Parathyroid Hormone(Shire Plc)

慢性肾脏病-矿物质骨紊乱治疗中降全段甲状旁腺激素药物研究进展 Research progress of drugs to reduce whole intact parathyroid hormone in  the treatment of chronic kidney disease-mineral and bone disorder 张倩楠1 ，汪年松2* ，李军辉1*  (1. 同济大学附属普陀人民医院肾内科，上海 200060；2. 上海交通大学医学院附属第六人民医院肾内科，上海 200233) 引用 张倩楠, 汪年松, 李军辉. 慢性肾脏病-矿物质骨紊乱治疗中降全段甲状旁腺激素药物研究进展[J]. 世界临床药物,  2025, 46(1): 23-28. DOI:10.13683/j.wph.2025.01.005 作者简介 张倩楠，主治医师，研究方向：慢性肾脏病的诊治。  通信作者：汪年松，主任医师，教授，博士生导师，研究方向：糖尿病 肾病、急性肾损伤发病机制和防治。  李军辉，副主任医师，副教授，研究方向：慢性肾脏病诊治。  基金项目：上海市普陀区科委课题(ptkwws202412)；上海市普陀区人民 医院院级课题(2022rmky12) 摘要 继发性甲状旁腺功能亢进 (secondary hyperparathyroidism，SHPT) 是慢性肾脏病 - 矿物质骨紊乱 (chronic kidney  disease-mineral and bone disorder，CKD-MBD) 的重要并发症之一，可显著增加患者骨骼畸形、心血管事件及死亡的发生风险。在目前 CKD-MBD SHPT 的临床治疗中，磷结合剂、拟钙剂、多核铁 - 氢氧化物及 tenapanor 等药物均展现出一定优势 ；新型活性维生素 D 类似物可有效降低全段甲状旁腺激素 (intact parathyroid hormone，iPTH) 水平。该文对近年来降 iPTH CKD 的 MBD 治疗药物进展作一综述，旨在为临床用药提供参考。 关键词 慢性肾脏病 - 矿物质骨紊乱 ；继发性甲状旁腺功能亢进症 ；全段甲状旁腺激素 章节导览 1 磷结合剂 1.1 含钙磷结合剂 1.2 非含钙磷结合剂  1.2.1 司维拉姆 1.2.2 碳酸镧 2 其他降磷药物  2.1 含铁磷结合剂 2.2 tenapanor 3 活性维生素 D 及其类似物 3.1 骨化三醇 3.2 帕立骨化醇 3.3 阿法骨化醇与度骨化醇 4 拟钙剂 4.1 西那卡塞 4.2 依特卡肽 4.3 依沃卡塞 (evocalcet) 5 调节肠道菌群治疗 6 联合用药 7 结语 文章节选 慢性肾脏病 (chronic kidney disease，CKD) 是 目前全球范围内的重要公共卫生问题。我国CKD患者约有 1.32 亿例，患病率高达10.8%。CKD- 矿物质骨紊乱(chronic kidney disease-mineral and  bone disorder，CKD-MBD) 是一种肾功能减退导致的矿物质及骨代谢异常综合征，主要表现为钙和磷代谢异常、全段甲状旁腺激素(intact parathyroid  hormone，iPTH) 水平升高、骨质疏松及血管钙化等，是引发CKD患者致残、致死等不良事件的重要原因之一 。 近年研究显示，肾脏排泄、内分泌功能异常等 可诱发 CKD 患者甲状旁腺过度增生及iPTH 分泌增加，最终引发继发性甲状旁腺功能亢进 (secondary  hyperparathyroidism，SHPT)，而 SHPT 又进一步加 重矿物质、骨代谢异常和异位钙化，影响预后，加 重社会医疗经济负担 。CKD 患者约从 3b 期开始 出现 iPTH 水平进行性升高 ；CKD 患者骨骼对 PTH 的反应性低，且调整轻中度 CKD 患者的 PTH 至正 常范围可能诱发高磷血症 (hyperphosphatemia) 。因此，CKD-MBD 患者降 iPTH 的治疗目标应为将 iPTH 水平控制于高于正常参考范围的合理区间 ， 但目前对不同 CKD 分期、不同治疗情况者 PTH 的 精准控制目标尚未统一。现将对 CKD-MBD 患者降 iPTH 治疗药物的研究进展作一综述，旨在为临床提 供参考。 ↑长按二维码阅读原文 聚焦药物综合评价  促进临床合理用药 请看《世界临床药物》！ 本刊为月刊，大16开。邮发代号4-302，全国各地邮局均可订阅。 定价：26元，全年312元。 订阅电话：021-62790477-751 订阅传真：021-62473200 订阅邮箱：guohx@pharmadl.com END 如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

Septerna just entered the clinic, and its lack of human data makes it an outlier among the companies able to successfully go public this year in what is still a cautious biotech IPO market. What the young company does have is technology based on research from a Nobel laureate and a lead drug candidate that could offer a key advantage over other treatments for a rare, inherited disease. Now it has $288 million in IPO cash to support its pipeline. Late Thursday, Septerna priced its offering of 16 million shares at $18 apiece, going beyond the preliminary financial terms it previously set. Those shares will trade on the Nasdaq under the stock symbol “SEPN.” South San Francisco-based Septerna will use most of the IPO proceeds to continue clinical testing of SEP-786 for hypoparathyroidism, an inherited deficiency of parathyroid hormone (PTH). This hormone regulates calcium and phosphate levels in the blood. Lacking this hormone leads to fatigue, brain fog, and muscle weakness. In more severe cases, patients can develop cardiovascular problems and renal failure. presented by Health Tech What’s Keeping Healthcare CIOs Up at Night: How to Improve Patient Satisfaction by Handling Calls More Efficiently Health systems have spent billions on portals while investments in modernizing the voice channel — the dominant preference of healthcare consumers — have taken a backseat. By Stephanie Baum Standard hypoparathyroidism treatment includes calcium and vitamin D supplements, which do not address all of the disease’s symptoms. Takeda Pharmaceutical’s Natpara, an engineered version of parathyroid hormone, will cease production by the end of the year due to manufacturing issues. In August, the FDA approved Ascendis Pharma’s Yorvipath, the first in what could be wave of new injectable peptide hypoparathyroidism drugs. Septerna takes a different approach to the disease with SEP-786, a small molecule that targets and activates the parathyroid hormone 1 receptor (PTH1R), sparking it to produce more of the key hormone. As an oral drug, SEP-786 would offer patients less burdensome dosing. “Hormone replacement with injectable PTH peptides, either marketed or in clinical development, may improve blood chemistry profiles of patients via PTH1R activation but will require lifelong daily injections,” Septerna said in the IPO filing. “We believe