by Dan Roberts
(Updated February 28, 2012)
Fenretinide (RT-101), a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin that leads to vision loss in Stargardt’s patients. The toxin, called A2E, is a byproduct of vitamin A, the formation of which encourages production of waste deposits called lipofuscin. These deposits accumulate in the retinal pigment epithelium (RPE), interfering with the RPE’s ability to nourish the photoreceptors.
The efficacy study was conducted by Sytera and collaborators at The Jules Stein Eye Institute. Sytera, Inc. has since merged with Sirion Therapeutics, Inc.
Researchers found that A2E accumulation was decreased by 60% in mouse models after 28 days of treatment with fenretinide. Since accumulation of lipofuscin is also a condition of eyes affected by age-related macular degeneration (AMD), Sirion is running FDA-approved multi-center studies using up to 225 AMD patients as subjects, with a proof-of-concept trial having begun in December 2006. AMD subjects provide a larger population for the study than the relatively small number of Stargardt’s patients available. If the drug proves effective with dry AMD patients, it may then be used off-label for treatment of Stargardt’s disease.
In April 2009 the FDA granted fast-track designation for fenretinide. This decision was based upon positive 12-month interim results from Sirion’s phase 2 trial. According to the company’s press release, among a subpopulation of 78 patients who reached the 18-month study visit, the median lesion growth rate in the 300-mg group was 22.7%, compared with 41.6% in the placebo group, representing a 45% reduction in median lesion growth rate. Subjects in the 100-mg group who had lesions smaller than approximately three disc areas also showed slower lesion growth, suggesting that early intervention may improve outcomes. Full analysis of all lesion size measurements is ongoing.
On September 1, 2010, ReVision Therapeutics, Inc. (a spinout from Sirion Therapeutics) announced that data from the Phase 2 trial also show that fenretinide reduced the incidence of choroidal neovascularization by about 50 percent in patients with geographic atrophy (GA).
In May 2011, results from Phase 2 trials were announced at the annual meeting of the American Academy of Ophthalmology (ARVO).
This phase was completed with a surprising outcome. In addition to expected continuing positive results, researchers found that the drug also reduced by 2-fold the rate of conversion to neovascularization in patients with geographic atrophy. This indicated that fenretinide, in addition to slowing the progression of dry AMD, might also become a pre-treatment for wet AMD.
Unfortunately, according to a company representative, trials have been suspended after the FDA ruled that the Phase 2 results were flawed. At this point, the high cost of continuing the trials has halted further research.