Long-acting Growth Hormone for Treating HIV-Associated Adipose Redistribution Syn

描述(申请人提供)：HIV相关脂肪再分配综合征(HARS)是一种脂肪营养不良症，是接受高效抗逆转录病毒治疗的艾滋病毒患者的常见问题，是抗病毒药物治疗的副作用。HARS的特点是内脏脂肪组织增加、血脂异常和胰岛素不敏感，所有这些都被认为增加了患者发生心血管疾病的风险。重组生长激素在治疗HARS方面是有效的，通过内脏脂肪组织的减少和血脂水平的改善来衡量。2006年，重组生长激素产品在全球的销售额为24亿美元，主要来自治疗儿童和成人生长激素缺乏症的药物的销售。GH的循环半衰期很短，必须每天给患者注射。我们创造了一种高效、长效的生长激素类似物BBT-031，与生长激素相比，它在生长激素缺乏的动物模型中具有显著延长的循环半衰期和优越的疗效。基于动物研究，我们预计我们的长效生长激素类似物在人类每周给药一次或较少频繁给药时将有效。这种新型生长激素类似物的体内特性得到改善，将减少频繁注射的需要，提高患者的生活质量，并有可能导致治疗HARS的更有效的疗法。我们的长效生长激素类似物有可能通过减少患者所需的药量、减少与患者到治疗中心就诊相关的成本以及通过减少医护人员与提供治疗相关的时间来显著降低医疗成本。这项SBIR建议的总体目标是开发这种长效生长激素类似物，用于治疗HARS以及艾滋病毒和艾滋病毒疗法的其他代谢并发症，如消瘦(恶病质)。在SBIR赠款的第一阶段，我们开发了GLP(良好实验室实践)制造流程和辅助分析方法，为GLP药理学和毒理学研究生产材料。我们进行了大鼠单次注射和重复注射GLP的毒理学研究和GLP在大鼠体内的药代动力学研究。当剂量超过人体预期剂量的30倍时，没有发现毒性反应，该蛋白质的药代动力学曲线表明，它将作为每周一次的治疗在人类身上有效。我们还表明，在生长激素缺乏的大鼠中，这种蛋白质比生长激素更有效地刺激体重增加和骨生长，特别是在使用频率较低的给药方案时。在第一阶段，我们还设计了人类第一阶段安全性和第二阶段剂量范围疗效研究的临床方案。第二阶段SBIR提案的主要目标是在第二个物种中完成动物毒理学和药理学研究，这是FDA在人体上测试该产品之前所要求的。我们还将继续优化蛋白质的制造工艺和分析测试，并进行实验，以确定用于人体的蛋白质的稳定液体配方。我们长效生长激素类似物的成功开发将为HARS患者提供更方便、更有效的治疗方法。该产品还具有治疗HIV相关的消瘦(恶病质)的潜力，GH已获得FDA的批准。尽管由于更有效的抗病毒疗法的广泛使用，在美国没有那么严重的问题，但在不发达国家，艾滋病毒相关的消瘦仍然是一个主要问题，因为那里的患者无法很好地获得艾滋病毒药物。公共卫生相关性HIV相关脂肪再分布综合征(HARS)是高效抗逆转录病毒疗法(HAART)的副作用，被认为在美国困扰着大约80,000名HIV患者。HARS的特征是内脏脂肪组织的积聚和血脂谱的改变。重组生长激素(GH)被广泛用于治疗儿童和成人的生长激素缺乏，已被证明通过减少内脏脂肪组织和改善血脂状况而使患有HARS的HIV患者受益。目前生长激素治疗的一个局限性是，由于生长激素在人体内的半衰期很短，它们必须每天给患者注射。我们创造了一种更有效、更有效的生长激素类似物BBT-031，它可能会为HARS患者提供更有效的治疗，减少每个患者所需的GH量，提高患者的安全性、依从性和生活质量，并为患者和医疗保健提供者节省大量成本。在第一阶段拨款期间，我们开发了BBT-031的GLP(良好实验室实践)制造工艺，开发了用于测量产品纯度和效力的分析分析方法，并在啮齿动物身上进行了短期(最长28天)GLP动物毒理学、药代动力学和疗效研究。当剂量超过人体预期剂量的30倍时，没有发现任何毒性。这一第二阶段赠款计划的目标是通过(1)按照FDA的要求在第二个动物物种上进行毒理学和药代动力学研究，然后再在人体上测试该化合物；(2)在两个动物物种上进行长期毒理学研究；(3)继续优化蛋白质的制造工艺和分析分析；以及(4)确定用于人类的蛋白质的稳定液体配方。

DESCRIPTION (provided by applicant): HIV-associated adipose redistribution syndrome (HARS), a form of lipodystrophy, is a common problem in HIV patients on highly active antiretroviral therapy and occurs as a side-effect of their anti-viral drug therapies. HARS is characterized by an increase in visceral adipose tissue, dyslipidemia, and insulin insensitivity, all of which are believed to increase the patient's risk for developing cardiovascular disease. Recombinant GH is effective at treating HARS, as measured by reductions in visceral adipose tissue and improvement in lipid profiles. Recombinant GH products had worldwide sales of $2.4 billion in 2006, primarily from sales of the drug to treat GH deficiency in children and adults. GH has a short circulating half-life and must be administered to patients by daily injection. We created a highly potent, long-acting GH analog, BBT-031 that has a significantly increased circulating half-life and superior efficacy in animal models of growth hormone deficiency compared to GH. Based upon animal studies we anticipate that our long- acting GH analog will be effective when administered once per week or less frequently in humans. The improved in vivo characteristics of this novel GH analog will reduce the need for frequent injections, improve patient quality of life and potentially lead to a more effective therapy for the treatment of HARS. Our long-acting GH analog has the potential to significantly reduce healthcare costs by reducing the amount of drug required by patients, by reducing costs associated with patient visits to treatment centers and by reducing healthcare worker time associated with providing treatments. The overall goal of this SBIR proposal is to develop this long-acting GH analog for the treatment of HARS and other metabolic complications of HIV and HIV therapies such as wasting (cachexia). During