there is a substantial opportunity for an oral small molecule therapy that offers convenience, improved compliance, and potentially superior efficacy.” PTH1R is a G protein coupled-receptor (GPCR), part of a family of receptors that regulate a wide range of physiological processes. The role of these receptors in both health and disease is known, and many of them are targeted by FDA-approved drugs. However, an estimated 75% of GPCR targets remain undrugged, Septerna said in the filing. Septerna’s platform technology enables scientists to isolate a GPCR and study it outside of a cell, but in a way that replicates what happens to that receptor inside a cell. With this greater understanding of GPCRs, the company designs, screens for, and optimizes small molecules that target the receptors. This technology platform, called Native Complex, is based on the research of Robert Lefkowitz, a Duke University professor of biochemistry and chemistry who was awarded the 2012 Nobel Prize in Chemistry for his work in the GPCR field. In animal tests, Septerna reported its small molecule agonists activated PTH1R and regulated key genes important for calcium homeostasis in manner similar to native parathyroid hormone. A placebo-controlled Phase 1 study will evaluate the safety and tolerability of once-daily and twice-daily dosing of the SEP-786 in healthy volunteers. The first patient was dosed last month. Preliminary data are expected in mid-2025. Sponsored Post What Healthcare Can Learn from Costco The path forward is clear: employers must evaluate their health plan the same way they do their Saturday shopping excursion. By Jeff Bak, Imagine360 CEO and President The Septerna pipeline includes two preclinical negative allosteric modulators. SEP-631 is in development for immunology and inflammation indications, such as the skin disease chronic spontaneous urticaria. TSHR has potential applications in endocrinology. Native Complex has also yielded small molecule agonists of the GLP-1, GIP, and glucagon receptors for the potential treatment of metabolic disorders. An oral Septerna drug that hits one or more of these receptors could put the biotech in competition with commercialized injectable peptide drugs, such as Eli Lilly’s Zepbound and Novo Nordisk’s Wegovy. But Septerna will likely aim to stand out from the next wave of metabolic medications in development as pills. This competition includes Structure Therapeutics, whose small molecules come from its own GPCR platform technology (when Structure went public last year, it snagged the fitting stock symbol “GPCR”). Lead Structure drug candidate GSBR-1290 is currently in mid-stage clinical development for type 2 diabetes and obesity. Since Septerna’s inception in 2019, the company had raised $224.2 million prior to the IPO, most recently a $150 million Series B round last year led by RA Capital Management. That firm holds a 7.7% post-IPO stake in Septerna, according to the prospectus. Third Rock Ventures is Septerna’s largest shareholder with a 23.6% post-IPO stake. Septerna is led by CEO Jeff Finer, who is also a venture partner at Third Rock. Septerna’s plans resonated with investors, whose interest in the biotech’s stock enabled the company to boost the IPO size twice. In preliminary financial terms set at the beginning of the week, Septerna planned to offer more than 10.9 million shares in the range of $15 to $17 each, which would have raised $175 million at the pricing midpoint. On Thursday, the biotech boosted the deal size to more than 15.2 million shares priced at $18 apiece, which would have raised $275 million at the pricing midpoint. Late Thursday, the biotech again revised the terms upward, boosting the deal to $288 million. As of the end of the second quarter of this year, Septerna reported its cash position was $155.7 million. Following the IPO, the company plans to spend $54 million to advance lead drug candidate SEP-786 through Phase 2 testing in hypoparathyroidism, according to the filing. The company also plans to use the capital to develop additional molecules that target the parathyroid hormone receptor. Another $24 million will support the completion of Phase 1 testing of SEP-631 and additional molecule inhibitors that could be potential treatments for chronic spontaneous urticaria. And $41 million is set aside for other R&D, including Septerna’s TSHR and incretin receptor programs.