PTHrP

●试验按计划持续至52周，以进一步确定风险获益状况。Jiuzhou News         CALYPSO III期试验的高级结果表明，与安慰剂相比，在研甲状旁腺激素（PTH） 受体1激动剂eneboparatide (AZP-3601）在24周时对患有慢性甲状旁腺功能减退症（HypoPT）的成年人达到了其主要终点，且具有统计学意义。主要终点是白蛋白调整血清钙水平恢复正常以及不再依赖活性维生素D和口服钙疗法的综合结果。阿斯利康罕见病业务Alexion首席执行官Marc Dunoyer表示：“患有HypoPT（一种罕见内分泌疾病）的人患高钙尿症、骨质减少和骨质疏松症的风险通常较高，而CALYPSO试验的结果强调了eneboparatide有可能成为这些患者的另一种选择。我们期待在52周时审查临床结果，以全面描述风险获益情况。”Eneboparatide耐受性良好。在24周随机治疗期后，所有患者在持续的长期延长期内接受eneboparatide治疗，直至52周。完整的疗效和安全性数据将在52周时进行分析。Alexion计划与全球卫生当局分享这些数据，并在即将召开的医学会议上展示它们。甲状旁腺功能减退症（HypoPT） HypoPT是一种罕见的内分泌疾病，由甲状旁腺激素（PTH）缺乏引起，其特征是血液中钙降低和磷酸盐水平升高。甲状旁腺激素（PTH）生理作用的失调可导致临床表现，包括对肾脏和骨骼的负面影响。HypoPT是已知的最大罕见疾病之一，影响美国和欧盟超过200,000人，其中约80%为女性。大约75%的甲状旁腺功能减退症患者的主要原因是颈部手术中甲状旁腺受伤或被切除。尽管有可用的治疗方法，但甲状旁腺功能减退症患者仍然面临巨大的未满足需求。CALYPSO试验 CALYPSO是一项全球性III期随机、双盲、安慰剂对照、多中心试验，旨在评估eneboparatide对慢性甲状旁腺功能减退症成人患者的疗效和安全性。共有202名接受标准治疗（活性维生素D和口服钙补充剂）的患者按2:1的比例随机接受eneboparatide或安慰剂治疗。主要疗效终点是治疗24周后，达到白蛋白调整血清钙水平正常范围且不再依赖标准治疗的患者比例的综合结果。关键次要疗效终点包括基线高钙尿症患者24 小时尿钙水平恢复正常，以及评估患者报告的反映身体症状和生活质量影响的结果。Eneboparatide (AZP-3601) Eneboparatide (AZP-3601）是一种研究性甲状腺旁素（PTH）受体1激动剂，用于治疗慢性甲状旁腺功能减退症（HypoPT）。它旨在与PTH受体1的特定构象以高亲和力结合，以恢复PTH功能，从而控制HypoPT的症状，同时保持肾功能和骨骼健康。Eneboparatide已被美国食品药品管理局授予快速通道资格和孤儿药资格，并被欧洲药品管理局授予孤儿药资格，用于治疗HypoPT。小结 据2022年第二届国际研讨会指南《甲状旁腺功能减退症的评估和管理》，甲状旁腺功能减退症除了具有典型的血钙低和磷酸盐升高的指征外，还有一些并发症，严重地影响着患者生活质量，如白内障、感染、肾钙化/肾结石、肾功能不全、癫痫、沮丧、缺血性心脏病和心律失常等。▲甲状旁腺功能减退症的并发症紊乱的钙调控导致PTH水平降低，影响着身体各个器官，大大增加了并发症的发生概率。目前临床上的常规治疗手段包括直接补钙（碳酸钙或柠檬酸钙）、间接补钙（活性维生素D来促进肠钙吸收和调节骨形成）以及限制钙排泄（噻嗪类利尿剂增加肾小管钙重吸收）。▲钙调控紊乱直到2024年美国FDA批准了Ascendis Pharma公司的palopegteriparatide，甲状旁腺功能减退症患者迎来了针对PTH减少这一病因的新型疗法。Teriparatide[1-34]是一种甲状腺旁素衍生物，最早在上个世纪用于治疗绝经后妇女具有高骨折风险的骨质疏松症，但由于它具有极短（1小时）的半衰期，无法产生足够的暴露量来维持体内活性，因而长期以来无法用来治疗甲状旁腺功能减退症。阿斯利康eneboparatide则通过修改M-PTH(1-30)/PTHrP多肽里的关键氨基酸，获得了活性更强的PTH衍生物。▲Eneboparatide的氨基酸序列天然的PTHrP[1-34] abaloparatide具有较弱的R0亲和力，而只有在R0状态下才会激活PTH1R的下游信号通路。▲Eneboparatide的设计机理阿斯利康的eneboparatide正是一种具有强力R0亲和力的PTH衍生物。▲Eneboparatide对R0具有高亲和力Eneboparatide能够持久地刺激下游cAMP信号的产生，并长时间维持血清钙水平。▲Eneboparatide的PD数据Eneboparatide哪怕半衰期与Teriparatide[1-34]相似，但它依旧能长时间地维持相应的药理学功能。▲Eneboparatide的PD数据Palopegteriparatide和eneboparatide是两种不同设计理念的药物，同样能够有效地用于治疗甲状旁腺功能减低症。除此之外，还有其他值得关注的目前临床在研的PTH衍生物。Entera Bio公司正在开发口服Teriparatide[1-34]，通过制剂配方的方式来实现，配方里有SNAC（增加多肽的渗透性，强化肠道吸收）和大豆胰蛋白酶抑制剂（减少多肽的胃肠道水解）。MBX Biosciences公司正在开发每周一次皮下注射的canvuparatide PTH[1-32]，也是一种前药的方式，通过脂肪酰化来结合体内的白蛋白，从而延长半衰期。还有信立泰的SAL056每周皮下注射一次的Teriparatide[1-34]，处于上市申请阶段，具体长效机理未披露。