Sun Yang, Wirta David, Murahashi Wendy, Mathur Vidhu, Sankaranarayanan Sethu, Taylor Lori K, Yednock Ted, Fong Donald S, Goldberg Jeffrey L
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, California.
Eye Research Foundation, Newport Beach, California.
Ophthalmol Sci. 2023 Feb 24;3(2):100290. doi: 10.1016/j.xops.2023.100290. eCollection 2023 Jun.
Complement C1q, the initiating molecule of the classical complement cascade, is involved in synapse elimination and neuronal loss in neurodegenerative diseases including glaucoma. Here we report an evaluation of the safety, tolerability, and ocular pharmacokinetics (PK) and pharmacodynamics of intravitreal (IVT) injections of ANX007, an anti-C1q monoclonal antibody fragment that blocks activation of the classical complement cascade.
An open-label, single-dose-escalation phase Ia study followed by a double-masked, randomized, sham-controlled, repeat-injection phase Ib study.
A total of 26 patients with primary open-angle glaucoma.
Nine patients with primary open-angle glaucoma (mean Humphrey visual field deviation between -3 and -18 decibels [dB]) were enrolled in phase Ia and received single doses of ANX007 (1.0 mg, n = 3; 2.5 mg, n = 3; or 5.0 mg, n = 3). Seventeen patients (mean Humphrey visual field deviation between -3 and -24 dB) were enrolled in phase Ib and randomized to 2 monthly doses of ANX007 (sham, n = 6; 2.5 mg ANX007, n = 6; or 5 mg ANX007, n = 5).
Safety and tolerability (including laboratory evaluation of urinalysis, complete blood count, and serum chemistries), ANX007 PK, target engagement, and immunogenicity.
The mean age overall was 70 years in phase Ia and 68 years in phase Ib. In both studies, no serious adverse events were observed, no non-ocular treatment-emergent adverse events (TEAEs) attributable to study drug were reported, and ocular TEAEs were mild. Intraocular pressure returned to normal levels for all patients within 45 minutes of IVT injection. No clinically significant deviations in laboratory results were observed. In the phase Ib study, C1q in the aqueous humor was reduced to undetectable levels in both the 2.5 mg and 5 mg cohorts 4 weeks after the first ANX007 dose.
In these studies, single and repeat IVT ANX007 injections were well tolerated and demonstrated full target engagement 4 weeks after dosing with both low and high doses, supporting monthly or less-frequent dosing. Further investigation in neurodegenerative ocular diseases is warranted.
Proprietary or commercial disclosure may be found after the references.
补体C1q是经典补体级联反应的起始分子，参与包括青光眼在内的神经退行性疾病中的突触消除和神经元丢失。在此，我们报告了玻璃体内（IVT）注射ANX007的安全性、耐受性、眼部药代动力学（PK）和药效学评估，ANX007是一种抗C1q单克隆抗体片段，可阻断经典补体级联反应的激活。
一项开放标签、单剂量递增的Ia期研究，随后是一项双盲、随机、假对照、重复注射的Ib期研究。
总共26例原发性开角型青光眼患者。
9例原发性开角型青光眼患者（平均汉弗莱视野偏差在-3至-18分贝[dB]之间）入选Ia期，接受单剂量的ANX007（1.0mg，n = 3；2.5mg，n = 3；或5.0mg，n = 3）。17例患者（平均汉弗莱视野偏差在-3至-24dB之间）入选Ib期，并随机分为每月2剂ANX007（假注射，n = 6；2.5mg ANX007，n = 6；或5mg ANX007，n = 5）。
安全性和耐受性（包括尿液分析、全血细胞计数和血清化学的实验室评估）、ANX007的PK、靶点结合和免疫原性。
Ia期患者的总体平均年龄为70岁，Ib期为68岁。在两项研究中，均未观察到严重不良事件，未报告任何归因于研究药物的非眼部治疗出现的不良事件（TEAE），且眼部TEAE均为轻度。IVT注射后45分钟内，所有患者的眼压均恢复到正常水平。实验室结果未观察到临床显著偏差。在Ib期研究中，首次注射ANX007后4周，2.5mg和5mg剂量组房水中的C1q均降至无法检测的水平。
在这些研究中，单次和重复IVT注射ANX007耐受性良好，且在低剂量和高剂量给药后4周均显示完全的靶点结合，支持每月或更低频率的给药。有必要对神经退行性眼病进行进一步研究。
专有或商业披露可在参考文献之后找到。
