Sirolimus formulation shows promise as DME treatment

Key Points

Boston-Interim results from a phase I trial evaluating a proprietary formulation of sirolimus, originally known as rapamycin, for the treatment of clinically significant diabetic macular edema (DME) demonstrate that it has a favorable safety profile and promising biologic activity, reported Mark S. Blumenkranz, MD, here at the Retina Society meeting.

Sirolimus is a macrolide approved by the FDA for systemic use to prevent organ rejection and to treat advanced renal carcinoma as well as for use in drug-eluting coronary stents to prevent coronary restenosis. It acts by binding to mTOR (mammalian target of rapamycin) and has a broad pharmacologic profile that includes anti-inflammatory, antiangiogenic, antifibrotic, and antiproliferative effects. It is being developed by MacuSight as a proprietary depot formulation for the treatment of DME and other retinal diseases.

The phase I study of DME enrolled 50 patients with refractory DME who were divided into 10 treatment groups. It has a dose-escalation design and evaluated five doses (range, 44 to 352 μg) administered as an intravitreal injection and five doses (range, 220 to 1,760 μg) delivered via a subconjunctival route.

Evaluations of ETDRS visual acuity and foveal thickness as measured by optical coherence tomography show promising signals of efficacy. Notably, in patients treated with the two lowest doses administered via the subconjunctival route, ETDRS visual acuity improved by an average of about eight letters from baseline to day 90. By day 180, a further gain in vision was seen among patients treated with the lowest dose, and only a slight reduction in vision was seen in the next higher dosage group. The functional benefit was accompanied by parallel reductions in foveal thickness.

"As our understanding of the pathogenesis of DME, age-related macular degeneration, and retinal vein occlusion is increasing, we have come to recognize that inflammation likely plays an important, early role in addition to various metabolic and vascular factors. This information provides a basis for optimism about the potential of a drug such as sirolimus that addresses the early inflammatory pathways as well as the later, angiogenic manifestations," said Dr. Blumenkranz, professor and chairman of ophthalmology, Stanford University School of Medicine, Stanford, CA.

"We are also excited about the possibility of using it in combination therapy with current anti-vascular endothelial growth factor (VEGF) agents that have highly potent antiangiogenic effects," he added.

Results of preclinical models suggested that sirolimus was highly effective in preventing both hypoxia-induced retinopathy of prematurity and laser-induced choroidal neovascularization. In addition, it was shown to be a potent inhibitor of VEGF-induced hyperpermeability.

Pharmacokinetics studies in rabbit eyes demonstrated that a single injection of sirolimus given either into the vitreous or as a periocular subconjunctival injection provided sustained drug delivery. In animals treated with doses in the range of those being evaluated in the phase I trial, therapeutic levels were maintained in the retina and choroidal tissue for 90 to 180 days.

"We were pleasantly surprised to find such durability and particularly that therapeutic levels could be achieved and sustained in the posterior ocular tissues after a single subconjunctival injection. . . .Until now, [this route] has not been found to be a viable option for providing therapeutic drug levels to the retina and choroid," Dr. Blumenkranz said.

An open-label, dose-ranging, phase I study in patients with age-related macular degeneration is ongoing, and a phase II DME trial is expected to be under way soon.