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W. R. Freeman, P. Leese, J. Khan, M. Martin, R. Danis, J. Shorr; A Topical (Eye Drop) Multi-kinase Inhibitor for Treatment of Choroidal Neovascularization in Age-Related Macular Degeneration: Rationale and Results of Early Clinical Trials. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3771.
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TG100801 is a novel prodrug of TG100572, an inhibitor of a targeted set of kinases involved in ocular leak and angiogenesis, including the validated receptor tyrosine kinase (RTK) target VEGFR and the non-RTK kinase Src. Preclinical ocular models of leak and angiogenesis after topical administration in rodents have demonstrated the efficacy of the compound, and transcleral transport of efficacious levels of the drug to the posterior compartment has been confirmed by whole body autoradiography of 14C-TG100801 and LC/MS/MS studies. Studies conducted to evaluate the use of TG100801 as a topical (eye drop) anti-edema, anti-angiogenic kinase inhibitor for the treatment of choroidal neovascularization in age-related macular degeneration are described.
The initial safety and tolerability of TG100801, administered twice a day, were evaluated in a randomized, double-masked, parallel-group, dose-escalation study in healthy volunteers treated with vehicle or 0.6% or 1.1% TG100801 for 1 day in one eye and artificial tears in the fellow eye, or artificial tears OU (n=6/group), or with 0.6% or 1.1% TG100801 for 14 consecutive days in one eye (n=6/group) and vehicle in the fellow eye (n=6/group) or vehicle OU (n=8). Tolerability was assessed via symptom-directed questionnaire.
No evidence of toxicity by slit lamp, tonometry, visual acuity or other measurements were noted. Mild, transient (generally ≤ 20 minutes) ocular irritation was reported for 50% of subjects treated with TG100801 for 14 days. Plasma levels of both TG100801 and TG100572 were below detectable limits.
TG100801 is de-esterified into TG100572, a small molecule, highly potent multi-kinase inhibitor that reaches therapeutic levels in the choroidal tissue in the posterior pole. A Phase 1 study shows no toxicity in humans following twice a day administration for up to 14 days. A Phase 2a study in patients with AMD and CNV is underway. OCT evidence of decreased retinal edema and sub-retinal fluid at 4 weeks is the primary outcome.
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