NCX 470 Reduces Intraocular Pressure More Effectively Than Lumigan in Dogs and Enhances Conventional and Uveoscleral Outflow in Non-Human Primates and Human Trabecular Meshwork/Schlemm's Canal Constructs.

IF 1.9 4区医学 Q2 OPHTHALMOLOGY

Journal of Ocular Pharmacology and Therapeutics Pub Date : 2024-07-01 Epub Date: 2023-12-12 DOI:10.1089/jop.2023.0102

Corinna Galli, Elena Bastia, Douglas A Hubatsch, Carol Toris, Shan Fan, Andrea Unser, Feryan Ahmed, Karen Y Torrejon, Francesco Impagnatiello

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引用次数: 0

Abstract

Purpose: To determine NCX 470 (0.1%) and Lumigan^® (bimatoprost ophthalmic solution, 0.01%-LUM) intraocular pressure (IOP)-lowering activity after single or repeated (5 days) dosing along with changes in aqueous humor (AH) dynamics. Methods: Ocular hypotensive activity of NCX 470 and LUM was compared with vehicle (VEH) in Beagle dogs using TonoVet^®. Non-human primates (NHP) and bioengineered three-dimensional (3D) human Trabecular Meshwork/Schlemm's Canal (HTM/HSC™) constructs exposed to transforming growth factor-β2 (TGFβ2) were used to monitor NCX 470 and LUM-induced changes in AH dynamics. Results: NCX 470 (30 μL/eye) showed greater IOP reduction compared with LUM (30 μL/eye) following single AM dosing [maximum change from baseline (CFB_max) = -1.39 ± 0.52, -6.33 ± 0.73, and -3.89 ± 0.66 mmHg (mean ± standard error of the mean) for VEH, NCX 470, and LUM, respectively]. Likewise, repeated 5 days daily dosing of NCX 470 resulted in lower IOP than LUM across the duration of the study (average IOP decrease across tests was -0.45 ± 0.22, -6.06 ± 0.15, and -3.60 ± 0.22 mmHg for VEH, NCX 470, and LUM, respectively). NCX 470 increased outflow facility (Cfl) in vivo in NHP (Cfl_VEH = 0.37 ± 0.09 μL/min/mmHg and Cfl_NCX470 = 0.64 ± 0.17 μL/min/mmHg) as well as in vitro (C_HTM/HSC) in HTM/HSC constructs (C_HTM/HSC__VEH = 0.47 ± 0.02 μL/min/mm²/mmHg and C_HTM/HSC__NCX470 = 0.76 ± 0.03 μL/min/mm²/mmHg). In addition, NCX 470 increased uveoscleral outflow (Fu_VEH = 0.62 ± 0.26 μL/min and Fu_NCX470 = 1.53 ± 0.39 μL/min with episcleral venous pressure of 15 mmHg) leaving unaltered aqueous flow (AHF_VEH = 2.03 ± 0.22 μL/min and AHF_NCX470 = 1.93 ± 0.31 μL/min) in NHP. Conclusions: NCX 470 elicits greater IOP reduction than LUM following single or repeated dosing. Data in NHP and 3D-HTM/HSC constructs suggest that changes in Cfl and Fu account for the robust IOP-lowering effect of NCX 470.

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NCX 470 比 Lumigan 更有效地降低狗的眼内压，并增强非人灵长类和人类小梁网/施莱姆管构建体的常规眼压和葡萄膜巩膜外流。

目的：测定 NCX 470（0.1%）和 Lumigan®（比马前列素眼药水，0.01%-LUM）单次或重复（5 天）用药后降低眼压（IOP）的活性以及房水（AH）动力学的变化。方法：使用 TonoVet® 在比格犬中比较 NCX 470 和 LUM 与药物（VEH）的降眼压活性。用暴露于转化生长因子-β2（TGFβ2）的非人灵长类（NHP）和生物工程三维（3D）人小梁网/施莱姆氏管（HTM/HSC™）构建体来监测 NCX 470 和 LUM 诱导的 AH 动态变化。结果与 LUM（30 μL/眼）相比，NCX 470（30 μL/眼）在单次上午给药后可降低更多的眼压[VEH、NCX 470 和 LUM 从基线的最大变化（CFBmax）分别为-1.39 ± 0.52、-6.33 ± 0.73 和 -3.89 ± 0.66 mmHg（平均值 ± 平均值标准误差）]。同样，在整个研究期间，每天重复服用 5 天 NCX 470 可使眼压低于 LUM（VEH、NCX 470 和 LUM 各次测试的平均眼压降幅分别为 -0.45 ± 0.22、-6.06 ± 0.15 和 -3.60 ± 0.22 mmHg）。NCX 470 增加了 NHP 体内的流出设施（Cfl）（CflVEH = 0.37 ± 0.09 μL/min/mmHg 和 CflNCX470 = 0.64 ± 0.17 μL/min/mmHg）以及体外（CHTM/HSC）HTM/HSC 构建（CHTM/HSC_VEH = 0.47 ± 0.02 μL/min/mm2/mmHg，CHTM/HSC_NCX470 = 0.76 ± 0.03 μL/min/mm2/mmHg）。此外，NCX 470 增加了葡萄膜巩膜外流（FuVEH = 0.62 ± 0.26 μL/min，FuNCX470 = 1.53 ± 0.39 μL/min，巩膜外静脉压为 15 mmHg），而 NHP 的水流（AHFVEH = 2.03 ± 0.22 μL/min，AHFNCX470 = 1.93 ± 0.31 μL/min）没有变化。结论与 LUM 相比，NCX 470 单次或多次给药可显著降低眼压。NHP和3D-HTM/造血干细胞构建体中的数据表明，Cfl和Fu的变化是NCX 470强效降低眼压的原因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Ocular Pharmacology and Therapeutics 医学-眼科学

CiteScore

4.60

自引率

4.30%

发文量

审稿时长

1 months

期刊介绍： Journal of Ocular Pharmacology and Therapeutics is the only peer-reviewed journal that combines the fields of ophthalmology and pharmacology to enable optimal treatment and prevention of ocular diseases and disorders. The Journal delivers the latest discoveries in the pharmacokinetics and pharmacodynamics of therapeutics for the treatment of ophthalmic disorders. Journal of Ocular Pharmacology and Therapeutics coverage includes: Glaucoma Cataracts Retinal degeneration Ocular infection, trauma, and toxicology Ocular drug delivery and biotransformation Ocular pharmacotherapy/clinical trials Ocular inflammatory and immune disorders Gene and cell-based therapies Ocular metabolic disorders Ocular ischemia and blood flow Proliferative disorders of the eye Eyes on Drug Discovery - written by Gary D. Novack, PhD, featuring the latest updates on drug and device pipeline developments as well as policy/regulatory changes by the FDA.