CLINICAL TRIAL SPOTLIGHT
Putting the Brakes on Geographic Atrophy
A new trial using Alimera's fluocinolone implant aims to treat advanced dry AMD.
ANDREW E. MATHIS, PhD, MEDICAL EDITOR
Alimera Sciences is just one of several companies to introduce an intravitreal implant for retinal disease over the last year or so. Meanwhile, anti-VEGF drugs have made their impact on the treatment of wet age-related macular degeneration. But relatively few treatments for dry AMD are in clinical trials. Now, Alimera has begun enrollment for a phase 2 trial of its Iluvien fluocinolone acetonide (FA) implant for the treatment of geographic atrophy, the key biological change seen in advanced dry AMD.
Raymond Iezzi, MD, of the Kresge Eye Institute at Wayne State University in Detroit, is the principal investigator on this trial, which is seeking to enroll 40 patients at Kresge to receive either 1 of 2 doses of fluocinolone (0.2 μg or 0.5 μg per day) or a sham injection. Enrollees must have geographic atrophy in both eyes.
ILUVIEN IN THE EYE
Dr. Iezzi explained the mechanism of action of the Iluvien implant to Retinal Physician. "Fluocinolone dampens retinal neuroinflammation," he said. "We identified this process in 2 animal models of retinal degeneration. In both the Royal College of Surgeons as well as the S334-ter line 4 rats, low-dose FA reduced the number of activated microglial cells by at least a factor of 5."
Microglial cells, Dr. Iezzi explained, are macrophage-derived glia that become phagocytes when activated by antigens, such as broken cell membranes or toxic molecules like tumor necrosis factor (TNF)–α. When activated, microglia release toxic molecules, such as TNF-α, nitric oxide, and superoxide anion. These toxins, in turn, promote accelerated death of adjacent cells, such as photoreceptors, via a process of bystander lysis, ie, damage of otherwise healthy cells as a consequence of the toxic milieu created by neuroinflammatory cells such as microglia.
Dr. Iezzi continued, "By dampening this intraretinal inflammatory response, FA reduces the collateral damage of healthy cells. Our hypothesis is that dampening of retinal neuroinflammation will slow the progression of geographic atrophy. FA will not shrink GA, but rather slow its progression."
One question that concerns researchers in dry AMD is whether geographic can be prevented, rather than just treated. Iluvien holds this promise, according to Dr. Iezzi. "We know that the geographic atrophy phenotype begins when drusen regression is nearly complete," he said. "A number of studies have shown that phagocytes are responsible for clearing drusen. Our hypothesis is that dampening the immune response within the eye will reduce bystander lysis and this reduction may reduce loss of photoreceptors and RPE cells, perhaps delaying or preventing the onset of geographic atrophy."
Alimera reported 3-month interim data in June 2008 from its phase 2 efficacy and safety study of Iluvien. Like the ongoing FAME study, this phase 2 study has enrolled patients with diabetic macular edema. At the 3-month mark, Alimera reported that it had seen no adverse reactions related to intraocular pressure in low-dose patients. However, 12% of the higher-dose group experienced IOP increases >30 mm Hg.
Meanwhile, the geographic atrophy study has only just begun to enroll, and with the time frame of the trial spanning 24 months and final data collection occurring approximately at the end of 2011, it will be some time before interim data is available on how well Iluvien slows the progression of geographic atrophy. If the results are anything like what has been observed in the FAME study thus far, Alimera has reason to be hopeful. So, for that matter, do patients with geographic atrophy. While Dr. Iezzi cautions that there are no data to suggest that Iluvien may prevent conversion from dry to wet AMD, several other studies are addressing this issue. With the current emphasis on combination therapies, Iluvien may play a key role in dry AMD therapy and treatment. RP