Long-acting PTH for hypoparathyroidism

项目摘要 甲状旁腺功能减退症是一种罕见的疾病，其原因是缺乏或不能产生足够的 甲状旁腺素(PTH)。未经治疗或治疗不当的甲状旁腺功能减退症导致临床 严重的矿物质代谢问题，包括低钙血症，这会导致心律失常、痉挛 声带和癫痫发作。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 意在维持血清钙，它不纠正潜在的甲状旁腺激素缺乏和生理性 甲状旁腺功能减退症的某些方面仍有可能发生。此外，补充与长期的 在无内源性甲状旁腺素的情况下使用超生理剂量钙的并发症 激素，导致肾功能恶化、肾结石、软组织钙化和 骨骼重塑的异常。Natpara(PTH1-84)是FDA批准的一种 甲状旁腺功能低下症患者，但由于维生素补充时间短，仅部分缓解了对维生素补充的需求 半衰期，一些患者仍然必须每天服用10片。临床试验表明，如果甲状旁腺素(1-34)是 在人体内通过泵连续给药，它可以模拟PTH的生理水平，以恢复正常的 钙、磷和骨转换的标志物。然而，泵介导的，持续输注甲状旁腺素 对病人来说将是昂贵和不便的。扩展生物科学公司开发了一种长效版本的 PTH(1-34)(EXT608)，可每周给药一次，并实现延长的药代动力学曲线， 接近内源性甲状旁腺素水平。SBIR II期结果显示EXT608比 天然甲状旁腺激素，根据在大鼠和NHP中的保留时间，EXT608预计在 人类。在甲状旁腺功能低下的大鼠模型中，EXT608能够使钙和磷水平正常化 同时，在为期四周的研究中，骨转换和骨密度的标记恢复到野生水平。 已完成的其他研究包括标准毒理学研究和GMP程序的开发。这个 在这一IIB阶段申请中提出的研究将集中于完成为数不多的支持IND的研究， 生产用于临床试验的GMP批次，并准备和提交IND。一旦IND申请获得批准 根据FDA的要求，我们将开始一期临床试验，以确定EXT608在健康人群中的安全性和耐受性 志愿者。这种长效甲状旁腺素(1-34)衍生物将提供一种真正的替代疗法来治疗 甲状旁腺功能减退症，使血、尿钙和磷恢复到生理水平 在一周的过程中保持它，从而显著提高患者的生活质量。

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), is 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 some patients still must take >10 pills/day. 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 could be dosed once a week and achieve a prolonged pharmacokinetic profile that approximates endogenous PTH levels. SBIR Phase II results showed that EXT608 is more efficacious than native PTH, and based on the retention time in rat and NHP, EXT608 is projected to be dosed once-weekly in humans. In a rat model of hypoparathyroidism, EXT608 was able to normalize calcium and phosphate levels while returning markers of bone turnover and bone mineral density to wild-type levels over the four-week study. Additional studies completed are the standard toxicology studies and the development of a GMP process. The studies proposed in this Phase IIB application will focus on completing the few remaining IND-enabling studies, produce a GMP batch for clinical trials, and to prepare and file an IND. Once the IND application is approved by the FDA, we will begin a Phase 1 clinical trial to determine safety and tolerability of EXT608 in healthy volunteers. This long-acting PTH(1-34) derivative will provide a true replacement 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 quality of life for patients.