A Topical Host Defense Peptide Mimetic for Oral Mucositis

用于治疗口腔粘膜炎的局部宿主防御肽模拟物

• 批准号: 8393799
• 负责人: RICHARD W SCOTT
• 金额: $ 16.14万
• 依托单位: POLYMEDIX, INC,
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393799
• 关键词: Absence of pain sensation; Accounting; Adverse effects; Affect; American; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacterial Infections; Biological; Caring; Cell Culture System; Cells; Clinical; Clinical Trials; Complex; Cost Savings; Cyclodextrins; Deglutition; Development; Diet; Dose; Dose-Limiting; Drug Formulations; Drug or chemical Tissue Distribution; Epithelium; Excipients; Freezing; Functional disorder; Future; Gastrostomy; Goals; Hamsters; Head and Neck Cancer; Hematologic Neoplasms; Host Defense; Human; Hydration status; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Interruption; Intervention; Investigation; Lead; Liquid substance; Mediating; Modeling; Mouth Neoplasms; Mucositis; Narcotics; Opioid; Oral; Oropharyngeal; Oxidative Stress; Pain; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmacologic Substance; Phase; Pilot Projects; Play; Populations at Risk; Prevalence; Prevention; Property; Proteins; Quality of life; Radiation; Regimen; Role; Safety; Severities; Solubility; Staging; Stem cell transplant; Sterility; Submucosa; Testing; Therapeutic; Time; Topical application; Total Parenteral Nutrition; Toxic effect; Toxicity due to chemotherapy; Treatment Protocols; antimicrobial; base; cancer radiation therapy; cancer therapy; cell type; chemotherapy; conditioning; cost; daily functioning; design; economic outcome; effective therapy; feeding; health economics; improved; in vivo; insight; keratinocyte growth factor; mimetics; novel; oral mucositis; palliative; patient population; phase 1 study; pre-clinical; response; secondary infection

DESCRIPTION (provided by applicant): Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of chemotherapy and radiation therapy for cancer, and represents an important unmet clinical need with 450,000 Americans suffering from mucositis each year. It impacts virtually all patients receiving concomitant chemoradiation therapy for tumors of the mouth and oropharynx. Aside from its devastating symptomatic impact, resulting in opiod-requiring pain and the need for gastrostomy feeding, mucositis is a major driver of adverse health and economic outcomes. The pathogenesis of mucositis is much more complex than previously hypothesized, involving more than a dozen mechanistic canonical pathways mediated by cells within the submucosa, as well as the epithelium. Furthermore, evidence suggests that the oral microflora does not play a primary role in the genesis of mucositis, although secondary infection might influence its course. Despite the prevalence of mucositis in cancer therapy, there is currently only one approved pharmaceutical for the treatment of oral mucositis: palifermin (keratinocyte growth factor-1) and its application is limited to mucositis associated with conditioning regimens for stem cell transplant for the treatment of hematologic malignancies; an indication that accounts for only 4% of the at risk population. Therefore, the care for mucositis i largely palliative and there is an urgent need for new, effective therapies for the broader patient population. Host defense proteins (HDPs) are cationic and amphiphilic components of the mammalian innate immune system that serve as a primary response in the prevention of bacterial infection. We are developing non- peptidic mimics of HDPs, capturing the structural and biological properties of HDPs within the framework of smaller inexpensive oligomers. These small synthetic oligomers are less expensive to produce, have better tissue distribution than HDPs, and are easier to fine-tune structurally to improve activity and minimize toxicity. Exclusive of their antimicrobial activity, HDPs have been shown to possess immune modulatory and anti- inflammatory activities. Recently, we observed that several of the PMX mimics demonstrate activity in attenuating anti-inflammatory pathways and reasoned that these activities could be leveraged into a mucositis intervention. Our hypothesis was borne out by the results of animal studies in which the severity and course of radiation-induced mucosal injury were dramatically altered after topical administration of three PMX mimics, including our lead compound PMX30063. The promising activity and observed tolerability of PMX30063, supports a dedicated effort for further preclinical profiling directed towards future clinical development. Accordingly, the overall goals of this Phase 1 proposal are to continue the preclinical development of PMX30063 for an oral mucositis indication by investigating its mechanism of action with a particular focus on anti-inflammatory and immune modulatory activities, optimizing its formulation as an oral rinse and helping to define dosing regimens for human clinical trials. PUBLIC HEALTH RELEVANCE: Oral mucositis is among the most significant, dose-limiting side effects of intensive cancer treatment and is associated with adverse clinical and economic outcomes. It can cause difficulty with speaking, swallowing, and alimentation and radically impair daily functioning and quality of life and may necessitate opioid analgesia, a liquid diet, I hydration and/or total parenteral nutrition and interruption of cancer therapy. Standard management options for mucositis are essentially palliative. We propose to develop a novel topical anti-mucositis therapeutic to ameliorate this pernicious side effect of cancer therapy.

