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Daniel M. Paskowitz, Charles P. Semba, Valerie L. Smith, Tom Gadek, Ovais Shaikh, Quan D. Nguyen, Diana V. Do, Wilmer SAR Study Group; A Phase 1 Clinical Trial of the Safety and Pharmacokinetics of SAR 1118, a Novel Topical LFA-1 Antagonist for Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2011;52(14):570.
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No topical medical therapy for diabetic macular edema (DME) has yet gained acceptance. Preclinical studies suggest that inflammation mediated by intercellular adhesion molecule-1 (ICAM-1) plays an important role in the pathogenesis of DME. This Phase 1 clinical trial assessed the safety, tolerability, and pharmacokinetics of topical SAR 1118, a novel non-steroidal anti-inflammatory small molecule that blocks binding of lymphocyte function-associated antigen-1 (LFA-1) to its ligand ICAM-1. SAR 1118 inhibits leukocyte-dependent aspects of inflammation and has potential therapeutic benefit for DME. Preclinical studies of topical SAR 1118 have demonstrated its penetration into the vitreous and retina, inhibition of leukocyte adhesion to retinal vessels, and decreased vascular leakage in diabetic rats.
This study was a randomized, prospective, single-masked clinical trial. Adult volunteers without DME, scheduled for vitrectomy for reasons unrelated to the study, were randomized to one of three doses (0.1%, 1.0%, 5.0%) of topical SAR 1118 in the surgical eye twice daily for one week prior to surgery. Undiluted aqueous and vitreous samples were collected at surgery. The primary outcome measure was the incidence of ocular and non-ocular adverse events. The secondary outcome measure was the concentration of SAR 1118 (sensitivity of detection, 0.50 ng/mL) in aqueous and vitreous.
Thirteen (13) patients completed the study. No patient discontinued the medication. The only adverse events noted (at the highest dose) were transient stinging on administration of the medication (4/13 patients) and a metallic taste (3/13 patients). SAR 1118 accumulated in aqueous humor in a dose-dependent fashion. SAR 1118 could not be detected in the vitreous except in one patient with a history of prior vitrectomy and pseudophakia with a dislocated IOL. Although a total of thirty patients had been planned, the study was discontinued because of the negative pharmacokinetic results.
Topical SAR 1118 was safe and well tolerated. While it was not possible to assess drug levels in the retina directly, it did not reach pharmacologically relevant levels in vitreous humor with the doses tested in this study. Further development of SAR1118 for treatment of DME may require intravitreal or trans-scleral delivery or chemical modification to improve topical bioavailability. Inhibition of LFA-1/ICAM-1 remains an appropriate target for drug discovery intended to benefit patients with DME.
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