Long-Acting Parathyroid Hormone Analog for the Treatment of Hypoparathyroidism

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PTH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，其特征与糖尿病患者使用基础胰岛素相似。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和尤妮斯·肯尼迪·施莱佛国家儿童健康和人类发展研究所（NICHD）的研究人员合作，进一步开发了甲状旁腺功能减退症的动物模型，以生成可靠的疗效数据。在美国食品药品监督管理局（FDA）的同意下，该团队将执行完整的临床前开发计划。TRND将支持向FDA准备和提交研究性新药（IND）申请，NICHD将为后续的患者临床试验提供支持。

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 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, with a profile similar to basal insulin use in patients with diabetes. 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. With concurrence from the U.S. Food and Drug Administration (FDA), the team will execute the full preclinical development plan. TRND will support the preparation and filing of the Investigational New Drug (IND) Application with the FDA, with NICHD providing support for subsequent clinical trials in patients.