A Phase 2 Study Investigating the Safety, Tolerability and Efficacy of EXT608 in Adults with Hypoparathyroidism (IND146180; October 14, 2022)

项目摘要 甲状旁腺功能减退症是一种罕见的疾病，由于缺乏或无法使足够的量， 甲状旁腺激素（PTH）。未经治疗或治疗不充分的甲状旁腺功能减退症导致临床上 显著的矿物质相关代谢问题，包括低钙血症，导致心律失常，痉挛 声带和癫痫目前对大多数患者的疾病管理包括 补充剂量的钙和活性维生素D来控制低钙血症。虽然这种方法是 旨在维持血清钙，它不纠正潜在的PTH缺乏和生理性 甲状旁腺功能减退的情况仍然会发生。此外，补充剂与长期 在缺乏内源性PTH的情况下使用超生理剂量钙的并发症 激素，其导致肾功能恶化、肾结石、软组织钙化 骨骼重塑异常Natpara（PTH 1-84），已被FDA批准用于以下疾病的子集： 甲状旁腺功能减退症患者，但由于其短暂的维生素补充， 半衰期，最近宣布将于2024年停止制造。临床试验已经证明 如果PTH（1-34）通过泵在人体中连续给药，它可以模拟PTH的生理水平， 恢复正常水平的钙，磷和骨转换的标志物。然而，泵介导的， PTH的连续输注对于患者来说是昂贵和不方便的。Extend Biosciences开发了一种 长效型PTH（1-34）（EXT 608），可实现延长的药代动力学特征， 接近内源性PTH水平。基于数据库建立前I期结果的中期数据分析 锁定，EXT 608是安全和耐受性良好的，并计划在人体中每周给药一次。研究 在这项拨款申请中提出的将集中在患者的2期双盲安慰剂对照试验。这 试验将有助于证明这种长效PTH（1-34）衍生物提供了一种基于上级PTH的治疗 治疗甲状旁腺功能减退，使血清和尿钙和磷酸盐恢复到生理水平， 在一周的时间内保持它，从而显着提高患者的依从性和生活质量。

Project Summary Hypoparathyroidism is a rare disease that results from a deficiency or inability to make sufficient amounts of parathyroid hormone (PTH). Untreated or inadequately treated hypoparathyroidism leads to clinically significant mineral-related metabolic issues including hypocalcemia, which leads to heart arrhythmias, spasms of the vocal cords, and seizures. Current management of the disease for the majority of patients consists of supplemental doses of calcium and active vitamin D to manage the hypocalcemia. While this approach is intended to maintain serum calcium, it does not correct the underlying PTH deficiency and the physiological aspects of hypoparathyroidism can still occur. Moreover, supplementation is associated with long-term complications from the use of supraphysiological doses of calcium in the absence of endogenous PTH hormone, which contribute to renal function deterioration, kidney stones, soft tissue calcifications and abnormalities in bone remodeling. Natpara (PTH 1-84), was approved by the FDA for a subset of hypoparathyroidism patients, but only partially alleviates the need for vitamin supplementation due to its short half-life, and it was recently announced that manufacturing will cease in 2024. Clinical trials have demonstrated that if PTH(1-34) is dosed continuously via a pump in humans, it can mimic physiological levels of PTH to restore normal levels of calcium, phosphorus and markers of bone turnover. However, a pump-mediated, continuous infusion of PTH would be costly and inconvenient for patients. Extend Biosciences has developed a long-acting version of PTH(1-34) (EXT608) that achieves a prolonged pharmacokinetic profile that approximates endogenous PTH levels. Based on an interim data analysis of Phase 1 results prior to database lock, EXT608 was safe and well-tolerated and is projected to be dosed once-weekly in humans. The studies proposed in this grant application will focus on a Phase 2 double-blind placebo-controlled trial in patients. This trial will help demonstrate that this long-acting PTH(1-34) derivative is provides a superior PTH based therapy to treat hypoparathyroidism that returns serum and urinary calcium and phosphate to physiological levels and maintains it over the course of week, thereby significantly improving compliance and quality of life for patients.