Retinoic acid may be key to dry, wet AMD treatments

Retinoic acid may be key to dry, wet AMD treatments

by Michelle Dalton EyeWorld Contributing Editor

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Patients receiving the 300 mg dose of fenretinide showed significant reduction of retinol binding protein and reduced lesion growth from baseline when compared to placebo Source: ReVision Therapeutics

A synthetic retinoid derivative has been able to slow lesion growth and preserve visual acuity in patients with geographic atrophy (GA). Further, when the patients were able to achieve sustained reductions in retinol binding protein (RBP) levels of 60-75% (indicating a positive response to fenretinide), these same patients had a lesion growth rate of about half what those receiving placebo experienced when the RBP reduction threshold was met. "Fenretinide may improve clinical outcomes for patients with both dry and wet forms of age-related macular degeneration," said Jason Slakter, M.D., clinical professor of ophthalmology, New York University School of Medicine, New York. "For the first time ever, we may have a biomarker to predict patient response to therapy, as about one-third of the patients who achieved a profound and sustained reduction in RBP levels experienced a beneficial treatment effect." Biomarkers are generally considered the "hot topic" in retinal diseases, Dr. Slakter said. "The difficulty with retinal diseases is that clinical studies require large numbers of patients and a long duration, and many of the diseases we are treating take a long time before they're seriously detrimental to vision. The question is whether we can find something that will give us a hint of what's going on with the treatment for the disease earlier in the course of the study. We're looking for markers to give a hint of what might be effective," he said.

Adding to the dilemma in retinal diseases is the fact that the technology wasn't initially there to make finding a biomarker viable, and for some diseases a natural animal model didn't exist.

"We can test all we want in an animal model, but that doesn't necessarily replicate what we might see in humans. Animal models are better than nothing, but it doesn't mean that a compound will have a positive action in humans just because a mouse was treated successfully," Dr. Slakter said.

In the case of fenretinide, "we may have a marker for the biologic activity of the drug by simply measuring the level to which fenretinide is able to reduce RBP in a particular patient, which may then indicate its ability to reduce the progression of the disease," he said. "The results of this Phase II study, which was initiated to determine if people who took the pill would have significant and sustained reductions in RBP and an associated delay in the progression of the disease, suggest that this may be possible."

The accumulation of retinol-derived toxins in the eye "is believed to exacerbate lesion growth leading to progression of GA," said Nathan L. Mata, Ph.D., chief scientific officer, ReVision Therapeutics, San Diego. Fenretinide is a once-daily oral compound being investigated for the treatment of GA, according to ReVision Therapeutics. Because fenretinide limits the delivery of retinol to the eye by reducing the serum RBP, retinol-derived toxin accumulation is also slowed, which, in turn, slows lesion growth, the company said. The U.S. FDA has granted the company Fast Track status for the drug.

Fenretinide "has been tested and used for more than 30 years in systemic doses from 100-7,200 mg; with more than 8,000 'patient years,' it's been proven safe," Dr. Slakter said. "Most of the adverse events reported in our study are commonly associated with retinoids."

Study details

ReVision completed a 2-year, placebo-controlled, double-masked, dose-ranging study enrolling a total of 246 patients with GA. All patients were between 50 and 89 years, and the overwhelming majority of study subjects were white (99.2%). The initial baseline GA readings were within 500 microns of the fovea. Doses studied were 100 mg (n=80) and 300 mg (n=84); placebo comprised 82 patients. There were no grade IV adverse events reported, and only 16 patients discontinued use due to drug-related events. Dr. Slakter noted that for this study, there were two manufacturers used for the different dosages, and this skewed some of the results initially. The material inside the capsule being used in the first iteration of the drug was "about 9 microns in size; the second version was about 30 microns," and this prevented the second formulation from being able to deliver the drug at the same level as the first formulation. Since discovering the differences, when ReVision moves ahead with its Phase III study, the first formulation will be followed, Dr. Slakter said. For the Phase IIb study, retinal lesion size was measured by color fundus photography, fundus autofluorescence, and fluorescein angiography. Patients were also evaluated by contrast sensitivity, reading rate, visual acuity, optical coherence tomography, the incidence of choroidal neovascularization, and serum RBP levels. According to ReVision, this is the largest study to date of an oral therapeutic agent for the treatment of GA. Results from the study found that 43% of the patients in the 300 mg group had a sustained RBP reduction of at least 60% throughout the trial. Those patients had a median lesion size growth of only 30% from baseline, compared to a median lesion growth of about 50% in the placebo group. Even visual acuity loss in patients who experienced reduced lesion size growth was stabilized from 12 months to 24 months at six letters lost. On the other hand, the placebo group showed a progressive loss throughout the trial, averaging an 11-letter loss at 24 months. The incidence of choroidal neovascularization was about 13-14% in the fenretinide group (regardless of dosage); it was about 22% in the placebo group.

Dry-to-wet AMD conversion

ReVision plans on initiating a Phase III study this year and believes it will take about 1,000 subjects to enable the study to be powered correctly. At this point, plans are to have only two arms—a 300 mg fenretinide arm and a placebo arm, the company said. Based on the Phase IIb results, "we have essentially slowed down the deterioration of the cells in the back of the eye," Dr. Slakter said. However, the ability of fenretinide to achieve a level of RBP below the threshold needed to slow the progression may not be sustainable in all people, he warned. An additional benefit of treating a chronic disease like AMD is that if the next phase proves successful, physicians can prescribe the medication and, over the course of time, be able to determine patient compliance based on RBP levels. As an aside, Dr. Slakter said fenretinide might have the capability to reduce the development of choroidal neovascularization by affecting the production of vascular endothelial growth factor. "That's a completely separate effect from reducing RBP," he said. "It means the compound might also work as a prevention drug, although we still need to confirm what we found initially."

Editors' note: Dr. Slakter has financial interests with Digital Angiography Reading Center (New York) and ReVision Therapeutics.

Contact information

Slakter: 917-951-5659, jslakter@aol.com

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