Xanthine oxidase inhibitor for congestive heart failure

简介(申请人提供)：充血性心力衰竭(CHF)是一种 针对基础病因的治疗学的市场机会 脑室损伤。尽管CHF的发病机制复杂，但近年来 数据表明，炎症基础继发于自由基的产生 嘌呤降解酶黄嘌呤氧化酶(XO)。在久负盛名的步态中 狗的模型，它产生了扩张型心肌病和许多经典的 CHF的特点是，XO活性增加了4倍，而XO抑制作用较弱 别嘌醇增加dp/dt(Max)，预负荷-可招募的卒中功，以及 脑室弹性。在心力衰竭犬身上使用别嘌醇，而不是对照组 降低MVO2，大幅提高机械效率。已被占用 综上所述，这些数据表明XO抑制是独特的变力作用， 增加心肌收缩能力的同时降低心脏 能源需求。由此导致的心肌收缩效率的提高 可能对临床充血性心力衰竭的治疗有益。中国的市场 别嘌醇受到其罕见但严重的副作用的限制。我们现在报道 发现了一种非嘌呤类的XO抑制剂，其作用是1000倍以上 比别嘌醇更有效。初步数据证实，这个的原型 CLASS可显著降低实验性急性肺损伤模型的炎症 损伤和小肠结肠炎。这项第一阶段赠款提案的中心目标是 就是在活体内证明领先候选人 剂量依赖性改善犬心力衰竭经典模型的收缩功能 由慢性起搏引起的。然后我们将定义其药效学特征 XO疗法，开始于心力衰竭建立后。心脏的收缩能力将 使用左心室压力-容量分析、dp/dt、每搏量、 和射血分数。经典的弱XO抑制剂别嘌醇将是 包括在所有研究中作为参考标准。我们希望我们的领先地位 非嘌呤超强XO抑制剂将剂量依赖性地改善dp/dt， 比别嘌醇大2倍以上的ED5O。 拟议的商业应用：仅在美国，每年的销售额预计为5亿美元，这是基于普通人群(=250万潜在受试者)1%的CHF发病率、10%的市场渗透率和每个患者每年2000美元的支出估计的。全球市场(仅限发达国家)要大四倍。考虑到10%的患者对别嘌醇的接受程度，以及目前缺乏二线药物，我们预计一种安全有效的替代XO抑制剂将在五年内迅速获得市场接受。我们认为，高价(每天6美元)是有充分理由的，因为没有别嘌醇的替代品。预计进入市场和成熟后(FDA批准后约4年)的全球总销售收入预计将达到每年10-20亿美元。

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) is a major market opportunity for therapeutics that targets the fundamental etiology of the ventricular injury. Although the pathogenesis of CHF is complex, recent data suggest an inflammatory basis secondary to free radical generation by the purine degradative enzyme xanthine oxidase (XO). In the well-established pacing dog model, which produces a dilated cardiomyopathy and many of the classic features of CHF, XO activity is 4-fold increased and the weak XO inhibitor allopurinol increases dP/dt(max), preload-recruitable stroke work, and ventricular elastance. In heart failure dogs, but not controls, allopurinol decreases MVO2 and substantially increases mechanical efficiency. Taken together, these data indicate that XO inhibition is uniquely inotropic, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of clinical CHF. The market for allopurinol is limited by its infrequent but severe side-effects. We now report the discovery of a non-purine class of XO inhibitors that is 1,000-fold more potent than allopurinol. Preliminary data confirm that a prototype of this class profoundly reduces inflammation in experimental models of acute lung injury and enterocolitis. The central objective of this Phase I grant proposal is to establish in vivo proof of principle that the lead candidate dose-dependently improves contractile function in the classic dog model of CHF induced by chronic pacing. We will then define the pharmacodynamic profile of XO therapy, begun after the establishment of CHF. Cardiac contractility will be assessed using left ventricular pressure-volume analysis, dP/dT, stroke volume, and ejection fraction. The classic weak XO inhibitor allopurinol will be included in all studies as a reference standard. We expect that our lead non-purine ultrapotent XO inhibitor will dose-dependently improve dP/dT, with an ED5O greater than 2-fold greater than allopurinol. PROPOSED COMMERCIAL APPLICATION: Sale of $500 million per annum are anticipated in the US alone, based upon an estimate of a 1% incidence of CHF in the general population (=2.5 million potential subjects), a 10% market penetration, and an annual expenditure per patient of $2,000. The worldwide market (developed countries only) is four times larger. Given the intoleerance for allopurinol in 10% of patients, and the current absence of a second-line medication, we expect the market acceptance of a safe and effective alternative XO inhibitor to be achieved rapidly over a five year period. We believe the high price point ($6 per day) is amply justified by the lack of an alternative to allopurinol. Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) are expected to equal $1-2 billion per annum.