Manufacturing pathogen inactivated platelet lysate to treat corneal inflammation

 描述（由申请人提供）：眼部移植物抗宿主病（O-GVHD）是异基因造血干细胞移植（HSCT）的一种特别严重和使人衰弱的并发症。O-GVHD在60-90%的慢性GVHD患者中发展。目前，Restasis（环孢素A，0.05%）是FDA批准的唯一治疗O-GVHD的处方外用药物。2012年，Restasis治疗干眼症的销售额不到10亿美元;然而，Restasis的治疗效果仅为~ 15%，并且其使用与17%的不良事件率相关。缺乏强大的临床有效性表明需要替代疗法。许多Restasis治疗失败的HSCT患者发现，使用配制成局部滴眼液的自体血清（自体血清泪液，AST）可以缓解症状。不幸的是，AST制剂（通常在医生办公室或药房制备）缺乏标准化，以及其储存和管理的挑战限制了该产品的广泛采用。为了解决AST的缺点，我们开发了一种专有方法来生产一种有前途的替代品：使用合格献血者的合并血小板收集物（phPL）制备标准化血小板裂解物（Elate-OcularTM; Ocular-phPL）。我们相信Elate-OcularTM在治疗O-GVHD和其他形式的干眼症患者方面上级Restasis或AST，因为Elate-OcularTM富含（与血清相比）许多促进角膜愈合的生长因子，具有强大的抗炎作用，可以减少GVHD患者的眼部炎症，并具有抑菌特性。这份STTR第一阶段申请由Cambium Medical Technologies LLC提交，Cambium Medical Technologies LLC是一家初创公司，由埃默里大学医学院的4名教师创立，他们开发了Ocular-phPL。埃默里大学将是本申请的分包研究机构。埃默里大学已经提交了一项专利申请，以保护我们专有的phPL制造工艺，Cambium拥有这项专利和技术的专有权。研究者之前已收到FDA CBER关于phPL其他应用的两份IND（IND 14825-NCT 01659762和IND 16191-NCT 02359929），我们现在正在寻求提交Elate-Ocular TM治疗IND，并在O-GVHD HSCT患者中开展I/II期临床研究。为了支持这些临床研究，我们在本申请中建议首先通过以下方式进一步改善和验证Elate-OcularTM的安全性和有效性：（i）证明在Elate-OcularTM生产过程中应用病原体灭活（PI）工艺的可行性;（ii）对Elate-OcularTM进行体外工作（+/- PI治疗）比较产品成分和作用机制;和（iii）在具有预先存在的炎症状况或泪液产生不足的动物中使用Elate-OcularTM（+/- PI治疗）进行动物毒理学/功效研究。成功完成这些目标将使我们能够完成FDA IND申请并启动I/II期研究（为此我们将寻求II期STTR支持），以证明Elate-Ocular TM在患有O-GVHD发病率的患者中是安全的且耐受良好，这是未来商业化的必要步骤。

 DESCRIPTION (provided by applicant): Ocular graft-versus-host disease (O-GVHD) is a particularly severe and debilitating complication of allogeneic hematopoietic stem cell transplantation (HSCT). O-GVHD develops in 60-90% of patients with chronic GVHD. Currently, Restasis (cyclosporine A, 0.05%) is the only FDA approved prescription topical medication to treat O-GVHD. In 2012, Restasis had sales of just under $1 billion for the treatment dry eye; however, the therapeutic efficacy of Restasis is only ~15%, and its use is associated with a 17% rate of adverse events. This lack of robust clinical effectiveness demonstrates that alternative therapies are needed. Many HSCT patients who fail Restasis therapy have found relief from using autologous serum formulated into topical eye drops (autologous serum tears, AST). Unfortunately, the lack of standardization of AST preparations (which are often prepared in doctor's offices or pharmacies), and challenges with its storage and administration, have limited widespread adoption of this product. In order to address the drawbacks of AST, we have developed a proprietary method to manufacture a promising alternative: a standardized platelet lysate preparation using pooled platelet collections (phPL) from qualified blood donors (Elate-OcularTM; Ocular-phPL). We believe Elate- OcularTM will be superior to Restasis or AST for treatment of patients with O-GVHD and other forms of dry eye since Elate-OcularTM is enriched (compared to serum) for a number of growth factors that promote corneal healing, has robust anti-inflammatory actions that can reduce ocular inflammation in patients with GVHD, and possesses bacteriostatic properties. This STTR Phase I application is submitted by Cambium Medical Technologies LLC, a start-up company founded by 4 faculty members from Emory University School of Medicine who developed Ocular-phPL. Emory will be the sub-contracting research organization for this application. Emory University has filed a patent application to protect our proprietary manufacturing process for phPL, and Cambium has exclusive rights to this patent and technology. The investigators have previously received two INDs from FDA CBER for other applications of phPL (IND14825-NCT01659762 and IND16191- NCT02359929), and we are now seeking to submit a treatment IND for Elate-OcularTM and conduct a Phase I/II clinical study in HSCT patients with O-GVHD. In order to support these clinical studies, we propose in this application to first further improve and validate the safety and efficacy profiles f Elate-OcularTM by: (i) demonstrating feasibility of applying a pathogen inactivation (PI) process during production of Elate- OcularTM; (ii) performing in vitro work on Elate-OcularTM (+/- PI treatment) to compare product compositions and mechanisms of action; and (iii) performing animal toxicology/efficacy studies with Elate-OcularTM (+/- PI treatment) in animals with a pre-existing inflammatory condition or deficient tear production. Successful completion of these aims will allow us to complete our FDA IND application and initiate the Phase I/II study (for which we will seek Phase II STTR support) in order to demonstrate that Elate- OcularTM is safe and well-tolerated in patients suffering O-GVHD morbidity, a required step toward future commercialization.