Rapamycin shown to be safe in phase I DME study

No serious ocular adverse events and only negligible system exposure were observed in a phase I dose escalation study of siroliumus (also known as rapamycin) in a trial involving 50 patients with diabetic macular edema (DME). Promising efficacy signals also were seen, and a phase II trial of subconjunctival administration of a liquid depot formulation of rapamycin is planned, according to Mark S. Blumenkranz, MD, professor and chairman, Department of Ophthalmology, Stanford University, Stanford, CA.

Rapamycin is a macrolide antifungal agent that inhibits the mammalian target of rapamycin (mTOR), a regulatory protein kinase that regulates cell growth, proliferation, motility, and survival. Inhibition of mTOR by rapamycin down-regulates hypoxia-inducible factor1 (HIF-1), which is a key regulator of oxygen homeostasis elevated in the diabetic eye. It has multiple mechanisms of action and is being studied for a number of potential therapeutic applications in ophthalmology, Dr. Blumenkranz said.

In this multicenter, open-label phase I trial, patients were randomly assigned to receive either a single intravitreal rapamycin injection of 44, 110, 176, 264, or 352 mg or a single subconjunctival injection of 220, 440, 880, 1,320, or 1,760 mg. The principle outcome measures were visual acuity and central subfield retinal thickness. Evaluations were performed at 14, 45, 90, and 180 days.

The average duration of DME was about 3 years in both treatment groups. At baseline, average visual acuity was 51 letters and the average foveal thickness was 462 µm in the subconjunctival group (n = 25); the figures were similar in the intravitreal group (n = 25).

The amount of drug administered systemically by either route was well below that which could be expected to produce immunosuppression, so that was not a safety concern in this study, Dr. Blumenkranz said.

Overall, the average patient had an improvement in best-corrected visual acuity of just under 4 letters and an average decline in retinal thickness of just under 50 µm.

Subgroup analysis also was performed.

"One thing that was interesting to us was the fact that the patients seemed to do at least as well with a subconjunctival injection as they did with the intravitreal injection," Dr. Blumenkranz said. The mean BCVA improvement in the subconjunctival group at 90 days was 7.4 letters, and the mean reduction in retinal thickness was 61 µm at 90 days. In the intravitreal group, the mean BCVA improved by 7.8 letters and the retinal thickness decreased by 61 µm at 90 days. These functional and anatomic improvements persisted through 180 days.