Novel Therapeutic for Duchenne Muscular Dystrophy (DMD)

描述(由申请人提供)：大量文献表明，肝细胞生长因子(HGF)通过有效和直接的抗纤维化活性保护许多器官免受纤维化驱动的病理影响。此外，HGF还可以促进肌肉前体细胞的增殖，以促进肌肉在受伤或重大工作负荷时的再生能力。在杜氏肌营养不良的情况下，Refanalyin可能会重现HGF的两种活性，并促进更有效的修复和预防纤维化。我们评估了Refanalyin在几种组织纤维化模型中的作用，包括肺和肝纤维化，以及在缺血性中风、肝、肾、肺和心肌缺血-再灌注损伤的临床前模型中，包括肝、肾和肺移植模型。使用瑞法林治疗与降低死亡率、改善器官功能和保护组织结构有关。这些疗效数据(这里列出了一些)，再加上出色的安全性和理想的药效性，使Refanalyin成为DMD评估的理想候选药物。我们处于一个独特的位置，在肌营养不良症的治疗中，我们处于一个独特的位置，测试我们的第一个小分子HGF模拟物，在那里治疗的“黄金标准”仍然只有皮质类固醇，它具有剂量限制的潜在严重副作用。瑞法林已在人类身上使用；第一阶段剂量--递增安全性和PK研究已经在健康志愿者中完成，目前正在IIa阶段PK中进行评估，这是一项针对透析患者的安全性研究，目的是在2009年第一季度之前进入更大规模的IIb阶段肾脏患者疗效研究。与公共健康相关：我们的先导分子Refanalyin已经在肾脏患者中进行了临床试验，它是一种小分子-HGF模拟物。实验室的广泛研究表明，Refanalyin在许多疾病环境中将发挥强大的抗纤维化作用。这些结果与Refanalyin将模拟HGF并促进卫星细胞激活的可能性--改善肌肉再生的潜力--相结合，使Refanalyin成为一种有吸引力的可能治疗儿童严重衰弱疾病--Duchenne肌营养不良症的药物。

DESCRIPTION (provided by applicant): A significant body of literature indicates that Hepatocyte Growth Factor (HGF) via potent and direct anti-fibrotic activity protects many organs from the fibrosis-driven pathology. In addition, HGF has been shown to also promote muscle progenitor cells to proliferate to promote the regenerative capacity of the muscle in response to injury or significant work load. Potentially Refanalin could recapitulate both activities of HGF and promote more efficient repair and prevent fibrosis in the setting of Duchenne Muscular Dystrophy. We have evaluated Refanalin in several models of tissue fibrosis including, lung and liver fibrosis, and in preclinical models of ischemic stroke, hepatic, renal, pulmonary and myocardial ischemia-reperfusion injury including models of liver, kidney and lung transplantation. Treatment with Refanalin was associated with reduced mortality, improved organ function and preservation of tissue architecture. These efficacy data (some presented here) coupled with an excellent safety profile and ideal drugability, makes Refanalin an ideal candidate for evaluation in DMD. We are in a unique position, to test our first in class, small molecule HGF mimetic, in the setting of muscular dystrophy where the "gold standard" of treatment remains only the corticosteroids, which have dose- limiting potentially severe side effects. Refanalin, has been dosed in man; phase I dose-escalation safety and pK studies having been completed in healthy volunteers, and it currently being evaluated in a phase IIa pK, safety study in dialysis patients with the intent to enter larger scale phase IIb efficacy studies in kidney patients by first quarter 2009. PUBLIC HEALTH RELEVANCE: Our lead molecule, Refanalin, which has advanced to clinical trial in kidney patients, is a small molecule-HGF mimetic. Extensive studies in the laboratory have shown that Refanalin will exert potent anti-fibrotic effects in many disease settings. These results in conjunction with the possibility that Refanalin will mimic HGF and promote satellite cell activation- potential improving on muscle regeneration, makes Refanalin an attractive possible therapy for the severely debilitating disease of young boys, Duchenne Muscular Dystrophy.