Retinol-binding protein inhibitor slows lesion growth in geographic atrophy

The oral medication may also hamper VEGF production and prevent wet age-related macular degeneration, investigator says.

CHICAGO — An oral retinol-binding protein inhibitor has been shown to treat geographic atrophy, a clinician said here.

Fenretinide (ReVision Therapeutics) may also prevent the onset of wet age-related macular degeneration, Jason S. Slakter, MD, said at a company-sponsored symposium during the joint meeting of the American Academy of Ophthalmology and Middle East Africa Council of Ophthalmology.

“The results are very encouraging, and future studies to confirm these effects are warranted,” Dr. Slakter told Ocular Surgery News in a subsequent e-mail interview. “There is no doubt that ophthalmologists will anxiously await the results.”

Fenretinide, a synthetic derivative of vitamin A, halts the accumulation of A2E, a toxic byproduct of retinol (vitamin A) that builds up in the retinal pigment epithelium and contributes to the death of these cells, ultimately leading to visual decline. It binds to retinol-binding protein, reduces the amount of retinol entering the photoreceptors, and thus slows the formation of A2E.

“The retinol levels getting into the eye are lower,” Dr. Slakter said at the symposium. “You essentially slow down the production of the toxins that are building up in the back of the eye. The end result is that you have slowed down the deterioration of the cells.”

Drug dosing, formulation

The 2-year, multicenter, randomized study included 246 patients with geographic atrophy; 178 patients completed the study. Of those 178 patients, 153 patients had baseline and 24-month color fundus images that were critical to the analysis of lesion progression, Dr. Slakter said.

In the final study group, 59 patients received placebo, 47 patients received a daily 300-mg dose of fenretinide and 47 patients received a daily 100-mg dose of fenretinide.

Patients underwent color fundus photography, fundus autofluorescence, fluorescein angiography, contrast sensitivity testing, microperimetry and optical coherence tomography. Investigators also assessed development of choroidal neovascularization.

Results showed that patients who enrolled early had a sustained reduction of retinol-binding protein levels throughout the study, while those who enrolled later did not maintain a reduction. This result was attributed to a change in drug lot made about 1 year into the trial, Dr. Slakter said.

“The second group was getting the second formulation and it was not as good,” he said. “Their [retinol-binding protein] suppression started to wane. The drug did not seem to be working as well.”

Investigators theorized that reducing serum retinol-binding protein levels would slow atrophic lesion growth. They found that fenretinide treatment lowered retinol-binding protein levels in a dose-dependent manner, and this in turn reduced lesion growth in the same fashion.

“From a clinical point of view, you start out with a hypothesis that says that if you reduce [retinol-binding protein] in circulation, you ought to get a good effect,” he said. “And if you show that in fact the more you suppress it, the better the effect, it demonstrates biological effectiveness.”

Lesion size, visual acuity, CNV

Among patients in the 300-mg group, 43% achieved retinol-binding protein reductions of more than 60%. In this group of patients, median lesion growth was 30% from baseline, compared with 50% from baseline in the placebo group, Dr. Slakter reported.

Patients with decelerated lesion size growth lost six letters of visual acuity between 12 months and 24 months. Patients in the placebo group lost 11 letters at 24 months, Dr. Slakter said.

Study results also showed that patients who received either dosage of fenretinide had approximately 40% less risk of progressing to wet AMD at 2 years compared with those who received placebo. The incidence of CNV at 24 months was 22% in the placebo group and approximately 14% in either fenretinide dosage group.

Unlike anti-VEGF agents, fenretinide may prevent neovascularization, Dr. Slakter said.

“That is the holy grail — to give a medication that prevents neovascularization from developing in the first place. That is very, very exciting. There are data to support it. That was a pleasant surprise.”

In addition, fenretinide presented few side effects and appeared to be well-tolerated by patients.

ReVision Therapeutics plans to launch phase 3 trials in 2011. – by Matt Hasson

• Jason S. Slakter, MD, can be reached at 519 E. 72nd St., Suite 203, New York, NY 10021; 212-861-9797; fax: 212-628-0698; e-mail: jslakter@aol.com.
• Disclosure: Dr. Slakter is a consultant to ReVision Therapeutics.