▲活跃的临床在研PTH衍生物▲活跃的临床在研PTH衍生物结构参考资料1.https://www.astrazeneca.com/media-centre/press-releases/2025/eneboparatide-phase-iii-trial-met-primary-endpoint.html2.https://onlinelibrary.wiley.com/doi/10.1002/jbmr.46913.https://www.nature.com/articles/nrdp2017554.https://amolytpharma.com/wp-content/uploads/2023/06/ECE-23-Ravel-et-al-AZP-3601-on-Bone-in-NHP-Final-5-8-23.pdf5.https://amolytpharma.com/wp-content/uploads/2024/07/12-ECE24-Culler-OC2.3-A-Translational-Approach-Final.pdf6.https://www.sciencedirect.com/science/article/pii/S2590156721000268?via%3Dihub7.https://mbxbio.com/our-science/#how-peps-work免责申明本公众号注明原创的内容权利均属九洲药业所有，未经授权，不得擅自使用或许可他人使用。如需获得授权，请和九洲药业提前联系。已获得授权的，应在授权范围内使用，并注明来源且不得再全部或部分转授权他人。本公众号对转载、分享的内容、陈述、观点判断保持中立，不对所包含内容的合法性、准确性、可靠性或完善性提供任何明示或暗示的保证，该等内容版权归原作者所有，仅供学习参考之用，若对转载、分享的内容有任何权利疑问，烦请联系九洲药业。

In March, British pharmaceutical giant AstraZeneca announced its intention to acquire Amolyt Pharma, a clinical-stage biotechnology company focused on developing innovative therapies for rare endocrine diseases. This acquisition will further strengthen AstraZeneca’s late-stage product development pipeline within its rare disease division, Alexion, and add a significant new element to its bone metabolism portfolio—the therapeutic peptide eneboparatide (AZP-3601), currently in Phase III clinical trials. In 2018, Amolyt Pharma obtained the development rights for the long-acting peptide candidate drug AZP-3601 from The General Hospital Corp. AZP-3601 is a unique parathyroid hormone (PTH) analogue designed by researchers at The General Hospital Corp. for the treatment of hypoparathyroidism as a PTH replacement therapy. AZP-3601 interacts powerfully with a specific conformation of the PTH receptor, leading to prolonged activation and effect on calcium metabolism. Early studies have indicated that AZP-3601 is significantly more effective and has a longer-lasting effect in raising and maintaining blood calcium levels compared to natural PTH, without increasing urinary calcium excretion. The unique mechanism of action of AZP-3601 is expected to translate into improved safety and efficacy profiles, making it an optimal choice for the treatment of this rare but serious endocrine disease. The PTH receptor is a G protein-coupled receptor that plays a pivotal role in regulating intracellular signaling pathways involved in bone growth and the homeostasis of blood calcium ions. Any disruption to the PTH receptor signaling system can be associated with a variety of bone diseases and abnormalities in mineral ion physiology. Dr. Gardella's research on the functional molecular mechanisms of the PTH receptor has revealed important clues that contribute to the development