Recombinant human lactoferrin to treat oral mucositis

描述：口腔粘膜炎是一个主要的剂量限制性毒性作用的密集癌症化疗和放疗。除了严重的口腔粘膜炎直接引起的发病外，它还可以通过限制口服摄入引起继发性发病，甚至导致剂量减少或延迟进一步的癌症治疗。粘膜炎可由细胞毒性作用直接引起，也可由细胞抑制治疗后持续的中性粒细胞减少间接引起。粘膜屏障受损使患者在再生障碍性贫血期间易发生危及生命的脓毒性并发症。据报道，发热性中性粒细胞减少症中口腔病灶的患病率高达30%。 重组人乳铁蛋白（rhLF）已在临床前实验中显示出具有免疫调节、抗炎和抗感染特性的组合。乳铁蛋白已经显示出（i）在几种体外和动物模型中促进愈合;（ii）在动物模型和人中抑制由刺激剂诱导的肠渗透性增加;（iii）降低肠粘膜对细菌的渗透性;（iv）在动物模型中降低口腔细菌攻击后的死亡率;和（v）降低接受骨髓抑制性化疗的急性髓性白血病患者的血小板减少性发热的严重程度。这些特性使rhLF成为预防和治疗严重口腔粘膜炎并减少其全身感染并发症的有希望的候选物。 基于上述结果，我们提出了一个IIa期临床试验的患者在发展严重的口腔粘膜炎的风险。目标人群是正在接受积极化疗以治疗急性髓性白血病的患者，这种治疗已知会导致严重粘膜炎的高发病率。化疗结束后，患者将接受rhLF或安慰剂治疗，我们将评估rhLF降低口腔粘膜炎发病率、严重程度或持续时间的能力，以及其对血小板减少性发热发病率和严重程度的影响。 除了上述支持rhLF在口腔粘膜炎中的潜在疗效的结果外，该药物已被证明是安全的和耐受性良好的，已口服给药至210名患者，没有单一的药物相关的严重不良事件。我们请求的支持将使我们能够继续这种新药的临床开发，并使其更接近患者的使用。

DESCRIPTION: Oral mucositis is a major dose-limiting toxic effect of intensive cancer chemotherapy and radiotherapy. In addition to the morbidity directly caused by severe oral mucositis, it can cause secondary morbidities by limiting oral intake or even lead to dose reduction or delay in further cancer treatment. Mucositis can be caused directly by cytotoxic effects and indirectly by sustained neutropenia after cytostatic therapy. An impaired mucosal barrier predisposes patients to life-threatening septic complications during aplasia. The prevalence of an oral focus in febrile neutropenia has been reported in up to 30 percent of cases. Recombinant human lactoferrin (rhLF) has been shown in pre-clinical experiments to exhibit a combination of immunomodulatory, anti-inflammatory and anti-infective properties. Lactoferrin has been shown to (i) promote healing in several in-vitro and animal models; (ii) inhibit increases in gut permeability induced by irritant agents in animal models and in humans; (iii) decrease the permeability of the gut mucosa to bacteria; (iv) reduce mortality following oral bacterial challenge in animal models; and (v) decrease the severity of neutropenic fever in patients receiving myelosuppressive chemotherapy for acute myelogenous leukemia. These properties make rhLF a promising candidate to prevent and treat severe oral mucositis and to reduce its systemic infectious complications. Based on the above results, we propose a Phase IIa clinical trial in patients at risk of developing severe oral mucositis. The target population is patients undergoing aggressive chemotherapy for the treatment of acute myelogenous leukemia, a therapy known to cause a high incidence of severe mucositis. The patients will receive either rhLF or placebo following completion of the chemotherapy and we will evaluate the ability of rhLF to reduce the incidence, severity, or duration of the oral mucositis, and its effect on the incidence and severity of neutropenic fever. In addition to the results described above which support the potential efficacy of rhLF in oral mucositis, the drug has been shown to be safe and well tolerated, having been administered orally to 210 patients without a single drug-related serious adverse event. The support we are requesting will enable us to continue clinical development of this novel drug and bring it closer to use by patients.