Allergan’s brimonidine is best known in glaucoma as the IOP-lowering agent Alphagan, but results of a Phase IIA trial reported at the American Academy of Ophthalmology meeting showed the drug, when injected into the eye in an Ozurdex-like intravitreal implant, showed some efficacy in reducing the progression of geographic atrophy in dry age-related macular degeneration.1
William R. Freeman, MD, distinguished professor of ophthalmology, director of the Jacobs Retina Center and vice chairman of the ophthalmology department at the Shiley Eye Center at the University of California, San Diego, reported results of the Phase IIA randomized trial of brimonidine DDS (for drug delivery system) implanted into the vitreous every six months in patients with geographic atrophy (GA) from dry AMD.
The trial compared a placebo and two dosing levels of first-generation brimonidine DDS tartrate in a 22-gauge implant at doses of 132 µm and 264 µm. The primary endpoint was change from baseline in GA area based on fundus photography, not visual acuity, and Dr. Freeman explains why: “One problem with geographic atrophy is that it continues to expand and visual acuity remains 20/20 even as the disease progresses, until it affects the foveal center. If you stop the disease from progressing, it will never affect visual acuity.”
The Phase IIA trial reported that at one year, the low-dose group showed a 19-percent reduction in lesion growth rate compared to placebo, the high-dose group a 28-percent reduction, Dr. Freeman says. Here, he discusses the trial.
The mechanism of action in his own words:
The cytoprotective and neuroprotective properties of brimonidine as an alpha-adrenergic drug have been well-documented, although the exact mechanism is not fully understood. It has been shown to protect against retinal degeneration in rodent studies, and to protect against toxicity in retinal pigment epithelium cells and other types of retina cells, including neurons.
When applied as a topical drop to the front of the eye, not enough active ingredient gets to the back of the eye to protect retinal cells, and no treatment exists to halt dry AMD progression to GA. The purpose of the Phase IIA trial, and the Phase IIB trial that has already enrolled, is to determine if brimonidine can protect RPE and photoreceptors.
The thinking behind brimonidine DDS is to administer injections less frequently than the monthly schedule for anti-VEGF agents. The Phase IIB trial will use a schedule of once every three months.
The advantage of a sustained-delivery insert:
Brimonidine DDS dissolves just as the Ozurdex dexamethasone implant does. Both use the Novadur solid polymer drug delivery system, made of a PLGA intravitreal solid polymer matrix that slowly degrades to lactic acid and glycolic acid, leaving no residue in the eye.
The advantage of the implant is that it sustains therapeutic levels of drug in the retina, whereas with an injection the drug levels drop very rapidly. The implant is injected through the pars plana and floats around in the vitreous, rarely interfering with vision.
The Novadur system is already FDA-approved, but brimonidine is not approved for treatment of AMD and other retinal diseases.
The take-home of the Phase IIA trial:
The major finding is that brimonidine DDS appears to slow down the rate of progression of geographic atrophy, and that the higher dose slows it more so than the lower dose. This trial showed a definite dose response.
The other key trial finding:
The trial found the implant has a safety profile similar to Ozurdex; the only adverse effect was the expected mild irritation around the injection site.
The Phase IIB trial, known as the BEACON trial, uses a second-generation formulation of brimonidine DDS that should deliver more drug to the retina: a dose of 400 μm of free-base brimonidine in a 25-gauge implant. If the results from BEACON are encouraging, the next step would be a large Phase III trial. RS
1. Freeman WR. Intravitreal brimonidine drug delivery system (brimonidine DDS) in patients with geographic atrophy: A phase 2 study. Presented at: American Academy of Ophthalmology annual meeting; October 14-18, 2016; Chicago.