Denosumab Biosimilar LY01011 Shows Equivalence to Reference Product for Bone Metastases

Biosimilar LY01011 is equivalent to the reference product denosumab for treating bone metastases in solid tumors, demonstrating similar efficacy in reducing bone metabolism biomarkers, comparable safety profiles, and a lack of unexpected adverse reactions. | Image Credit: Nasr - stock.adobe.com

The efficacy of LY01011 in reducing the bone metabolism biomarker NTX was equivalent to that of the reference product denosumab (Xgeva; Amgen), thus meeting the primary end point with safety characteristics of LY01011 and denosumab similar, and no unexpected adverse reactions were reported, according to a study published in the Journal of Bone Oncology.¹

Bone metastases, which cause an estimated 35,000 deaths in the US each year, have seen evolving treatment options for patients with cancer.² However, these treatments often come with a significant socioeconomic burden.

Treatments for bone metastases are diverse, encompassing external-beam radiation, surgery, endocrine therapies, chemotherapy, and targeted and immunological therapies.¹ Of the available bone-targeted agents, bisphosphonates and denosumab are the most frequently used.

Denosumab received FDA approval in 2010 for the treatment of skeletal-related events (SREs) in patients with bone metastases.³ More recently, the first US biosimilars referencing denosumab, Wyost/Jubbonti (denosumab-bddz), were approved to treat osteoporosis and hypercalcemia, in addition to preventing SREs caused by bone metastases from solid tumors.⁴

LY01011, a denosumab biosimilar developed by Shandong Boan Biotechnology Co, Ltd, was shown to have comparable pharmacokinetic, pharmacodynamic, safety, tolerability, and immunogenicity profiles.¹ To establish its clinical equivalence, researchers conducted a multi-center, randomized, double-blind phase 3 clinical trial in patients with bone metastasis from solid tumors.

Following screening, 850 eligible patients were enrolled and randomized at a 1:1 ratio into a LY01011 group (n = 424) and a denosumab group (n = 426). The full analysis set (FAS) included all randomized participants, whereas the per-protocol set (PPS) included 739 patients. The mean age was 57.2 years, 42.5% identified as men, and 54.2% had lung cancer. No significant differences were observed between the treatment groups regarding the time frame from baseline to weeks 25 and 53 (uNTx/uCr ratios) and the time frame from baseline to weeks 13, 25, and 53 (s-BALP levels).

Equivalence between the LY01011 and denosumab groups was established, meeting the primary end point. Both treatments resulted in significant and sustained decreases in uNTX/uCr ratios, with a maximum median reduction of approximately 80% from baseline within 1 week. The least-squares mean difference of the logarithmic change in uNTX/uCr ratios was well within the prespecified equivalence margins for the FAS at week 13 from baseline (LY01011 group, –1.810 [0.0404]; denosumab group, –1.791 [0.0406]) and the PPS also met the predefined equivalence margins.

Subgroup analyses confirmed this equivalence across different patient demographics and tumor types. Both treatment groups also exhibited a continuous reduction in s-BALP levels over the course of the study. At weeks 13, 25, and 53, the median percent change in s-BALP levels from baseline was comparable between the 2 treatment groups. The changes for LY01011 were –36.980%, –46.853%, and –43.551%, while for denosumab, they were –37.674%, –48.681%, and –37.598%, respectively. The incidence of SREs was comparable between the 2 groups, with no statistically significant difference observed.

Adverse events (AEs) were monitored during both the double-blind treatment period and the entire study. During the double-blind treatment period, 91.3% of all patients experienced at least 1 treatment-emergent AE (TEAE), with comparable proportions in the LY01011 (91.7%) and denosumab (90.8%) groups.

The 2 study groups, LY01011 and denosumab, had similar rates of TEAEs throughout the study (97.4% vs 96.7%). The most frequent TEAEs ( ≥ 20%) were a decreased white blood cell count (32.5% vs 34.8%), a decreased neutrophil count (32.1% vs 33.6%), anemia (30.7% vs 28.7%), and hypocalcemia (20.3% vs 18.4%). The proportion of patients experiencing more severe TEAEs (≥ grade 3) and serious TEAEs was also comparable between the groups (54.7% vs 57.9% and 28.1% vs 30.4%, respectively). The proportions of patients with TEAEs (38.4% in both groups) and treatment-emergent serious AEs (TESAEs, 13.2% vs 14.1%) were similar. Hypocalcemia was the most common treatment-related AE (20% vs 18.1%). Over the entire study, the safety profile remained consistent, with no cases of osteonecrosis of the jaw or any other adverse events of special interest identified.

In both drug groups, predose plasma concentrations increased through week 13, then slowed between weeks 16 and 17, and reached a steady state by week 21. Before each dose, blood concentrations were similar in both groups. A 2 compartment pharmacokinetic model showed no significant differences between the LY01011 and denosumab groups in key parameters like clearance (P = .6879) or central volume of distribution (P = .9984).

All patients in the study were antidrug antibody (ADA) negative at the start. In the LY01011 group, 1 patient tested positive for ADAs with a titer of 80 at week 5, but subsequent tests were negative. Similarly, 1 patient in the denosumab group had a positive ADA test at week 21 with a titer of less than 5. No patients developed neutralizing antibodies.

This study's limitations include the absence of long-term follow-up data for patients with bone metastasis from solid tumors. However, given denosumab's established mechanism of action and existing clinical evidence, extended observation for SREs and overall survival may not be a prerequisite for a comparable biosimilar study. Furthermore, the exclusion of non-Chinese participants provides no data on the safety and efficacy of LY01011 in a global patient population.

“Switching therapeutic drugs after week 13 did not affect the efficacy, safety, or immunogenicity profiles of either group,” study authors concluded.

References

1. Zhao M, Hu X, Zhuang P, et al. A multicenter, randomized, double-blind trial comparing LY01011, a biosimilar, with denosumab (Xgeva) in patients with bone metastasis from solid tumors. J Bone Oncol. 2025;51:100661. doi:10.1016/j.jbo.2025.100661
2. Long N, Woodlock D, D'Agostino R, et al. Incidence and prevalence of bone metastases in different solid tumors determined by natural language processing of CT reports. Cancers (Basel). 2025;17(2):218. doi:10.3390/cancers17020218
3. FDA approves Amgen’s Xgeva (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Press release. Amgen. November 18, 2010. Accessed August 13, 2025. https://www.amgen.com/newsroom/press-releases/2010/11/fda-approves-amgens-xgevatm-denosumab-for-the-prevention-of-skeletalrelated-events-in-patients-with-bone-metastases-from-solid-tumors
4. Jeremias S. FDA approves first denosumab biosimilars. The Center for Biosimilars^®. March 5, 2024. Accessed August 13, 2025. https://www.centerforbiosimilars.com/view/fda-approves-first-denosumab-biosimilar