CLINICAL TRIAL SPOTLIGHT

An AMD Treatment on Steroids

If steroids can extend the interval between injections, can extended-release steroids extend them even more?

Andrew E. Mathis, PhD, Medical Editor

Combination therapies for AMD focus to a large extent on trying to extend the period between injections of anti-VEGF agents such as ranibizumab (Lucentis, Genentech), which is prescribed in monotherapy for monthly dosing.

The corticosteriod triamcinolone acetonide has been tested to treat AMD, both as monotherapy and in combination with anti-VEGF drugs, and has been demonstrated in clinical trials to lead to patients needing fewer intravitreal injections. This period between treatments may get even longer if an extended-release form of triamcinolone called Verisome, developed by Icon Bioscience, Inc. (Sunnyvale, CA), proves effective in a clinical trial that recently began enrolling. Jennifer I. Lim, MD, director of retina services at the University of Illinois–Chicago (UIC), spoke with Retinal Physician about the trial, called the Icon Combo study.

Dr. Lim explained how the sustained-release liquid drug-delivery system works. “The Verisome is a proprietary technology comprised of a wide variety of excipients,” she said, “including carbonates, tocopherols, and citrate esters. A unique combination of these excipients are combined with each specific active drug ingredient. The dose and duration of release is designed for the respective clinical application. The resultant biodegradable formulation can be injected, delivering the drug in a controlled release manner.

“The Verisome can be formulated with small molecules or large biologics,” she continued. “It creates a round, partially translucent sphere in the eye in the pars plana area. The beauty of this design is that you can get a steady concentration of sustained-release drug,” she noted, indicating that this is an inherent problem with some steroid implants. “We're achieving relatively stable nanogram-level concentrations over the whole time.”

The Icon Combo study is examining the safety and efficacy of 6.9 and 13.8 mg injections. Both dosages have already been studied for safety and evidence of efficacy in eyes with cystoid macular edema from retinal vein occlusion. Dr. Lim presented one-year data from this trial at last year's ARVO meeting, indicating substantial decrease in central retinal thickness with the combination and better evidence of efficacy with the higher dose.

“We saw evidence of thinning of the central subfield thickness on OCT,” Dr. Lim said, “and we thought, ‘Why not try it in patients with AMD in combination with ranibizumab and attack the neovascular process from another angle to decrease the need for retreatment and limit fibrosis?’” Thus was born the current trial, which will enroll five patients in each dosage arm.

When asked about the small study size, Dr. Lim remarked, “If we examine the patients and we see the combination is working, then certainly we can expand it.” As the trial is a phase 1 study, the primary endpoint will be safety. However, the secondary outcome measure will be the need for retreatment. “The criteria here will be very strict,” Dr. Lim said. “Any sign of fluid or cystic formation, or visual acuity worse than 20/40, will lead to reinjection with ranibizumab.”

Perhaps the biggest issue Dr. Lim must deal with in the Icon Combo trial is the wisdom of conducting yet another combination therapy trial with a combination therapy that has already been proven to work. “That's why we're enrolling patients who need to be treated every 30 days,” Dr. Lim explained. “These patients have demonstrated a pattern of persistent cystic change or subretinal fluid despite monthly ranibizumab therapy. They can't stop the chronic treatment.”

Furthermore, besides the possible benefit of the trial for refractory patients, there is also the possibility that, as in the RVO trial, the higher dose of triamcinolone may lead to greater efficacy. While the current trial will not allow for rigorous statistical analysis, it is expected that higher phase trials will address the issue of efficacy from the standpoint of statistical significance. “For now,” Dr. Lim said, “we are looking for evidence of an abrupt change in the frequency of retreatment.” RP