LZM-004(Livzon Group Livzon Pharmaceutical Factory)

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].

Denosumab is an approved monoclonal antibody therapeutic for the treatment of bone loss in the postmenopausal osteoporosis and oncology settings and acts by binding and neutralizing the activity of receptor activator of nuclear factor-kappa-B ligand (RANKL). Anti-drug antibodies (ADAs) to denosumab are measured via a standard electrochemiluminescence- (ECL) based bridging assay. In this format, the presence of soluble RANKL (sRANKL) in clinical samples can lead to false positive results. In a denosumab bioequivalence study, approximately 50 % of the serum samples showed reactivity to denosumab in the absence of a specific reagent to sequester the sRANKL. However, upon addition of osteoprotegerin (OPG) as a reagent to neutralize the sRANKL, the overall ADA incidence was lowered to <1 %. To address this RANKL reactivity over the long-term use of this assay, the performance of 3 RANKL inhibitors was evaluated using healthy donor sera samples spiked with different concentrations of positive control ADA, sRANKL, or both, in an ECL based immunoassay utilizing the Meso Scale Discovery (MSD) platform. Based on these data, the denosumab antibody assay was modified to include a neutralizing anti-RANKL monoclonal antibody to eliminate the assay reactivity or false positivity due to sRANKL. Use of an anti-RANKL antibody did not impact the ADA-specific signal but inhibited the false positive assay signal due to sRANKL, resulting in an accurate detection of ADA incidence. Therefore, inhibition of interference posed by sRANKL in study samples is critical for the accurate assessment of ADA incidence towards denosumab and any biosimilars for this product that are undergoing clinical development.