Novel Small Molecule Anti-Inflammatory Eye Drops for Ocular Graft Versus Host Disease

摘要 眼移植物抗宿主病(OGVHD)是一种严重的眼表炎症性疾病， 在接受异基因造血干细胞移植(HSCT)的患者中。OGVHD的特点是 干眼症、汗腺功能障碍、结膜疤痕、眼睑边缘疤痕、角膜病变和角膜病变。 溃烂，对受影响的患者造成严重的眼部疾病和视力丧失。目前，没有 OGVHD的有效疾病修正疗法。这项SBIR第二阶段拨款申请的目的是 开发治疗OGVHD和潜在的其他OSID的新的有效疗法。海流 脉冲星生命科学的提案重点是开发钙/钙调蛋白依赖的蛋白激酶 激酶2(CAMKK2)-眼科疾病的靶向治疗。我们的初步研究和一个阶段的结果 眼科生物科学公司(母公司)的1项研究表明，小鼠OGVHD与 结膜浸润的T细胞和M-Ф，这两种细胞类型的CAMKK2已被证明是一种 炎性细胞功能的调节剂；外用工具化合物SMIC，STO-609，显著 体内小鼠OGVHD严重程度降低；以及来自新型SMIC专利文库的许多化合物 由Eyedesis发明的在体外抑制CAMKK2的活性。这些发现支持这样一种假设，即 可以开发CAMKK2的抑制剂来治疗OGVHD。Eyedesis已成功完成第一阶段目标 证明许多新的SMIC在体外对CAMKK2有很强的抑制作用，大多数新的SMICs表现良好 局部应用于眼部时耐受性良好，两种新型局部应用SMIC对 治疗小鼠OGVHD。在这一后续的第二阶段SBIR应用中，Pulsar将完成领先的优化和 我们提交IND申请所需的IND使能研究。目标1将最终确定销售线索优化并选择 主要候选人，AIM 2将执行技术转让，以合同GMP药品制造商和合同 GMP药物配方，建立CMC属性，并表征制剂稳定性，目标3将执行 支持IND的药理学和毒理学研究。最终交付成果将提交IND申请至 FDA使用这种外用滴眼液治疗OGVHD，并进行首次人类临床研究。

SUMMARY Ocular graft versus host disease (OGVHD) is a severe ocular surface inflammatory disease (OSID), occurring in patients undergoing allogenic hematopoietic stem cell transplantation (HSCT). OGVHD is characterized by dry eye, meibomian gland dysfunction, conjunctival scarring, lid margin scarring, keratopathy, and corneal ulceration, causing significant ocular morbidity and vision loss for affected patients. Presently, there are no effective disease-modifying therapies for OGVHD. The purpose of this SBIR Phase II grant application is to develop novel and effective therapies for the treatment of OGVHD and potentially other OSIDs. The current proposal from Pulsar Life Sciences is focused on developing calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-targeted therapies for ocular diseases. Our preliminary studies and the results from a Phase 1 STTR to Eyedesis Biosciences (parent company) demonstrate that murine OGVHD is associated with conjunctival infiltration by T cells and MФ, two cell types in which CaMKK2 has been previously shown to be a regulator of inflammatory cell function; topical application of the tool compound SMIC, STO-609, significantly reduced murine OGVHD severity in vivo; and many compounds from a proprietary library of novel SMICs invented by Eyedesis inhibited CaMKK2 activity in vitro. These findings support the hypothesis that novel inhibitors of CaMKK2 can be developed to treat OGVHD. Eyedesis has successfully completed Phase 1 aims to demonstrate that many novel SMICs were potent inhibitors of CaMKK2 in vitro, most novel SMICs were well tolerated when applied topically to the eye, and two novel SMICs administered topically were efficacious in treating murine OGVHD. In this follow-on Phase 2 SBIR application, Pulsar will complete lead optimization and IND-enabling studies required for our filing of an IND application. Aim 1 will finalize lead optimization and select the lead candidate, Aim 2 will perform the technical transfer to contract GMP drug manufacturer and contract GMP drug formulation, establish CMC properties, and characterize formulation stability, and Aim 3 will perform IND-enabling pharmacology and toxicology studies. The end deliverable will be to submit an IND application to the FDA and perform the first-in-human clinical studies with this topical eyedrop for OGVHD.