Long-Acting Parathyroid Hormone Analog for the Treatment of Hypoparathyroidism

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(PTH 184)或活性氨基末端结构域(PTH 134)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长期日常钙水平管理。 礼来公司的科学家已经确定了一种长效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的研究人员合作，进一步开发和验证了甲状旁腺功能低下的大鼠模型，以产生稳健的疗效数据。该团队将执行完整的临床前开发计划。TRND将支持向FDA提交研究新药申请的准备和提交工作，与临床专家合作，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 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.