of new therapies for diseases such as Jansen's metaphyseal chondrodysplasia, hypocalcemia, and osteoporosis. A patent from 2002 (US 6362163 B1) describes the properties of derivative peptides and mutants of the PTH peptide. Under physiological conditions, PTH1R can be activated by two different endogenous peptide agonists (Parathyroid Hormone (PTH) and Parathyroid Hormone-related Protein (PTHrP)), to regulate multiple signaling pathways and exert unique biological effects. PTH secreted by the parathyroid glands primarily regulates the homeostasis of calcium and phosphate in the bones and kidneys, whereas PTHrP is involved in the proliferation and differentiation of cells in developing bone and other tissues. In this patent, researchers studied combinations of amino acid sequences at the N-terminus and C-terminus of PTH and PTHrP peptides and tested the selective activation of PTH and PTHrP peptides and their derivatives on PTH1R and PTH2R. The patent also tested substitutions at key amino acid positions 5 and 23, confirming the impact of these two amino acids on the specificity of the peptides. A study in a patent from 2006 (US 7022815 B1) investigated mutant variants of PTH peptide derivatives and disclosed several peptide derivatives as well as pharmaceutical compositions containing peptides, along with methods to screen candidate compounds of the invention. Researchers conducted mutational studies on the first 14 amino acids of the N-terminal of PTH peptides and tested the role of each residue in ligand recognition. Overall, mutations in certain N-terminal amino acids such as positions 4, 5, 6, 8, and 9 had a significant impact on the activity of the peptides. A patent from 2009 (US61164284P0) studied the structural information related to PTH peptides and the derivatives of PTH peptide C-terminal mutants, as well as their role in regulating receptor activity. The invention involves peptides or polypeptides that activate the parathyroid hormone receptor and potential applications of these peptides or polypeptides in promoting bone growth (such as treating osteoporosis) or in cancer therapy. A patent from 2016 (WO 2017/173372 A1) investigated antagonists or inverse agonist derivatives of PTH peptides. Overactive signaling of PTHR1 may be associated with higher than normal serum calcium levels, serum phosphate levels lower than normal, or constitutive activity of PTHR1 mutants. These peptides can be used in methods for treating conditions or diseases characterized by overactive PTH1R signaling.

