Chi Yue, Li Yukun, Cheng Qun, Cai Hanqing, Zeng Yuhong, Sheng Hui, Song Bing, Li Hongmei, Shen Lin, Li Min, Xing Ying, Cheng Mei, Ma Yujin, Wang Difei, Zhu Mei, Lu Weiping, Yan Shuang, Zhang Xueyuan, Yuan Jing, Yang Baofang, Li Jun, Wang Juan, Wu Zhufeng, Xia Weibo
Department of Endocrinology, Key Laboratory of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Dongcheng District, National Commission of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, Heibei, 050000, China.
EClinicalMedicine. 2025 Jul 4;85:103329. doi: 10.1016/j.eclinm.2025.103329. eCollection 2025 Jul.
This study aimed to preliminarily explore the efficacy and safety of narlumosbart, an anti-RANKL monoclonal antibody, in treating postmenopausal women with osteoporosis.
This multi-center, randomized, double -blind, placebo- and active-controlled study was conducted at 23 clinics across China between April 21, 2022 and April 19, 2023. Eligible patients were randomly assigned (1:1:1:1:1) to receive either 45 mg. 60 mg, 90 mg of narlumosbart, 60 mg of denosumab, or placebo, administered once every 6 months over a 12-month period, with the treatment allocation masked for participants, sponsors, and clinical investigators. The primary efficacy endpoint was the percentage change in lumbar spine bone mineral density (BMD) from baseline to 12 months. The secondary measures were percentage changes in lumbar spine, total hip, and femoral neck BMD, height changes, bone turnover markers, safety, and immunogenicity. Study registration: www.clinicaltrials.gov (NCT05278338).
207 postmenopausal women with osteoporosis were enrolled and randomly assigned to received narlumosbart 45-90 mg (n = 41 in each group), denosumab (n = 42), or placebo (n = 42). At month 12, patients receiving narlumosbart 45 mg, 60 mg, and 90 mg had the percentage change in lumbar spine BMD from baseline (least-squares [LS] mean [standard error]) of 4.83% (0.65), 6.52% (0.62), and 5.74% (0.64), respectively, and all showed significant increases compared with the placebo group (0.63% [0.67]), with LS mean differences (99% confidence interval [CI]) of 4.20% (1.92∼6.48), 5.90% (3.63∼8.16), and 5.11% (2.84∼7.39), respectively (all P < 0.001). Treatment-emergent adverse events (TEAEs) were observed in 91.9% of patients in the pooled narlumosbart groups, and 92.9% in both the placebo and the denosumab groups. Most common TEAEs were decreased vitamin D levels (34.1% [pooled narlumosbart] vs. 35.7% [placebo] vs. 33.3% [denosumab]), COVID-19 (38.2% vs. 40.5% vs. 35.7%), and increased serum parathyroid hormone (22.8% vs. 14.3% vs. 19.0%).
In this phase II trial of postmenopausal women with osteoporosis, narlumosbart demonstrated superiority over placebo in increasing BMD at 12 months following administration at 6-month intervals, with a tolerable safety profile in the short term, consistent with that of anti-RANKL monoclonal antibodies.
This study was supported by Shanghai JMT-Bio Technology Co., Ltd.; National Key R&D Program of China [2021YFC2501700]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-002]; National High Level Hospital Clinical Research Funding [2022-PUMCH-D-006]; the National Natural Science Foundation of China [No. 82270938, No. 81970757]; and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2023-PT320-10].
本研究旨在初步探讨抗RANKL单克隆抗体那芦莫司巴特治疗绝经后骨质疏松症女性的疗效和安全性。
本多中心、随机、双盲、安慰剂对照和活性药物对照研究于2022年4月21日至2023年4月19日在中国23家诊所进行。符合条件的患者被随机分配（1:1:1:1:1）接受45毫克、60毫克、90毫克那芦莫司巴特、60毫克地诺单抗或安慰剂，在12个月内每6个月给药一次，参与者、申办者和临床研究人员对治疗分配情况不知情。主要疗效终点是腰椎骨密度（BMD）从基线到12个月的百分比变化。次要指标包括腰椎、全髋和股骨颈BMD的百分比变化、身高变化、骨转换标志物、安全性和免疫原性。研究注册：www.clinicaltrials.gov（NCT05278338）。
207例绝经后骨质疏松症女性入组并随机分配接受45 - 90毫克那芦莫司巴特（每组n = 41）、地诺单抗（n = 4）或安慰剂（n = 42）。在第12个月时，接受45毫克、60毫克和90毫克那芦莫司巴特治疗的患者腰椎BMD较基线的百分比变化（最小二乘法[LS]均值[标准误]）分别为4.83%（0.65）、6.52%（0.62）和5.74%（0.64），与安慰剂组（0.63%[0.67]）相比均显著增加，LS均值差异（99%置信区间[CI]）分别为 4.20%（1.92∼6.48）、5.90%（3.63∼8.16）和5.11%（2.84∼7.39）（均P < 0.001）。在那芦莫司巴特合并组中，91.9%的患者观察到治疗中出现的不良事件（TEAE），安慰剂组和地诺单抗组均为92.9%。最常见的TEAE是维生素D水平降低（那芦莫司巴特合并组为34.1%，安慰剂组为35.7%，地诺单抗组为33.3%）、新型冠状病毒肺炎（38.2%对 40.5%对35.7%）和血清甲状旁腺激素升高（22.8%对14.3%对19.0%）。
在这项绝经后骨质疏松症女性的II期试验中，那芦莫司巴特在每6个月给药一次后12个月时，在增加BMD方面显示出优于安慰剂的效果，短期内安全性可耐受，与抗RANKL单克隆抗体一致。
本研究由上海君实生物科技有限公司资助；中国国家重点研发计划[2021YFC2501700]；中国医学科学院医学创新基金（CIFMS）[2021-I2M-1-002]；国家高水平医院临床研究基金[2022-PUMCH-D-006]；中国国家自然科学基金[82270938号、81970757号]；以及中国医学科学院公益性中央级科研院所基本科研业务费[2023-PT320-10]。
