Kocab Andrew J, Cano Marisol, Bacellar-Galdino Marianna, Jamison Jeffrey A, Brock William J, Zacks David N, Handa James T
ONL Therapeutics, Inc., Ann Arbor, MI 48104, USA.
Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA.
Biomedicines. 2025 Aug 22;13(9):2052. doi: 10.3390/biomedicines13092052.
: Age-related macular degeneration (AMD) is a major cause of irreversible vision loss in the developed world, and the approved products for geographic atrophy (GA), a late-stage form of dry AMD, have shown limited efficacy and require frequent administration. Therefore, longer-lasting therapies with improved efficacy would be a welcome addition to AMD treatment. One potential therapeutic is ONL1204, a small peptide inhibitor of the Fas receptor that has prevented cell death and inflammation in retinal disease models. This study characterizes the pharmacokinetics (PK) and durability of protection conferred by ONL1204. : Ocular pharmacokinetic profiles were generated over 3 months in rabbit and minipig following a single intravitreal (IVT) injection of ONL1204 at multiple doses. Ocular pharmacodynamics were evaluated in two models: a rabbit model using a single IVT injection of ONL1204 with a delayed sodium iodate challenge coupled with fluorescein angiography to quantify RPE loss, and a chronic mouse model that reflects key features of dry AMD disease pathology to assess the efficacy of repeat IVT administrations of ONL1204. : ONL1204 had prolonged residence in the ocular tissues of rabbit and minipig, with a vitreous humor half-life of over 100 days. ONL1204 demonstrated significant protection of the retinal pigment epithelium (RPE) in the rabbit sodium iodate model. In the chronic mouse model, two administrations of ONL1204 preserved RPE morphology, reduced caspase-8 activity, and decreased inflammation. : These data represent key characteristics of ONL1204, highlighting its clinical potential as a therapeutic for chronic retinal diseases, including GA.
年龄相关性黄斑变性（AMD）是发达国家不可逆视力丧失的主要原因，而针对干性AMD晚期形式地理萎缩（GA）的获批产品疗效有限且需要频繁给药。因此，疗效更佳且作用持久的疗法将是AMD治疗领域的一大福音。一种潜在的治疗药物是ONL1204，它是一种Fas受体小肽抑制剂，已在视网膜疾病模型中预防了细胞死亡和炎症。本研究对ONL1204的药代动力学（PK）和所提供保护的持久性进行了表征。在兔和小型猪中，单次玻璃体内（IVT）注射多剂量的ONL1204后，在3个月内生成了眼部药代动力学概况。在两种模型中评估了眼部药效学：一种兔模型，单次IVT注射ONL1204后进行延迟的碘酸钠激发，并结合荧光素血管造影术以量化视网膜色素上皮（RPE）损失；另一种慢性小鼠模型，反映干性AMD疾病病理的关键特征，以评估重复IVT给药ONL1204的疗效。ONL1204在兔和小型猪的眼组织中停留时间延长，玻璃体液半衰期超过100天。在兔碘酸钠模型中，ONL1204对视网膜色素上皮（RPE）表现出显著的保护作用。在慢性小鼠模型中，两次给药的ONL1204保留了RPE形态，降低了半胱天冬酶-8活性，并减轻了炎症。这些数据代表了ONL1204的关键特征，突出了其作为包括GA在内的慢性视网膜疾病治疗药物的临床潜力。
