Oral fenretinide given once daily may slow the progression of geographic atrophy in patients with age-related macular degeneration, according to an interim analysis.

Key Points

Fort Lauderdale, FL-Fenretinide may be effective in slowing and halting the disease progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD), according to the preliminary results of ongoing research presented at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting.

Dry macular degeneration accounts for approximately 90% of all AMD, and in many patients, the classic clinical lesion seen is GA. Research has shown that GA is related to the buildup of lipofuscin and A2E in the retinal pigment epithelium (RPE), leading to the death of the RPE and the overlying photoreceptors, ultimately resulting in severe central vision loss.

The various therapies tried in the past have not shown any efficacy in slowing, stopping, or reversing the ongoing macular degeneration in patients suffering from this disease. Anecdotally, dietary supplements of xanthine and zinc, likely due to their antioxidant effect, were largely believed to be effective in preventing or reducing the incidence of macular degeneration related to cataracts; however, past trials also have shown this approach to be ineffective in stemming the progression of GA. In the preliminary analysis of an ongoing trial with fenretinide, however, a slowing in the progression of GA was observed, giving hope to patients who are otherwise faced with a bleak prognosis for their disease.

In the ongoing 2-year, multiple-site, double-masked, placebo-controlled, dose-comparison study, 246 patients with GA due to AMD were randomly assigned to receive either fenretinide 100 or 300 mg or placebo soft-gel capsules once a day. Participants included in the study had a total atrophic area of 2.54 mm² to 20.32 mm² (more than 1 to less than 8 disc areas) in one or both eyes as assessed by fundus photography and fluorescein angiography. Baseline measurements included fundus autofluorescence, visual acuity (VA), reading rate, contrast sensitivity, microperimetry, night vision, serum retinol-binding protein (RBP) levels, and full labs. Patients were to be followed up at 1, 3, 6, 12, 18, and 24 months. The primary outcome was the growth rate of the aggregate GA lesion area.

Interim analysis

Results of the interim analysis undertaken when all subjects had completed at least 12 months showed that at baseline, the mean age of participants was 78 years. These patients had a mean GA lesion area of 9.72 (±5.19) mm² . The mean serum RBP level was 5.94 (±1.58) mg/dl, and the mean VA was 67.69 (±10.73) letters. Fenretinide treatment was associated with a dose-related reduction in RBP. In patients who received 300 mg once a day and had been followed for at least 18 months, the rate of GA lesion progression appeared reduced, although statistical significance has not been reached in this subgroup analysis.

The study reported that there was no tendency for lesion area to be correlated to serum RBP before the initiation of treatment. No correlation was found between the age of the patient and lesion size at baseline, nor was any correlation found between lesion area and VA. In an interim analysis of the progression of GA lesions above and below the median at baseline, the smaller lesions seemed to have responded better than the larger lesions. There was evidence of some response in the 100 mg treatment group and a very good response in the 300 mg treatment group in the smaller lesions.

It appears that by initiating therapy in earlier stages of the disease, the disease is being treated before serious damage has been done, meaning before too much lipofuscin and A2E have been allowed to build up in the RPE. This finding may have an impact on when to start treatment as well as on prognosis.

Potential advantages

The potential advantage of fenretinide treatment for GA is that it is an oral therapy taken once a day, which is very different from periodic injections of growth hormone inhibitors and other painful as well as ineffective therapies that have been tried in AMD.

Roger Vogel, MD, chief medical officer of Sirion Therapeutics, Tampa, FL, which is investigating fenretinide for GA associated with AMD, is a co-author on the poster presented at ARVO. He said that fenretinide binds with the RBP, resulting in a reduction in the retinol uptake by the RPE. In previous studies in animals, this process caused a reduction of lipofuscin and A2E (toxic end products of the visual cycle) products, which are increased in GA and thought to play an integral role in the etiology of the disease.

"No other therapeutic approach as of yet has been shown to reduce the progression of GA lesions. The 1-year preliminary data are promising, and if these positive trends are maintained throughout the remainder of the study, this could be the first evidence of a significant advance in the treatment of this disease," Dr. Vogel said.

Safety, tolerability

In this study, fenretinide appeared to be relatively safe, and the study participants tolerated the drug well. Adverse events included night blindness or delay in dark adaptation, dry eye, anemia, rash, pruritus, diarrhea, and elevated liver enzyme levels. Because no other treatment exists, however, as well as because of the repercussions involved in this progressive blinding disease, patients were willing to continue their therapy because they determined that the potential benefits outweighed the side effects.

According to Dr. Vogel, the final results will be available at the completion of the 2-year trial in the spring of 2010 and will show whether this oral therapy should be evaluated in phase III studies and might one day become a treatment for AMD.