Efficacy and safety of narlumosbart, an anti-RANKL monoclonal antibody, in postmenopausal women with osteoporosis: a multi-center, randomized, double-blind, placebo- and active-controlled, phased II study.

Background: This study aimed to preliminarily explore the efficacy and safety of narlumosbart, an anti-RANKL monoclonal antibody, in treating postmenopausal women with osteoporosis. Methods: 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). Findings: 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%). Interpretation: 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. Funding: 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].