Carol A Rasmussen1, Paul L Kaufman1, Robert Ritch2, Reza Haque3, R Kim Brazzell3, Jason L Vittitow3. 1. Department of Ophthalmology, University of Wisconsin, Madison, Wisconsin. 2. Einhorn Clinical Research Center, New York Eye and Ear Infirmary at Mount Sinai School of Medicine, New York, New York. 3. Inspire Pharmaceuticals, Durham, North Carolina.
Abstract
PURPOSE: To evaluate the safety, tolerability, and intraocular pressure (IOP)-lowering effect of Latrunculin-B (Lat-B), a marine macrolide that disrupts the actin cytoskeleton, in patients with ocular hypertension (OHT) or early primary open-angle glaucoma (POAG). METHODS: In this Phase I, multicenter, double-masked, randomized, placebo-controlled, ascending-dose study, subjects with bilateral OHT or early POAG (>22 mm Hg) received one of four concentrations of INS115644 (Lat-B ophthalmic solutions, 0.005%, 0.01%, 0.02%, or 0.05%) in one eye over 3 days (5 single-dose instillations, separated by 12 hours). One eye was randomly assigned to active drug, the other to placebo. IOP was measured prior to treatment initiation (day 0) and on days 1 and 3. RESULTS: Baseline IOPs were 22.9 ± 2.4 mm Hg and 23.5 + 3.1 mm Hg in the 0.02% and 0.05% dose groups, respectively. At 4 hours post instillation of the first dose, 0.02% INS115644 reduced IOP from baseline (mean ± SE) by 3.8 ± 0.7 mm Hg (P = 0.002) and 0.05% by 3.9 ± 1.0 mm Hg (P = 0.004). A maximum IOP decrease of 24% was noted at 4 hours after the fifth instillation of 0.02%. Adjusting for diurnal baseline and IOP in the contralateral, placebo-treated eye, the maximal 12-hour hypotensive effect was 4.0 ± 0.5 mm Hg (adjusted mean ± SE), a 17% decrease, following the fifth instillation of 0.02% (day 3). Adverse events were few and consisted mainly of mild redness, irritation, and a transient, clinically insignificant increase (≤2.5%) in central corneal thickness. CONCLUSIONS: In OHT or POAG patients, twice daily Lat-B significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events. TRANSLATIONAL RELEVANCE: Lat-B may be a potential therapeutic agent for glaucoma.
PURPOSE: To evaluate the safety, tolerability, and intraocular pressure (IOP)-lowering effect of Latrunculin-B (Lat-B), a marine macrolide that disrupts the actin cytoskeleton, in patients with ocular hypertension (OHT) or early primary open-angle glaucoma (POAG). METHODS: In this Phase I, multicenter, double-masked, randomized, placebo-controlled, ascending-dose study, subjects with bilateral OHT or early POAG (>22 mm Hg) received one of four concentrations of INS115644 (Lat-B ophthalmic solutions, 0.005%, 0.01%, 0.02%, or 0.05%) in one eye over 3 days (5 single-dose instillations, separated by 12 hours). One eye was randomly assigned to active drug, the other to placebo. IOP was measured prior to treatment initiation (day 0) and on days 1 and 3. RESULTS: Baseline IOPs were 22.9 ± 2.4 mm Hg and 23.5 + 3.1 mm Hg in the 0.02% and 0.05% dose groups, respectively. At 4 hours post instillation of the first dose, 0.02% INS115644 reduced IOP from baseline (mean ± SE) by 3.8 ± 0.7 mm Hg (P = 0.002) and 0.05% by 3.9 ± 1.0 mm Hg (P = 0.004). A maximum IOP decrease of 24% was noted at 4 hours after the fifth instillation of 0.02%. Adjusting for diurnal baseline and IOP in the contralateral, placebo-treated eye, the maximal 12-hour hypotensive effect was 4.0 ± 0.5 mm Hg (adjusted mean ± SE), a 17% decrease, following the fifth instillation of 0.02% (day 3). Adverse events were few and consisted mainly of mild redness, irritation, and a transient, clinically insignificant increase (≤2.5%) in central corneal thickness. CONCLUSIONS: In OHT or POAG patients, twice daily Lat-B significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events. TRANSLATIONAL RELEVANCE: Lat-B may be a potential therapeutic agent for glaucoma.
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