A phase IIA trial for the safety and tolerability of CD24Fc in prophylaxis of graft vs host disease.

项目总结/摘要 急性移植物抗宿主病（aGVHD）是移植相关死亡的主要原因 (TRM)在接受无关供体造血干细胞移植的受者中， 尽管有标准的免疫抑制预防，但仍存在HSCT。因此，新的GVHD预防 成功地减弱aGVHD和相关并发症如感染的治疗迫切需要 needed.此外，异基因HSCT的一个重要功能是利用供体T细胞消除异基因造血干细胞， 白血病细胞，这被称为移植物抗白血病（GVL）。然而，目前的预防和治疗 GVHD基于一般免疫抑制，其导致高感染风险并引起显著的免疫排斥反应。 死亡率，同时通过减少GVL而促进白血病复发。这个研究项目的最终目标是 为了进一步临床开发用于预防性治疗aGVHD的新型候选药物， 接受异基因清髓性HSCT的白血病患者。在小鼠模型的临床前试验中， 候选者CD 24 Fc已显示出显著降低GVHD严重程度并改善存活率， 保留了GVL，是预防白血病患者GVHD的理想药物。关联的活动 与GHVD减少和GVL保存是强有力的支持，在体外数据，描述了 CD 24 Fc制剂的作用机制。CD 24 Fc已被证明在健康人中是安全的。 人类受试者的I期临床试验和目前的项目，IIa期临床试验，旨在提供 CD 24 Fc在人体中的首次毒性/安全性、药代动力学、药效学和生物活性数据 HSCT移植患者这些数据表明，我们已经达到了里程碑， 通常为第一阶段SBIR赠款设置，因此使我们有资格申请第二阶段直接SBIR。拟议 IIa期试验是一项随机双盲单次剂量递增试验，包括3个剂量队列，每组8人 患者（3：1治疗：安慰剂），计划共入组24例受试者。临床试验将有两个 不同阶段的具体目标：具体目标I将确定CD 24 Fc的安全性和耐受性 在单次递增剂量递增研究中，并定义推荐的II期剂量（或最大剂量） 耐受剂量）用于在大型IIb期扩展试验中预防GVHD;具体目标II将评估 CD 24 Fc在白血病和髓系发育不良综合征患者体内药代动力学和活性 接受HSCT。CD 24 Fc将用于接受标准治疗背景预防治疗的患者 包含钙调磷酸酶抑制剂和甲氨蝶呤以使患者安全性最大化。拟定研究 代表了一个重要的里程碑，不仅是开发新型免疫调节药物所必需的， 一个GVHD，但也为公司的商业化努力。

Project Summary/Abstract Acute graft-versus-host disease (aGVHD) is a principal contributor to transplant related mortality (TRM), and develops in approximately 60-80% of recipients receiving unrelated donor hematopoietic stem cell transplantation (HSCT) despite standard immunosuppressive prophylaxis. Thus, novel GVHD prophylaxis treatments which successfully attenuate aGVHD and related complications such as infection are urgently needed. In addition, an important function of allogeneic HSCT is to use donor T cells to eliminate allogeneic leukemia cells, this is called the graft-versus-leukemia (GVL). However, current prophylaxis and treatment of GVHD is based on general immunosuppression, which causes high risk of infection and cause significant mortality, while contributing to leukemia relapse by reducing GVL. The ultimate goal of this research project is to further the clinical development of a novel drug candidate for the prophylactic treatment of aGVHD in leukemia patients undergoing allogeneic myeloablative HSCT. In preclinical testing in murine models, the drug candidate, CD24Fc, has been shown to significantly reduce GVHD severity and improve in survival while preserving GVL, making it an ideal drug for prophylaxis of GVHD in leukemia patients. The activity associated with GHVD reduction and GVL preservation is strongly supported by in vitro data that describes the mechanism of action of the CD24Fc drug product. CD24Fc has been demonstrated to be safe in healthy human subjects in a Phase I clinical trial and the current project, a Phase IIa clinical trial, aims to provide the first toxicity/safety, pharmacokinetics, pharmacodynamics and biological activity data for CD24Fc in human HSCT transplantation patients. These data demonstrate that we have more than reached the milestones typically set for phase I SBIR grant, and thus qualify us for phase II direct SBIR application. The proposed Phase IIa trial is a randomized double blind single ascending dose trial comprised of 3 dosing cohorts of 8 patients (3:1 treatment:placebo), for a total planned enrollment of 24 subjects. The clinical trial will have two specific aims addressed by different phases: specific aim I will determine the safety and tolerability of CD24Fc in a single ascending dose-escalation study, and define the recommended Phase II dose (or Maximum Tolerated Dose) for prophylaxis of GVHD in a large Phase IIb expansion trial; and specific aim II will assess the pharmacokinetics and in-human activity of CD24Fc in leukemia and myeloid dysplasia syndrome patients receiving HSCT. CD24Fc will be administered to patients on a background of standard of care prophylaxis comprising a calcineurin inhibitor and methotrexate to maximize patient safety. The proposed study represents a major milestone necessary not only for the development of the novel immunomodulating drug for a GVHD, but also for commercialization effort of the company.