In December of 2023, Ascendis Pharma announced that the U.S. FDA has accepted the company's resubmitted New Drug Application (NDA) for palopegteriparatide (TransCon PTH) for the treatment of adult patients with hypoparathyroidism. The resubmitted application constitutes a complete response to the second round of queries, and the Prescription Drug User Fee Act (PDUFA) target date is set for May 14, 2024. TransCon PTH, developed by Ascendis Pharma, is an investigational prodrug of PTH hormone undergoing research and development. It is a mPEGylated modification of the parathyroid hormone (PTH 1-34) designed for once-daily injection that provides a sustained release of active PTH and is currently in development for the treatment of hypoparathyroidism in adults. Therapeutic Drugs Targeting PTH1RThe parathyroid hormone 1 receptor (PTH1R) is a member of the Class B G protein-coupled receptor family. This receptor can be activated by two different endogenous peptide agonists, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), and activates Gs, Gq, and β-arrestin pathways, thereby regulating various signaling pathways and exerting different biological effects. In November 2023, Apotex announced that the U.S. FDA approved the company's Teriparatide injection for the treatment of osteoporosis. The Teriparatide injection is supplied in a pre-filled pen form for single patient use, containing 250 mcg/mL, with a dosage of 20 mcg per administration. In November of 2023, the U.S. FDA approved the marketing of Teva Pharmaceuticals' Teriparatide injection, which is also used for the treatment of osteoporosis. Teriparatide is a recombinant peptide and a synthetic form of the natural human parathyroid hormone. This medication can help the body to form new bone, increase bone mineral density, and enhance bone strength. Abaloparatide is an N-terminal analog of parathyroid hormone-related peptide (PTHrP) originally researched and developed by Ipsen SA. It is an agonist of the parathyroid hormone 1 receptor (PTH1R), as well as a synthetic 34-amino acid peptide sharing 41% homology with human parathyroid hormone 1-34 and human PTHrP 1-34. Following its approval in the United States in 2017, it has been approved in countries and regions such as Japan and the European Union for the treatment of osteoporosis and postmenopausal osteoporosis. Currently, there are two PTH1R-targeting candidate drugs for the clinical treatment of hypoparathyroidism in Phase 1 clinical trials: MBX-2109, a PTH1R agonist from MBX Life Sciences, and Chugai Pharmaceutical's PTH1R agonist PCO-371. In 2016, Chugai Pharmaceutical published an article in the journal Nature Communications on the development of PCO-371, an orally active small molecule PTHR1 agonist for the treatment of hypoparathyroidism. PCO-371 is a novel orally active small molecule and serves as a full agonist of PTHR1. Oral administration of PCO-371 in osteoporotic rats significantly increased bone turnover rates, yet there was a limited increase in bone mass. In hypocalcemic rats, PCO-371 restored serum calcium levels without increasing urinary calcium, and its effects were stronger and more durable than injectable PTH. These results suggest that PCO-371 could offer a new therapeutic option for PTH-related disorders, including hypoparathyroidism. In July of 2023, GPCR drug discovery startup Septerna announced that the company had secured $150 million in Series B funding to advance the development of a novel pipeline of GPCR-targeted drugs. According to the news release, this round of financing will be used to support the development and clinical mechanism validation of leading programs targeting PTH1R. About OsteoporosisOsteoporosis is a skeletal disorder primarily caused by a reduction in bone density and the destruction of bone microarchitecture, leading to bones becoming fragile and prone to fractures. The main symptoms of osteoporosis include susceptibility to fractures, decreased height, back pain, and loss of weight. The goal of osteoporosis treatment is to prevent fractures. At present, clinical targets developed for the treatment of osteoporosis mainly include PTH1R, RANKL, ER, ERα, CALCR, and others. Bisphosphonates are the most widely used anti-bone resorption drugs, capable of reducing bone turnover markers to low premenopausal concentrations and decreasing fracture rates (vertebral fracture rates by 50%-70%, non-vertebral fracture rates by 20%-30%, and hip fracture rates by approximately 40%). Bisphosphonates can tightly bind with bone mineral and their effects may be eliminated over several months to years. Denosumab is a monoclonal antibody targeting RANKL that can effectively inhibit the development and activity of osteoclasts. Denosumab is administered subcutaneously every six months. The anti-fracture efficacy of denosumab is similar to that of bisphosphonates, but after the last injection at 7 months, the anti-resorption effect significantly reduces, which may lead to a rebound in vertebral fractures. Romosozumab is a monoclonal antibody against sclerostin that can stimulate bone formation and inhibit bone resorption. Romosozumab is administered subcutaneously once a month, with a treatment course of 1 year. Head-to-head studies indicate that, compared with anti-resorption drugs, anabolic agents have stronger anti-fracture efficacy, and also a greater increase in bone density. The effects of anabolic agents are transient, thus necessitating a transition to anti-resorption drugs. The optimal cycling strategy involving anabolic agents, anti-resorption drugs, and periods off medication remain to be determined.