Long-Acting Parathyroid Hormone Analog for the Treatment of Hypoparathyroidism

长效甲状旁腺激素类似物用于治疗甲状旁腺功能减退症

• 批准号: 9354957
• 负责人: Na Yang
• 金额: $ 176.51万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354957
• 关键词: Animal Model; Blood; Calcium; Cataract; Chronic; Clinical Trials; Collaborations; Convulsions; Data; Development Plans; Dose; Drug Kinetics; Equilibrium; Goals; Hypercalcemia; Hypocalcemia result; Hypoparathyroidism; Intellectual functioning disability; Investigational New Drug Application; Length; Muscle Cramp; National Institute of Child Health and Human Development; PTH gene; Parathyroid Hormone Receptor; Patients; Phase; Preparation; Property; Rattus; Research Personnel; Role; Scientist; Serum; Symptoms; Syndrome; Therapeutics for Rare and Neglected Diseases; United States Food and Drug Administration; calcium phosphate; heart rhythm; hormone analog; hormone deficiency; pre-clinical

The primary symptoms of hypoparathyroidism include muscle cramping, convulsions, intellectual disabilities, cataracts and abnormal heart rhythm. Symptoms are due to low serum calcium (hypocalcemia). Replacement of parathyroid hormone (PTH) has been explored to remedy the calcium deficiency, but maintaining an optimal calcium level has proven problematic because hypercalcemia can occur as a result of excess PTH. Multiple efforts are under way targeting either full-length PTH (PTH 1-84) or the active amino-terminal domain (PTH 1-34), but these molecules have undesirable pharmacokinetic properties for chronic daily management of calcium levels in patients with hypoparathyroidism. Eli Lilly scientists have identified a PTH receptor modulator (PTH-RM) that can normalize serum calcium. At fairly low doses, the PTH-RM was shown to normalize calcium levels in parathyroidectomized rats. The investigators are collaborating with TRND to develop this PTH-RM toward a Phase II proof-of-concept study for hypoparathyroidism by leveraging the existing data package. TRND scientists, in collaboration with researchers from Eli Lilly & Company and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), have further developed the animal model of hypoparathyroidism to generate robust efficacy data. The team will execute the full preclinical development plan. TRND will support the preparation and filing of the Investigational New Drug application with the Food and Drug Administration, with NICHD providing support for subsequent clinical trials in patients.

甲状旁腺功能减退症的主要症状包括肌肉抽筋、抽搐、智力残疾、白内障和心律失常。症状是由于血清钙过低(低钙血症)。已探索用甲状旁腺激素(PTH)替代来弥补钙缺乏，但维持最佳的钙水平已被证明是有问题的，因为过量的PTH可导致高钙血症。针对全长甲状旁腺激素(PTH1-84)或活性氨基末端结构域(PTH1-34)的多种努力正在进行中，但这些分子具有不良的药代动力学特性，适用于甲状旁腺功能减退症患者的慢性日常钙水平管理。 礼来公司的科学家已经确定了一种甲状旁腺素受体调节剂(PTH-RM)，可以使血清钙正常化。在相当低的剂量下，PTH-RM被证明能使去甲状旁腺的大鼠的钙水平正常化。研究人员正在与TRND合作，通过利用现有的数据包，开发这一PTH-RM，以进行甲状旁腺功能低下症的第二阶段概念验证研究。 TRND的科学家与礼来公司和尤尼斯·肯尼迪·施莱弗国家儿童健康与人类发展研究所(NICHD)的研究人员合作，进一步开发了甲状旁腺功能低下的动物模型，以产生可靠的疗效数据。该团队将执行完整的临床前开发计划。TRND将支持准备和向食品和药物管理局提交研究用新药申请，NICHD将为随后的患者临床试验提供支持。