Calcitonin for treating X-linked hypophosphatemia

描述（由申请人提供）：1995年HYP联盟的报告阐明了x连锁低磷血症（XLH）的病理生理学，该报告指出中性内肽酶PHEX的突变是该疾病的遗传基础。通过一个尚不清楚的途径，PHEX的功能丧失突变导致FGF23循环水平升高。现在已经确定FGF23是该综合征的近似生物学介质。FGF23通过抑制近端肾小管磷酸钠共转运蛋白的转录抑制肾小管磷酸重吸收。它还抑制1-1羟化酶活性，导致血清125 (OH)2维生素D水平低或低于正常水平，从而损害肠道磷酸盐和钙的吸收。这些联合的生化异常导致骨骼矿化缺陷，表现为儿童佝偻病和成人骨软化症。口服磷酸盐和骨化三醇治疗XLH的传统疗法有几个局限性，包括治疗/毒性比低，不能纠正儿童的生长迟缓或成人的神经衰弱。此外，这种治疗方案导致循环中FGF23水平进一步上升。因此，迫切需要针对XLH的基本病理生理进行更好的治疗。正如研究策略中详述的那样，我们已经确定降钙素是XLH中FGF23产生的一种新的抑制因子。单次皮下注射降钙素可导致该疾病患者FGF23水平持续下降，并在给药后持续16小时；在对照组中没有观察到这种变化。血清FGF23的下降与血清磷酸盐和循环中1,25(OH)2维生素d水平的升高有关。这些令人兴奋的数据提示了一种治疗XLH的新方法。本探索性临床试验旨在确定降钙素在改善未经治疗的成人XLH患者生化异常方面的疗效。我们将通过以下具体目的来检验降钙素通过降低FGF23循环水平和提高血清1,25(OH)2维生素D水平来改善XLH中磷酸盐稳态的假设：确定3个月400 IU/天剂量的鼻降钙素是否显著降低XLH患者24小时血清FGF23综合水平。2. 评估鼻降钙素是否通过提高TmP/GFR和24小时综合血清磷酸盐浓度来改善磷酸盐稳态。3. 评估鼻降钙素是否通过增加24小时血清125 (OH)2维生素D综合水平和增强肠道钙吸收来改善XLH患者的钙代谢，通过24小时尿钙来评估。4. 通过量化试验期间的副作用和鼻腔刺激，确认鼻降钙素耐受性良好。如果成功，这项研究将为fda批准的治疗XLH药物的新用途提供原理证明。与传统治疗方法不同，该方法解决了这种疾病的潜在病理生理，并将代表30年来XLH治疗的第一个进展。

DESCRIPTION (provided by applicant): The pathophysiology of X-linked hypophosphatemia (XLH) was clarified with the report in 1995 by the HYP Consortium that mutations in the neutral endopeptidase PHEX are the genetic basis for this disorder. By a pathway that remains unclear, loss-of-function mutations in PHEX lead to elevated circulating levels of FGF23. It is now well established that FGF23 is the proximate biological mediator of this syndrome. FGF23 suppresses renal tubular phosphate reabsorption by inhibiting transcription of sodium phosphate co-transporters in the proximal renal tubule. It also suppresses 1-1 hydroxylase activity leading to low or low-normal serum levels of 1,25(OH)2vitamin D, which impairs intestinal phosphate and calcium absorption. These combined biochemical abnormalities result in defective skeletal mineralization manifested as rickets in children and osteomalacia in adults. Conventional therapy for XLH with oral phosphate and calcitriol has several limitations including a low therapeutic/toxicity ratio, and a failure to correct growth retardation in children or the enthesopathy seen in adults. In addition, this treatment regimen causes a further rise in circulating levels of FGF23. Thus, there is a pressing need for better therapy directed at the basic pathophysiology of XLH. As detailed in the Research Strategy, we have identified calcitonin as a novel suppressor of FGF23 production in XLH. A single, subcutaneous injection of calcitonin results in a sustained fall in FGF23 levels in patients with this disease that persists for 16 hrs after drug administration; a change not observed in control subjects. The fall in serum FGF23 is associated with a rise in serum phosphate and circulating levels of 1,25(OH)2vitamin D. These exciting data suggest a novel therapy for XLH. This exploratory clinical trial seeks to establish the efficacy of calcitonin in improving the biochemical abnormalities in untreated adults with XLH. We will test the hypothesis that calcitonin, by lowering circulating levels of FGF23 and raising serum levels of 1,25(OH)2vitamin D, improves phosphate homeostasis in XLH by pursuing the following specific aims: 1. Determine whether 3 months of nasal calcitonin administered at a dose of 400 IU/day significantly lowers integrated 24-hr serum levels of FGF23 in patients with XLH. 2. Evaluate whether nasal calcitonin improves phosphate homeostasis by raising the TmP/GFR and integrated 24 hr serum phosphate concentrations. 3. Assess whether nasal calcitonin improves calcium metabolism in patients with XLH by increasing integrated 24 hr serum levels of 1,25(OH)2vitamin D and enhancing intestinal calcium absorption, as estimated by 24-hr urine calcium. 4. Confirm that nasal calcitonin is well tolerated by quantifying side effects and nasal irritation during the trial. If successful, this study will provide proof-of-principal for the novel use of an FDA-approved drug in treating XLH. This approach, unlike conventional treatment, addresses the underlying pathophysiology in this disorder and would represent the first therapeutic advance for XLH in 30 years. PUBLIC HEALTH RELEVANCE: X-linked hypophosphatemia (XLH) is the most common form of inherited rickets and osteomalacia in the United States. XLH is caused by overproduction of a hormone call FGF23, which makes the body waste phosphate. This study is designed to determine if nasal calcitonin, an already approved drug in the USA, can lower blood levels of FGF23 and reduce phosphate wasting in patients with XLH.