Martin Patrick, Cohen Alisa, Uddin Sharif, Epelbaum Laura, Josiah Serene
Shire, A Takeda Company, Lexington, MA, USA.
Clin Ophthalmol. 2020 Mar 20;14:885-896. doi: 10.2147/OPTH.S242932. eCollection 2020.
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.
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.
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.
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.
TAK-639是一种局部用的、含九个氨基酸的合成C型利钠肽类似物，正处于1期开发阶段，用于治疗高眼压症（OHT）和原发性开角型青光眼（POAG）。据推测，TAK-639通过一种增加小梁网房水流出的新型作用机制（MOA）来降低眼压（IOP）。我们研究了TAK-639在高眼压症或原发性开角型青光眼患者中的安全性和耐受性。
这是一项1期、多中心、随机、双盲、安慰剂对照、单剂量和多剂量递增研究。高眼压症或原发性开角型青光眼患者（年龄18 - 90岁）以5:2的比例随机分为TAK-639组或安慰剂组。计划了三个剂量水平（0.1%、0.3%、0.6%的TAK-639），每个剂量水平有四种给药方案（每日一次、每日两次、每日三次、每日四次）。安全措施包括治疗中出现的不良事件（TEAE）和眼科检查。还评估了药代动力学和药效学（眼压降低情况）。
总共63名受试者被随机分组，接受了0.1%、0.3%和0.6%的TAK-639，给药方式为单剂量、每日一次、每日两次，以及0.1%和0.3%每日三次。在研究0.6%每日三次或每日四次给药队列之前，该研究终止；取而代之的是，在一个新队列中重复进行了0.6%每日两次的给药。TEAE与滴眼有关，强度为轻度至中度。没有导致提前停药的TEAE，也没有严重的TEAE。最常见的与治疗相关的TEAE是滴眼部位疼痛和荧光素染色导致的短暂角膜染色。对于所有其他安全措施，包括滴眼液舒适度、最佳矫正视力、裂隙灯生物显微镜检查和角膜上皮完整性，各剂量组均无临床显著问题。几乎未观察到全身暴露。在测试的最高剂量（0.6%）和给药方案（每日两次）的一个队列中，眼压有轻微降低，这表明通过该机制靶向小梁网具有生物学合理性。
TAK-639在高达0.6%每日两次的剂量下总体耐受性良好。进一步的非临床研究将有助于更好地理解其作用机制以及TAK-639在前房的渗透情况。
