraocular pressures and nearly all patients who have not previously had cataract surgery will have developed visually significant cataract that may require cataract surgery. The most frequently reported side effects are cataract development, intraocular pressure elevation, procedural complications and eye pain. Surgical complications of the implant include choroidal detachment, endophthalmitis, hypotony, retinal detachment, vitreous hemorrhage, vitreous loss, exacerbation of intraocular inflammation and wound dehiscence.

The NIH sponsored MUST trial is currently evaluating the effectiveness of the Retisert implant as compared with conventional therapy (oral corticosteroids) in the management of posterior uveitis in 400 patients at 20 sites throughout North America. This is a five-year study that is presently recruiting patients.

Medidur (Alimeira Sciences)

Medidur is an injectable non-erodable intravitreal device for the treatment of diabetic macular edema (DME). Diabetic macular edema is a common complication of diabetic retinopathy and is a leading cause of visual loss for those under age 65. Similar to Retisert, Medidur also contains the corticosteroid fluocinolone. Unlike Retisert, Medidur implants are injectable in the office. It releases a constant amount of fluocinolone into the back of the eye and is estimated to last for 18 to 36 months. It is a 3mm long cylindrical tube that is injected in the office using a 25 gauge injector.

Medidur may have a more favorable ocular hypertension side-effect profile as compared with the other fluocinolone implant (Retisert). This may have to do with the position of these implants relative to the ciliary body and/or the trabecular meshwork (anteroposterior implant localization in the eye). Studies are underway by both manufacuters to further evaluate this possibility. The product is currently in Phase III clinical trials and has been granted “fast track” by the FDA. There are two separate studies under evaluation - one device that releases fluocinolone for 18 months and another for 36 months.

Encapsulated Cell Technology (ECT, Neurotech)

ECT implants, developed by Neurotech, consist of genetically modified cells that are encapsulated in a semi-permeable fiber membrane and designed to release therapeutic factors into the back of the eye. ECT implants containing human cells genetically modified to release ciliary neuritrophic factor (CNTF) have been implanted in rabbits and long-term (18 months) protein release has been achieved.

ECT based products can be produced to address three main clinical manifestations of retinal disease:

Neurotrophic Factors for the treatment of retinitis pigmentosa and geographic atrophy, glaucoma and retinal vein occlusions
Anti-angiogenic Factors for the treatment of wet age-related macular degeneration and diabetic retinopathy
Anti-inflammatory Factors for the treatment of uveitis

Phase II/III Study for the treatment of retinitis pigmentosa and Phase II study of the treatment of dry age-related macular degeneration are currently being done.

Posurdex (Allergan, Inc.)

Posurdex is an injectable steroid in small biodegradable pellets containing dexamethasone. The implant lasts for 37 days and dissolves completely. It can be injected in the office setting as opposed to the surgical setting.

Phase II clinical trials evaluated patients who received Posurdex containing 350 microgram, 700 microgram of dexamethasone and placebo. 36% of 700 micrograms group of patient and 27% of 350 microgram patients showed an improvement of 2 lines of visual acuity or better compared to 19% of placebo. In terms of adverse effects, 17% of 700 microgram group and 12% of 350 microgram group experience an intraocular pressure elevation of 10 mmHg or higher compared to 3% of placebo.

It is currently in Phase III clinical trial for the treatment of macular edema from retinal vein occlusion and diabetic retinopathy. Smaller pre-approval studies are also underway, one of which includes a combination of Posurdex with Lucentis to determine if the addition of Posurdex can reduce the frequency of Lucentis therapy in patients with neovascular age-related macular degeneration.

Future Directions

Surmodics Inc. has introduced an implantable titanium screw (I-Vation) that is coated with triamcinolone acetonide. The hub of the screw is on the scleral surface and is covered by conjunctiva. The helical shaft of the screw is on the internal surface of the eye penetrating the sclera via the pars plana inferotemporally. Initially, there were concerns about conjunctival exposure with the screw, however, these problems were later dealt with by making sure the hub of the screw is flush with the scleral surface and not angled. This device is currently under clinical investigation for the treatment of diabetic macular edema.

Everyone asks why Genentech Inc. hasn’t created a sustained intraocular drug delivery device for ranibizumab (Lucentis) or bevacizumab (Avastin). For one, it would be outrageously expensive to market, considering the on-label cost of 12 doses of intravitreal ranibizumab injections exceeds $25,000. But, practically speaking, both of these drugs are proteins, which destabilize at body temperature after short periods of time. One would not expect these proteins to remain biologically active after several months inside the human body. One way around this problem, would be to engineer a drug with similar bioactivity that consists of an aptamer instead of a protein. Pegaptanib (Macugen, OSI Eyetech) is an aptamer against VEGF-165, but this isoform target limitation presumably prevents it from having the superior efficacy seen with ranibizumab and bevacizumab. An ideal posterior segment implant would contain and release a stable aptamer with broad VEGF isoform blockade, but such a drug is not on the horizon anytime soon.

However, as we have seen from the growing list of implantable drug delivery devices for the posterior segment, that several exciting new drugs are coming down the pipeline to add to our treatment armamentarium. The side-effect profile of these devices is typically related to the drug itself, with the implant carriers being generally well-tolerated.

Bausch & Lomb Pharmaceuticals, Inc.
Retisert™ (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant designed to release fluocinolone acetonide locally to the posterior segment of the eye at a nominal initial rate of 0.6 µg/day, decreasing over the first month to a steady state between 0.3-0.4 µg/day over approximately 30 months.