CLINICAL TRIAL SPOTLIGHT

Sirion Eyes Fenretinide as a Treatment for Geographic Atrophy in AMD
Phase 2 trial is under way for final-stage dry AMD patients.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

Sirion Therapeutics, Inc. (Tampa, Fla), began enrollment Dec. 4, 2006, for a phase 2 study of the efficacy of fenretinide in treating patients with geographic atrophy (GA), the final stage of nonexudative age-related macular degeneration (AMD). Fenretinide is a synthetic retinoid already unsuccessfully used in trials treating several forms of cancer.
According to a Sirion press release, nearly 1 million people in the United States suffer from GA. The company intends to enroll up to 225 patients at approximately 20 US sites. The phase 2, multicenter, randomized, doublemasked, placebo-controlled, dose-comparison study will last for 24 months with a 4-week follow-up.
Sirion acquired fenretinide in July 2006 when the company merged with Sytera, Inc. (San Diego). The mechanism of fenretinide action in treating GA is the drug’s ability to reduce systemic vitamin A levels. This effect will ultimately result in the reduction of toxic fluorophores and lipofuscin levels in the eye, which are key to the development of several retinal disorders, including AMD.
As a synthetic vitamin A homologue, it may seem as if fenretinide would hurt rather than help patients with AMD. However, the opposite is true. “It is the structural homology of fenretinide to vitamin A that underlies its mechanism of action,” says Nathan Mata, PhD, vice president of discovery research for Sirion. “Importantly, vitamin A and fenretinide do not interconvert. Fenretinide competes with vitamin A for binding to retinol binding protein (RBP) and does not allow transthyretin to bind to the complex. The relatively small size of the RBP-fenretinide complex causes it to be lost through glomerular filtration.”
Dr. Mata continues, “The net effect is reduced RBP and vitamin A in the circulation. Because the eye has a unique requirement for vitamin A delivered by RBP, the effect of reduced RBP-vitamin A will be most pronounced in ocular tissue.”
Notably, this is not the same mechanism of action for fenretinide that had been explored in previous clinical trials for the treatment of cancer. In theory, when given to cancer patients, fenretinide causes apoptosis through programmed cell death, targeting malignant cells only.
However, Dr. Mata says, the success with this usage of fenretinide has been limited. “Although fenretinide showed promise in preclinical studies,” Dr. Mata says, “it failed as a chemopreventative agent in all of the human clinical trials.” However, Dr. Mata notes, thanks to these fenretinide trials for cancer, “there has been extensive human exposure to fenretinide.” Thus the side effects are already known. Fenretinide causes a slight delay in dark adaptation. In addition, some patients may experience dry eye and dry skin. Dr. Mata carried out an earlier study using fenretinide in an animal model of Stargardt’s disease. “In our study, electrophysiologic and histologic analyses showed no deleterious functional or morphologic effects in the retina after chronic and acute fenretinide administration,” he says.
Although this fenretinide trial is directed toward treatment for geographic atrophy, one possible outcome of treatment with fenretinide may be the prevention of the conversion of dry AMD to wet AMD. Approximately 10% to 15% of dry AMD cases will convert to wet AMD. “Clearly,” Dr. Mata says, “if we could halt, or even slow, the progression of dry AMD, we might expect a therapeutic benefit for patients in this subgroup.” According to Roger Vogel, MD, chief medical officer for Sirion, “We are not actively exploring this area. If the product proves to benefit this subgroup, that is a bonus. The focus of our development effort is clearly dry AMD and GA.We are excited about this program and hope that it will produce a viable treatment option for the millions of people around the world at risk of losing vision because of this disease.”