Denosumab Biosimilar LY01011 Demonstrates Safety, Immunogenicity

Pharmacokinetics, pharmacodynamics, as well as comparable safety and immunogenicity, were demonstrated with the denosumab biosimilar, LY01011, in a cohort of healthy Chinese participants, according to a study published in Journal of Bone Oncology.¹

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The reference product was US Food and Drug Administration (FDA)-approved in 2010 to prevent skeletal-related events in patients with multiple myeloma and those with bone metastasis from solid tumors. However, in certain countries, access to the drug is limited due to high cost. Therefore, biosimilar options can offer more treatment options and overcome cost barriers.²

“LY01011, a recombinant fully human anti-receptor activator of nuclear Kappa-B ligand (RANKL) monoclonal antibody injection, is a biosimilar of the reference product denosumab and was developed by Shandong Boan Biotechnology Co, LTD,” wrote a group of Chinese investigators. “Preclinical studies, including pharmacokinetics, pharmacodynamics, and pharmacological toxicities, showed no statistically significant differences between LY01011 and denosumab, which further supported the clinical development of LY01011.”

Investigators conducted a randomized, single-center, double-blind, single-dose, active-parameter, parallel-controlled phase 1 study in healthy, adult (aged 18 – 50 years) Chinese participants. The study was performed in compliance with the provisions of the Declaration of Helsinki.

A total of 168 patients were assigned 1:1 to receive either a 120 mg subcutaneous dose of the reference drug (n = 83) or the biosimilar (n = 83). Parameters of interest were the pharmacokinetics, including the maximum plasma concentration (Cmax) and area under the concentration–time curve from time zero to last quantifiable concentration (AUC0→t). Safety, immunogenicity, and pharmacodynamics were also evaluated. Safety was evaluated using adverse events, vital signs, laboratory tests, a physical examination, and a 12-lead electrocardiogram (ECG). To test for immunogenicity, blood samples were collected pre-dose and at 312 hours, 1320 hours, 1992 hours, 2664 hours, 3336 hours, 4680 hours, and 6024 hours following drug administration.

In the full analysis set, approximately half (55.3%) were female in the biosimilars group and 57.8% were female in the reference drug cohort. The geometric mean ratios of LY01011 and the reference drug for the primary pharmacokinetic parameters were 98.13% and 100.32%, respectively, meeting the 90% confidence intervals (CIs) acceptance range between 80 – 125%. Additionally, the geometric mean ratios of the pharmacodynamic parameters, including AUEC0→t and the maximum effect (Emax) were 98.71% and 99.80%, respectively, were within the pre-defined acceptance range of 80%-125%. Results also demonstrated pharmacokinetics.

Regarding safety, the biosimilar was deemed comparable and tolerable between groups. Compared with patients receiving LY01011, a similar number of patients reported a Grade 3 or above treatment-emergent adverse events (TEAEs) in the reference product cohort (4 vs 2 participants, respectively). Additionally, 3 subjects reported a serious adverse event. However, none of the grade 3 or above Grade 3 TEAEs or serious adverse events were linked to the study drug, LY01011.

No participant was anti-drug antibody (ADA) positive in either group prior to the study drug administration. Only 1 patient in the reference drug cohort tested positive for ADA; however, no patient was ADA-positive in the LY01011 cohort. No neutralizing antibody (Nab) was reported in either group throughout the trial.

“LY01011, a recombinant fully human anti-RNAKL monoclonal antibody, was processed as a biosimilar to the reference product denosumab,” investigators concluded. “LY01011 has the same active pharmaceutical ingredient as denosumab along with dose strength and dose administration for demonstration of biosimilar between the 2 products. LY01011 is similar to denosumab regarding the manufacturing process, quality control, pharmacological studies and data from non-clinical studies.”

^References

^{Ding Y, Liu Y, Dou C, Guo S. A randomized trial comparing LY01011, biosimilar candidate, with the reference product denosumab (Xgeva®) in healthy Chinese subjects. J Bone Oncol. 2023;42:100499. Published 2023 Sep 1. doi:10.1016/j.jbo.2023.100499}

^{Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res. 12(20) (2006) 6243-49.}