Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma

Patrick Martin, Alisa Cohen, Sharif Uddin, Laura Epelbaum, Serene Josiah Shire, A Takeda Company, Lexington, MA, USACorrespondence: Patrick Martin Email ptmartin@alum.mit.eduPurpose: TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the tr...

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Autores principales:	Martin P, Cohen A, Uddin S, Epelbaum L, Josiah S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	glaucoma intraocular pressure ocular hypertension shp-639 tak-639 Ophthalmology RE1-994
Acceso en línea:	https://doaj.org/article/2c2d43da11da46e8add0e5975df32bb4
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spelling	oai:doaj.org-article:2c2d43da11da46e8add0e5975df32bb42021-12-02T06:42:01ZRandomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma1177-5483https://doaj.org/article/2c2d43da11da46e8add0e5975df32bb42020-03-01T00:00:00Zhttps://www.dovepress.com/randomized-double-masked-placebo-controlled-dose-escalation-study-of-t-peer-reviewed-article-OPTHhttps://doaj.org/toc/1177-5483Patrick Martin, Alisa Cohen, Sharif Uddin, Laura Epelbaum, Serene Josiah Shire, A Takeda Company, Lexington, MA, USACorrespondence: Patrick Martin Email ptmartin@alum.mit.eduPurpose: TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG.Methods: This was a phase 1, multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose escalation study. Subjects (aged 18– 90 years) with OHT or POAG were randomized 5:2 to TAK-639 or placebo. Three dose levels were planned (0.1%, 0.3%, 0.6% TAK-639), each with four dosing regimens (QD, BID, TID, QID). Safety measures included treatment-emergent adverse events (TEAEs) and ophthalmologic examinations. Pharmacokinetics and pharmacodynamics (reduction of IOP) were also evaluated.Results: In total, 63 subjects were randomized and received 0.1%, 0.3% and 0.6% TAK-639, as single dose, QD, or BID, and 0.1% and 0.3% TID. The study was terminated before 0.6% TID or QID dosing cohorts were studied; instead, 0.6% BID was repeated in a new cohort. TEAEs were instillation related and of mild-to-moderate intensity. There were no TEAEs leading to premature discontinuation, and no serious TEAEs. The most common treatment-related TEAEs were instillation site pain and transient corneal staining with fluorescein. There were no clinically significant concerns across dose groups for all other safety measures, including drop comfort, best corrected visual acuity, slit-lamp biomicroscopy, and corneal epithelial integrity. Little or no systemic exposure was observed. There was a marginal reduction in IOP in one cohort at the highest dose (0.6%) and regimen (BID) tested, suggesting biological plausibility of targeting the trabecular meshwork through this mechanism.Conclusion: TAK-639 was generally well tolerated up to 0.6% BID. Further non-clinical studies will improve understanding of the MOA and the penetration of TAK-639 to the anterior chamber.Keywords: glaucoma, intraocular pressure, ocular hypertension, SHP-639, TAK-639Martin PCohen AUddin SEpelbaum LJosiah SDove Medical Pressarticleglaucomaintraocular pressureocular hypertensionshp-639tak-639OphthalmologyRE1-994ENClinical Ophthalmology, Vol Volume 14, Pp 885-896 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	glaucoma intraocular pressure ocular hypertension shp-639 tak-639 Ophthalmology RE1-994
spellingShingle	glaucoma intraocular pressure ocular hypertension shp-639 tak-639 Ophthalmology RE1-994 Martin P Cohen A Uddin S Epelbaum L Josiah S Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma
description	Patrick Martin, Alisa Cohen, Sharif Uddin, Laura Epelbaum, Serene Josiah Shire, A Takeda Company, Lexington, MA, USACorrespondence: Patrick Martin Email ptmartin@alum.mit.eduPurpose: TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG.Methods: This was a phase 1, multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose escalation study. Subjects (aged 18– 90 years) with OHT or POAG were randomized 5:2 to TAK-639 or placebo. Three dose levels were planned (0.1%, 0.3%, 0.6% TAK-639), each with four dosing regimens (QD, BID, TID, QID). Safety measures included treatment-emergent adverse events (TEAEs) and ophthalmologic examinations. Pharmacokinetics and pharmacodynamics (reduction of IOP) were also evaluated.Results: In total, 63 subjects were randomized and received 0.1%, 0.3% and 0.6% TAK-639, as single dose, QD, or BID, and 0.1% and 0.3% TID. The study was terminated before 0.6% TID or QID dosing cohorts were studied; instead, 0.6% BID was repeated in a new cohort. TEAEs were instillation related and of mild-to-moderate intensity. There were no TEAEs leading to premature discontinuation, and no serious TEAEs. The most common treatment-related TEAEs were instillation site pain and transient corneal staining with fluorescein. There were no clinically significant concerns across dose groups for all other safety measures, including drop comfort, best corrected visual acuity, slit-lamp biomicroscopy, and corneal epithelial integrity. Little or no systemic exposure was observed. There was a marginal reduction in IOP in one cohort at the highest dose (0.6%) and regimen (BID) tested, suggesting biological plausibility of targeting the trabecular meshwork through this mechanism.Conclusion: TAK-639 was generally well tolerated up to 0.6% BID. Further non-clinical studies will improve understanding of the MOA and the penetration of TAK-639 to the anterior chamber.Keywords: glaucoma, intraocular pressure, ocular hypertension, SHP-639, TAK-639
format	article
author	Martin P Cohen A Uddin S Epelbaum L Josiah S
author_facet	Martin P Cohen A Uddin S Epelbaum L Josiah S
author_sort	Martin P
title	Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma
title_short	Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma
title_full	Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma
title_fullStr	Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma
title_full_unstemmed	Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma
title_sort	randomized, double-masked, placebo-controlled dose escalation study of tak-639 topical ophthalmic solution in subjects with ocular hypertension or primary open-angle glaucoma
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/2c2d43da11da46e8add0e5975df32bb4
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Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma

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