Phase I of the SBIR grant, we developed a GLP (Good Laboratory Practices) manufacturing process and supporting assay methods to produce material for GLP pharmacology and toxicology studies. We performed single injection and repeat injection GLP toxicology studies in rats and a GLP pharmacokinetic study in rats. No toxicities were noted at doses up to 30 times the expected dose to be used in humans, and the pharmacokinetic profile of the protein suggested it will be effective as a once weekly therapy in humans. We also showed that the protein was more potent than GH at stimulating weight gain and bone growth in growth hormone deficient rats, particularly when using a less frequent dosing regimen. During Phase I we also designed clinical protocols for Phase 1 safety and Phase 2 dose ranging efficacy studies in humans. The main goal of the Phase II SBIR proposal is to complete animal toxicology and pharmacology studies in a second species, which is required by the FDA prior to testing this product in humans. We also will continue to optimize the manufacturing process and analytical assays for the protein and perform experiments to identify a stable liquid formulation for the protein for use in humans. Successful development of our long-acting GH analog will provide HARS patients with a more convenient and potentially more effective treatment for their disease. This product also has potential for treating HIV-associated wasting (cachexia), for which GH has received approval by the FDA. Although not as significant a problem in U.S. due to wider use of more effective antiviral therapies, HIV-associated wasting still is a major problem in undeveloped countries where patients do not have as good access to HIV medications. PUBLIC HEALTH RELEVANCE HIV-associated adipose redistribution syndrome (HARS) occurs as a side-effect of highly active antiretroviral therapy (HAART) and is believed to afflict approximately 80,000 HIV patients in the U.S. HARS is characterized by an accumulation of visceral adipose tissue and alterations in lipid profiles. Recombinant growth hormone (GH), which is widely used to treat growth hormone deficiency in children and adults, has been shown to benefit HIV patients with HARS by reducing visceral adipose tissue and improving lipid profiles. A limitation of current GH therapies is the fact that they must be administered to patients by daily injection due to the short half-life of GH in people. We created a longer acting and more potent GH analog, BBT-031, which may potentially provide HARS patients with a more effective therapy, reduce the amount of GH required per patient, improve patient safety, compliance and quality of life, and result in considerable cost savings to patients and healthcare providers. During the Phase I grant we developed a GLP (Good Laboratory Practices) manufacturing process for BBT-031, developed analytical assays for measuring product purity and potency, and performed short term (up to 28 days) GLP animal toxicology, pharmacokinetic and efficacy studies in rodents. No toxicities were noted at doses up to 30 times the expected dose to be used in humans. The goals of this Phase II grant proposal are to build upon these positive results by (1) performing toxicology and pharmacokinetic studies in a second animal species, which is required by the FDA prior to testing the compound in humans; (2) perform longer term toxicology studies in two animal species; (3) continue to optimize the manufacturing process and analytical assays for the protein; and (4) identify a stable liquid formulation for the protein for use in humans.