描述（由申请人提供）：口腔溃疡性粘膜炎是癌症化疗和放疗的常见、疼痛、剂量限制性毒性，并且代表了每年有45万美国人患有粘膜炎的重要未满足的临床需求。它几乎影响了所有接受口腔和口咽部肿瘤同步放化疗的患者。除了其破坏性的症状影响，导致需要阿片类药物的疼痛和需要胃造口术喂养外，粘膜炎是不利健康和经济后果的主要驱动因素。粘膜炎的发病机制比以前假设的要复杂得多，涉及由粘膜下层以及上皮细胞介导的十几种机械经典途径。此外，有证据表明，口腔微生物菌群并没有发挥主要作用的粘膜炎的发生，虽然继发感染可能会影响其过程。尽管粘膜炎在癌症治疗中普遍存在，但目前仅有一种获批用于治疗口腔粘膜炎的药物：帕利佛明（角质形成细胞生长因子-1），其应用仅限于与用于治疗恶性血液病的干细胞移植的预处理方案相关的粘膜炎;该适应症仅占风险人群的4%。因此，粘膜炎的治疗在很大程度上是姑息性的，迫切需要新的、有效的治疗方法来治疗更广泛的患者。 人口 宿主防御蛋白（HDPs）是哺乳动物先天免疫系统的阳离子和两亲性组分，其在预防细菌感染中起主要反应。我们正在开发HDP的非肽模拟物，在较小的廉价低聚物的框架内捕获HDP的结构和生物学特性。这些小的合成低聚物生产成本较低，比HDPs具有更好的组织分布，并且更容易在结构上进行微调以提高活性并使毒性最小化。独家 在抗微生物活性方面，HDPs具有免疫调节和抗炎活性。最近，我们观察到几种PMX模拟物在减弱抗炎途径中表现出活性，并推断这些活性可用于粘膜炎干预。我们的假设得到了动物研究结果的证实，其中局部施用三种PMX模拟物（包括我们的先导化合物PMX 30063）后，辐射诱导的粘膜损伤的严重程度和过程发生了显着变化。PMX 30063的有希望的活性和观察到的耐受性支持了针对未来临床开发的进一步临床前分析的专门努力。因此，委员会认为， 该1期提案的总体目标是通过研究PMX 30063的作用机制（特别关注抗炎和免疫调节活性）、优化其作为口腔冲洗剂的制剂并帮助确定用于人类临床试验的给药方案，继续PMX 30063用于口腔粘膜炎适应症的临床前开发。 公共卫生关系：口腔粘膜炎是强化癌症治疗中最显著的剂量限制性副作用之一，并与不良临床和经济结果相关。它可能导致说话、吞咽和营养困难，并从根本上损害日常功能和生活质量，可能需要阿片类镇痛、流质饮食、补液和/或全肠外营养和中断癌症治疗。粘膜炎的标准治疗选择基本上是姑息性的。我们建议开发一种新的局部抗粘膜炎治疗，以改善这种恶性副作用的癌症治疗。