Oral fenretinide investigated for dry age-related macular degeneration

Key Points

Structurally similar to retinol, fenretinide competes with retinol for binding to its carrier protein, retinol-binding protein (RBP), and causes a dose-dependent, reversible reduction in circulating levels of retinol. Based on this activity, it is hypothesized that fenretinide will reduce retinol delivery to the eye and subsequently mitigate the accumulation of toxic vitamin A-derived retinal fluorophores that are implicated in the pathogenesis of AMD, according to Dr. Singerman, president, Retina Associates of Cleveland, and clinical professor of ophthalmology, Case Western Reserve University School of Medicine, Cleveland.

"In advanced AMD, continued accumulation of the retinal fluorophore A2E leads to degeneration of photoreceptors and vision loss," he said. "Since A2E is derived from retinol, which enters the eye from the circulation, it is conceivable that reducing circulating levels of retinol would reduce the retinal level of A2E."

The 2-year, dose-ranging study was launched in December 2006, and it has completed its enrollment of 245 patients. Eligible patients are aged 50 to 89 years and have geographic atrophy measuring >1 to ≤8 disc areas in size located within 250 μm of the fovea and best-corrected visual acuity between 20/25 and 20/100.

The study is evaluating the effects of fenretinide on lipofuscin accumulation and vision loss. The primary efficacy end point is change in lesion size measured using autofluorescence. A 1-year interim analysis is planned, and those data are expected to be available in the first half of this year.

"Fundus autofluorescence is observed in patients with AMD and is seen prior to the onset of death of [retinal pigment epithelium (RPE)] and photoreceptor cells," he said. "Biochemical analysis of postmortem AMD tissues has shown that the retinal fluorophores are primarily vitamin A metabolites and most notably A2E, which is highly toxic to RPE cells via multiple mechanisms."

Vitamin A

Discussing vitamin A delivery to the eye and the mechanism through which it is reduced by fenretinide treatment, Dr. Singerman said that ingested vitamin A (retinol) is mobilized from the liver as a complex bound to RBP and another carrier protein, transthyretin (TTR). Retinol binds first to RBP, which leads to creation of a high-affinity binding site for TTR. The resultant vitamin A complex is a large molecule that resists filtration in the kidney and is preferentially taken up by the eye, where it is transformed into a visual chromophore and delivered to the photoreceptors, producing vision, he said.

In the healthy eye, undigested cellular debris (lipofuscin) and vitamin A metabolites are removed through RPE cell-mediated phagocytosis. When these processes are compromised, however, because of environmental or genetic factors, an accumulation of lipofuscin and the toxic vitamin A metabolites forms, two features that are hallmarks of early AMD.

By binding to RBP, fenretinide may limit this process because the RBP-fenretinide complex is small enough to be excreted from the body through glomerular filtration.

"Retinol delivery to the eye requires that it be bound to RBP, whereas other extrahepatic tissues can obtain retinol from other sources," Dr. Singerman said. "Therefore, the eye is more susceptible than other tissues to reductions in serum levels of RBP-retinol."

Studies in animal models of Stargardt disease established that treatment with fenretinide causes a dose-dependent reduction in serum vitamin A that was associated with a proportionate reduction in ocular levels of retinoids and A2E, along with a reduction in autofluorescence within the RPE. These changes occurred without any adverse effects on the structural integrity of the retina or RPE.