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A recent study evaluating the efficacy of an investigational dexamethasone delivery system (Posurdex, Allergan) for the intravitreal treatment of uveitis in rabbits demonstrated that it significantly reduced intraocular inflammation.
Irvine, CA-A recent study evaluating the efficacy of an investigational dexamethasone delivery system (Posurdex, Allergan) for the intravitreal treatment of uveitis in rabbits demonstrated that it significantly reduced intraocular inflammation.
Oral corticosteroids are standard therapy for uveitis. The drugs' adverse events, however, can be a limiting factor for some patients. The investigational intravitreal implant aims to avoid these adverse events through the sustained release of therapy. The device consists of a blend of polylactic acid and polyglycolic acid polymers that over time biodegrade into carbon dioxide and water. As they break down, dexamethasone is released into the eye.
In the study, uveitis was induced by an intracameral injection of 20 ug of mycobacterium tuberculosis (Mbt) in one eye in each of 18 rabbits pre-immunized 20 days previously with two subcutaneous doses of 10 mg of Mbt. Four days after disease induction, 12 of the rabbits were treated with 700 ug of dexamethasone, and six control rabbits received a sham injection.
"The main problem with corticosteroids is side effects. Many patients are intolerant to corticosteroids due to a host of systemic adverse events," said Scott M. Whitcup, MD, a member of the clinical faculty at the Jules Stein Eye Institute, University of California, Los Angeles, and executive vice president and head of research and development, Allergan, Irvine, CA, which is testing the implant. "When you treat locally into the eye, you get higher levels of the drug where you need them and can avoid systemic adverse events.
"The implant releases dexamethasone into the eye, and from our pharmacokinetic studies, we have detected levels of the drug up to at least 6 months following implantation of the device," he added.
The intravitreal drug delivery system is being used in several phase III trials under way, including one for macular edema associated with retinal vein occlusions, one for macular edema associated with diabetes, and one for uveitis. According to Dr. Whitcup, FDA approval for the device is expected for macular edema associated with retinal vein occlusions in 2009 and for uveitis in 2010.
"I believe that this device will have the ability to make a major impact on the way we treat patients with uveitis," he said. "There are currently a number of patients who could benefit from local treatment with corticosteroids, and we believe dexamethasone has some unique pharmacologic properties, making it an ideal choice for sustained-release intravitreal therapy."
The investigational intravitreal implant delivers dexamethasone in a unique way, Dr. Whitcup said. A pulsed dose emits high levels of the drug over the first 6 to 8 weeks and then emits very low levels for about 6 months. This time period is followed by a drug "holiday" because the implant runs out of drug. This break allows the physician the flexibility of deciding whether treatment should be continued.
"We believe that the efficacy can be maximized with this approach and decrease the side effects of steroids in the eye such as cataract and glaucoma," he said. "This biodegradable, office-based implant could allow the physician to decide how many treatments are really needed and if a drug holiday is necessary to decrease side effects."
An intravitreal implant currently available on the market (Retisert, Bausch and Lomb) releases fluocinolone acetonide and works quite similarly to the investigational device, according to Dr. Whitcup. The investigational intravitreal implant has two major advantages over the one on the market, however, he said. The investigational implant biodegrades over time, and once the drug is released, nothing is left in the eye.
In contrast, Dr. Whitcup said, the existing implant is non-biodegradable and once surgically placed remains in the eye. Also, the investigational implant can be inserted in an office-based setting, unlike the available one.
A benefit of the existing, permanent implant is that the steroid effect lasts longer, somewhere from 30 to 36 months, Dr. Whitcup said, so patients potentially would need fewer implants. The chronic administration/release of corticosteroids over years could increase the adverse events of the drug in these patients, however, he added. The experimental implant allows the physician to treat an acute exacerbation of uveitis without committing a patient to years of steroid exposure from the start, Dr. Whitcup said.
"Ophthalmologists have been using eye drops for many years now, and that tends to work well for diseases of the anterior segment of the eye or diseases on the ocular surface, but it is difficult for eye drops to get sufficient drug levels to the vitreous and the retina," he said. "The ability to treat with sustained-release implants in the vitreous is an excellent approach and a great platform for treating diseases of the retina."
Other potential uses
The investigational implant is the product furthest along in development using this drug-delivery technology, Dr. Whitcup said. The potential exists to administer many different drugs using this delivery system, he added, and the potential may lead to the ability to locally treat other diseases by delivering treatments directly to the tissues that need the drugs.