sirolimus and Macular-Edema

To evaluate the safety and tolerability of a single subconjunctival (SCJ) or intravitreal (IVT) injection of an ophthalmic sirolimus formulation in eyes with diabetic macular edema (DME).. Randomized, open-label, dose-escalating phase I study.. Fifty eyes among 50 patients with DME, retinal thickness ≥ 300 microns and best-corrected visual acuity (BCVA) 20/40 to 20/200.. A single dose of sirolimus administered SCJ (220, 440, 880, 1320, or 1760 μg) or IVT (44, 110, 176, 264, or 352 μg) on day 0; observation through day 90.. Primary end points were the frequency and severity of ocular and systemic adverse events. Secondary end points were changes in BCVA and retinal thickness.. No dose-limiting toxicities were observed and ocular adverse events were mostly mild and transient. Conjunctival hyperemia, hemorrhage, and edema were common after the SCJ injection procedure and conjunctival hemorrhage was common after the IVT injection procedure. Three patients experienced ocular adverse events considered possibly related to study drug: Conjunctival edema and reduced visual acuity were reported in 1 SCJ patient each and iritis was reported in 1 IVT patient. No serious ocular adverse events were reported. No nonocular adverse events were considered related to study drug. Systemic exposure to sirolimus was low, with blood concentrations below levels necessary for systemic immunosuppression. For the SCJ group (n = 25), a median increase in BCVA started at day 7 (5.0 letters) and was 3.0, 4.0, and 4.0 letters at days 14, 45 and 90, respectively. At day 45, median decrease in retinal thickness was -23.7 μm. For the IVT group (n = 25), the median increase in BCVA was 2.0 letters at day 7; at days 14, 45, and 90, the median increase was maintained (4.0 letters); the median decrease in retinal thickness was -52.0 μm at day 45.. Locally administered sirolimus was well-tolerated with minimal systemic exposure at all doses tested in this small phase I population. These findings support advancing the present sirolimus formulation into phase II studies.. Proprietary or commercial disclosure may be found after the references.

Topics: Conjunctiva; Diabetic Retinopathy; Female; Humans; Immunosuppressive Agents; Intravitreal Injections; Macular Edema; Male; Middle Aged; Ophthalmic Solutions; Prospective Studies; Sirolimus; Tomography, Optical Coherence; Treatment Outcome; Visual Acuity

Diabetic macular edema (DME) is a leading cause of blindness in the developed world. Sirolimus has been shown to inhibit the production, signaling, and activity of many growth factors relevant to the development of diabetic retinopathy. This phase I/II study assesses the safety of multiple subconjunctival sirolimus injections for the treatment of DME, with some limited efficacy data.. In this phase I/II prospective, open-label pilot study, five adult participants with diabetic macular edema involving the center of the fovea and best-corrected ETDRS visual acuity score of ≤74 letters (20/32 or worse) received 20 μl (440 μg) of subconjunctival sirolimus at baseline, month 2 and every 2 months thereafter, unless there was resolution of either retinal thickening on OCT or leakage on fluorescein angiography. Main outcome measures included best-corrected visual acuity and central retinal thickness on OCT at 6 months and 1 year, as well as safety outcomes.. Repeated subconjunctival sirolimus injections were well-tolerated, with no significant drug-related adverse events. There was no consistent treatment effect related to sirolimus; one participant experienced a 2-line improvement in visual acuity and 2 log unit decrease in retinal thickness at 6 months and 1 year, two remained essentially stable, one had stable visual acuity but improvement of central retinal thickness of 1 and 3 log units at 6 months and 1 year respectively, and one had a 2-line worsening of visual acuity and a 1 log unit increase in retinal thickness at 6 months and 1 year. Results in the fellow eyes with diabetic macular edema, not treated with sirolimus, were similar.. Subconjunctival sirolimus appears safe to use in patients with DME. Assessment of possible treatment benefit will require a randomized trial.

Topics: Aged; Blood Glucose; Conjunctiva; Diabetic Retinopathy; Female; Fluorescein Angiography; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Injections, Intraocular; Macular Edema; Male; Middle Aged; Pilot Projects; Prospective Studies; Sirolimus; Tomography, Optical Coherence; Visual Acuity

Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) represent the most common causes of vision loss in patients affected by diabetes mellitus. Diabetic retinopathy (DR) needs special attention because of its high public health impact and impact on quality of life of patients. Actually, laser retinal photocoagulation is the standard of care for the treatment of DR. However, laser treatment reduces the risk of moderate visual loss by approximately 50%, without a remarkable vision recovery. Thus, new approaches in the treatment of DR have been taken into account and, more specifically, the therapy employing antivascular endothelial growth factor (anti-VEGF) drugs could play a meaningful role. VEGF is a pluripotent growth factor that functions as an endothelial cell-specific mitogen and vasopermeability factor. Through these mechanisms VEGF plays a critical role in promoting angiogenesis and vascular leakage. A high level of VEGF has been detected in eyes presenting DME and PDR, and thereby VEGF is an attractive candidate as therapeutic target of pharmacological treatment in the management of DR. In the current chapter, the concepts and results of anti-VEGF therapy in the treatment of the DME and PDR are presented.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Bevacizumab; Diabetic Retinopathy; Humans; Macular Edema; Ranibizumab; RNA, Small Interfering; Sirolimus; Vascular Endothelial Growth Factor A