Rapamycin safe for treating diabetic macular edema

Key Points

At the annual meeting of the American Academy of Ophthalmology, Dr. Blumenkranz reported, on behalf of a group of investigators, the results of a phase I study that evaluated locally administered rapamycin for the treatment of DME.

Rapamycin is a macrolide antifungal agent that has been isolated from a Streptococcus species, he said.

mTOR also inhibits translation and activation of HIF-1a, which is upstream of vascular endothelial growth factor (VEGF).

"Theoretically, mTOR precedes the production of VEGF and as such may have interesting additive or synergistic effects, such as inhibition of VEGF-driven endothelial cell proliferation," Dr. Blumenkranz said. "HIF-1a is thought to be important in ocular disease through a variety of mechanisms."

The company's formulation of rapamycin has low viscosity and can be injected through a small-bore needle. The drug forms a depot when injected, leading to extended delivery. Rapamycin seems to penetrate the sclera, the choroid, and the retina in therapeutic concentrations for extended periods.

Ocular safety study

Dr. Blumenkranz reported the results of one of two phase I studies of rapamycin. The study under discussion evaluated the safety of rapamycin for DME; the second evaluated the safety of the drug for exudative age-related macular degeneration (AMD).

A total of 50 patients with DME were included in the prospective, randomized, dose-escalation trial. The patients received either one intravitreal injection or one subconjunctival injection of one of five doses of rapamycin. For the 25 patients in the intravitreal group, the drug doses ranged from 44 to 352 μg; for the 25 patients in the subconjunctival group, the doses ranged from 220 to 1,760 μg. The baseline demographics of the groups were similar. The average visual acuity (VA) was about 56 and 51 letters, and the average macular thickness was about 453 and 463 μm in the intravitreal and the subconjunctival groups, respectively.

The investigators found no significant systemic exposure to rapamycin that would induce substantial immunomodulation.

Dr. Blumenkranz reported that the drug was relatively well tolerated, and no dose-limiting toxicity was encountered. Five serious ocular adverse events (vitreous hemorrhages and epiretinal membranes) occurred, none of which were considered by the investigators to be related to the drug.

"Importantly, there was no progression of cataract, and there was no significant increase in IOP levels aside from the transient IOP increases that occur immediately following the injection," Dr. Blumenkranz recounted.

Signs of biologic activity were detected with both routes of administration. The median increase in VA was four letters in both groups by day 90 after treatment. It was accompanied by a decrease in the macular thickness seen on optical coherence tomography scanning.

"There was, however, not a perfect correlation between patients who had increased VA and decreased central macular thickness," he said.

Both routes of administration were effective; slightly better efficacy was seen in the subconjunctival group. The investigators found a median VA increase of nine letters with the two lowest subconjunctival doses (200 and 440 μg) at day 45; a median improvement in the VA of more than six letters persisted in those groups until day 90, according to Dr. Blumenkranz.

"The sustained formulation of rapamycin designed for ocular use, both intraocularly and subconjunctivally, was judged to be safe as the result of the absence of serious adverse events related to the drug," he said. "There appeared to be preliminary efficacy signals, although this study was not designed to show efficacy."

The drug is moving into a phase II trial for patients with DME and AMD, Dr. Blumenkranz said.