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: 9551298
• 负责人: Na Yang
• 金额: $ 245.31万
• 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/9551298
• 关键词: Blood; Calcium; Cataract; Chronic; Clinical; Clinical Trials; Collaborations; Convulsions; Data; Development Plans; Dose; Drug Kinetics; Equilibrium; Goals; Heart Abnormalities; Hypercalcemia; Hypocalcemia result; Hypoparathyroidism; Intellectual functioning disability; Investigational New Drug Application; Length; Modeling; Muscle Cramp; PTH gene; Parathyroid Hormone Receptor; Patients; Phase; Preparation; Property; Rattus; Research Personnel; Role; Scientist; Serum; Symptoms; Syndrome; Therapeutics for Rare and Neglected Diseases; calcium phosphate; heart rhythm; hormone analog; hormone deficiency; preclinical development

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 184) or the active amino-terminal domain (PTH 134), but these molecules have undesirable pharmacokinetic properties for chronic daily management of calcium levels in patients with hypoparathyroidism. Eli Lilly scientists have identified a long acting 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, have further developed and validated the rat 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 FDA, partnering with clinical experts to support for subsequent clinical trials in patients.

甲状旁腺功能减退的主要症状包括肌肉痉挛、抽搐、智力障碍、白内障和心律异常。症状是由于低血清钙（低钙血症）。甲状旁腺激素（PTH）的替代已被探索，以弥补缺钙，但保持最佳的钙水平已被证明是有问题的，因为高钙血症可能会发生作为一个结果过量的PTH。目前正在进行多种努力，靶向全长PTH（PTH 184）或活性氨基末端结构域（PTH 134），但这些分子对于甲状旁腺功能减退患者的钙水平的长期日常管理具有不良的药代动力学特性。 礼来公司的科学家已经确定了一种长效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显示出使甲状旁腺切除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，将PTH-RM开发为甲状旁腺功能减退症的II期概念验证研究。 TRND的科学家与礼来公司的研究人员合作，进一步开发和验证了甲状旁腺功能减退症的大鼠模型，以生成可靠的疗效数据。该团队将执行完整的临床前开发计划。TRND将支持研究性新药申请的准备和向FDA提交，并与临床专家合作，为后续的患者临床试验提供支持。