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Tomas Navratil, Andres Garcia, Rozemarijn S Verhoeven, Leo Trevino, Brian C Gilger, Steven L Mansberger, Donald L Budenz, Iqbal Ike K. Ahmed, Richard A. Lewis, Benjamin R Yerxa; Advancing ENV515 (travoprost) Intracameral Implant into Clinical Development: Nonclinical Evaluation of ENV515 in Support of First-Time-in-Human Phase 2a Clinical Study. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5706.
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© ARVO (1962-2015); The Authors (2016-present)
ENV515 (travoprost) Intracameral Implant is a biodegradable polymer drug delivery system for glaucoma using an extended release formulation of travoprost. Previously, ENV515 demonstrated 6 months of IOP lowering effect in ongoing nonclinical studies. To advance ENV515 into first-time in human studies, we evaluated key pharmacodynamic, pharmacokinetic, and safety/tolerability attributes of ENV515 in non-GLP and GLP toxicology studies based on ENV515 material fabricated in an aseptic manufacturing process. ENV515 is being developed with the aim to address the shortcomings of the topical glaucoma therapies.
Normotensive Beagle dogs were used to evaluate 1) efficacy and the full duration of action of ENV515 for a period of 12 months in non-GLP pharmacology studies; 2) safety and tolerability in GLP toxicology studies for 28-days and for 6 months; and 3) 28 day and 6-month PK in aqueous humor and other ocular tissues. ENV515 implants used in the GLP studies were manufactured in an aseptic manufacturing process developed utilizing PRINT microparticle engineering technology.
The treatment effect was maintained over 8 months with 35±3% or 6.4 ± 0.6 mmHg average decrease in IOP from a baseline of 18.6 ± 0.2 mmHg (mean ± SEM, p < 0.001, n=6 eyes). The IOP reverted to baseline by 9 months after a single dose of ENV515. The Beagle dog aqueous humor concentration of travoprost, based on ENV515 dose showing robust and sustained IOP-lowering effect, was significantly lower than historical aqueous humor concentration of travoprost in human subjects dosed with topical TRAVATAN Z. The ENV515 implants for GLP studies, manufactured in PRINT-based aseptic process, tested with dose content uniformity meeting USP <905> requirements for a US-based commercial product (103.6% of label claim, 2.7% RSD). The completed 28-day GLP toxicology study identified the highest dose of 6 ENV515 implants/eye as the no adverse effect level.
ENV515 demonstrated robust and sustained IOP-lowering effect for 8 months following a single dose via intracameral injection, with excellent safety and tolerability in GLP toxicology studies in Beagle dogs. The ENV515 implants tested in GLP toxicology studies were manufactured in an aseptic manufacturing process developed to support a planned Phase 2a clinical study of ENV515 in glaucoma patients.
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