Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle 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.