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Charles P. Semba, Gail Torkildsen, John Lonsdale, Eugene McLaurin, Joel Geffin, Thomas Mundorf, Kathryn Kennedy, George Ousler; A Phase 2 Multicenter, Double-masked, Placebo-controlled Study Of A Novel Lymphocyte Function-associated Antigen-1 (LFA-1) Antagonist (SAR 1118) For Treatment Of Dry Eye. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3823.
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To investigate the efficacy and safety of SAR 1118 ophthalmic solution in subjects with dry eye (keratoconjunctivitis sicca). SAR 1118 is an investigational small molecule antagonist that blocks binding of LFA-1 (CD11a/CD18; αLβ2) to its cognate ligand ICAM-1 (CD54) to inhibit T-cell mediated inflammation.
A multicenter, randomized, double-masked, placebo-controlled Phase 2 study was conducted in 230 dry eye subjects (M 51: F 179; mean age 62.3 yrs) selected with the Controlled Adverse Environmental (CAE) Model. Principle eligibility criteria included exacerbation in corneal staining and ocular symptoms with CAE exposure, no active meibomian gland disease/blepharitis, and Schirmer tear test (STT; mm) > 1 and < 10. After a 2-week open-label placebo wash-out, eligible subjects were randomized 1:1:1:1 to SAR 1118 (0.1, 1.0, 5.0%) or placebo (vehicle) eyedrops administered BID for 12 wks. Ocular signs and symptoms (Ocular Surface Disease Index, OSDI) were assessed at 2, 6, and 12 wks. No supplemental artificial tears were allowed during the course of treatment. Primary outcome variable was inferior corneal staining (ICS; environmental).
The study demonstrated clinically relevant dose-responses for SAR 1118 in ICS at Week 12 (p=0.0566, repeat measures). Mean change from baseline to Week 12 analysis showed significant improvement (p<0.05) in ICS, total corneal staining, OSDI visual-related functions (ability to read, drive at night, use computer, watch television), and total OSDI score (visual-related functions, triggers, symptoms). STT showed improved tear production at 2 weeks (p<0.05) with a consistent dose-response through Week 12 (p=0.09) for SAR 1118 subjects vs. placebo. Adverse events (AEs) were mild and transient in nature with no serious or severe ocular AEs. There was no evidence of local ocular infections in SAR 1118 subjects. SAR 1118 5.0% showed increased instillation site AEs relative to placebo but events were limited to the initial dose of drug.
SAR 1118 ophthalmic solution demonstrated improvements (p<0.05; 1.0, 5.0%) in signs (corneal staining) and symptoms (OSDI visual-related functions) compared to placebo and appears safe and well-tolerated when administered BID over 12 weeks. Confirmatory Phase 3 studies are planned.
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