Denosumab Biosimilar LY01011 Demonstrates Bioequivalence in Phase 1 Trial
核心洞察
LY01011, a denosumab biosimilar developed by Shandong Boan Biotechnology, demonstrated bioequivalence to the reference drug Xgeva® in a randomized phase 1 study of 168 healthy Chinese participants.
The biosimilar met primary pharmacokinetic endpoints with geometric mean ratios of 98.13% for Cmax and 100.32% for AUC0-t, both falling within the predefined 80-125% acceptance range.
Safety profiles were comparable between groups, with 97.6% of LY01011 recipients and 96.4% of reference drug recipients experiencing treatment-emergent adverse events, mostly Grade 1 in severity.
A phase 1 clinical trial has demonstrated that LY01011, a biosimilar candidate to denosumab (Xgeva®), exhibits comparable pharmacokinetics, pharmacodynamics, and safety profiles to the reference drug in healthy Chinese participants. The findings, published in the Journal of Bone Oncology, support the continued development of this more affordable alternative to treat bone metastases (搜索) from solid tumors (搜索) and multiple myeloma (搜索).
Study Design and Participants
Investigators conducted a randomized, single-center, double-blind, single-dose, parallel-controlled phase 1 study involving 168 healthy Chinese adults aged 18-50 years. Participants were randomized 1:1 to receive either a 120 mg subcutaneous dose of LY01011 (n=85) or the reference drug denosumab (n=83). The study population was well-balanced, with 55.3% female participants in the biosimilar group and 57.8% in the reference drug cohort.
LY01011, developed by Shandong Boan Biotechnology Co (搜索), LTD, is a recombinant fully human anti-receptor activator of nuclear Kappa-B ligand (RANKL (搜索)) monoclonal antibody designed as a biosimilar to denosumab. Preclinical studies showed no statistically significant differences between LY01011 and denosumab in pharmacokinetics, pharmacodynamics, and pharmacological toxicities.
Pharmacokinetic Bioequivalence Achieved
The primary pharmacokinetic analysis demonstrated bioequivalence between LY01011 and the reference drug. The geometric mean ratios for key parameters were 98.13% for maximum plasma concentration (Cmax) and 100.32% for area under the concentration-time curve from time zero to last quantifiable concentration (AUC0-t). Both values fell within the predefined acceptance range of 80-125%, with 90% confidence intervals of 88.96-108.26% and 91.04-110.54%, respectively.
Secondary pharmacokinetic parameters also supported biosimilarity, with the geometric mean ratio for AUC0-∞ reaching 100.39% (90% CI: 91.15-110.57%). The mean elimination half-life was 19.30 days for LY01011 compared to 20.20 days for denosumab, consistent with historical data for the reference drug.
Pharmacodynamic Similarity Confirmed
Pharmacodynamic assessments using serum C-terminal telopeptide of type I collagen (sCTX-1) as a biomarker of bone resorption showed comparable effects between treatments. The geometric mean ratios for area under the effect curve (AUEC0-t) and maximum effect (Emax) were 98.71% and 99.80%, respectively, both within the 80-125% acceptance range.
Mean sCTX-1 concentrations declined rapidly by 6 hours following administration, with more than 80% reduction from baseline by Day 6 in both groups. The maximum mean percentage reductions were 85.27% for LY01011 and 85.02% for denosumab, with effects lasting until Day 140.
Comparable Safety Profiles
Safety analysis revealed similar adverse event profiles between groups. In the LY01011 group, 83 participants (97.6%) experienced 383 treatment-emergent adverse events (TEAEs), compared to 80 participants (96.4%) with 343 TEAEs in the reference drug group. The majority of events were Grade 1 in severity, with 82 participants (96.5%) in the LY01011 group and 78 participants (94.0%) in the denosumab group experiencing drug-related TEAEs.
The most commonly reported adverse events included blood parathyroid hormone increased (90.6% vs 81.9% for LY01011 vs denosumab) and hypophosphatemia (55.3% vs 59.0%). Grade 3 or higher TEAEs occurred in 4 participants (4.7%) in the LY01011 group and 2 participants (2.4%) in the denosumab group, with none considered related to the study drugs.
Three participants experienced serious adverse events leading to study withdrawal, including contusion, neck injury, head injury, and lumbar vertebral fracture in the LY01011 group, and ectopic pregnancy and scrotal injury in the denosumab group. All serious adverse events were deemed unlikely related to study drugs.
Low Immunogenicity Risk
Immunogenicity assessments showed favorable results for LY01011. All participants tested negative for anti-drug antibodies (ADA) at baseline. Only one participant in the reference drug group (1.2%) tested positive for ADA on Day 196, while no participants in the LY01011 group developed ADA responses. No neutralizing antibodies were detected in either group throughout the study.
Clinical Implications
The study results support LY01011's potential as a biosimilar alternative to denosumab, which was FDA-approved in 2010 for preventing skeletal-related events in patients with multiple myeloma (搜索) and bone metastases (搜索) from solid tumors (搜索). In certain countries, access to the reference product is limited due to high costs, making biosimilar options valuable for overcoming cost barriers and expanding treatment access.
"LY01011 has the same active pharmaceutical ingredient as denosumab along with dose strength and dose administration for demonstration of biosimilar between the two products," the investigators concluded. "LY01011 is similar to denosumab regarding the manufacturing process, quality control, pharmacological studies and data from non-clinical studies."
The company's related product LY06006, a biosimilar to denosumab (Prolia®) for osteoporosis (搜索) treatment, was already approved by China's National Medical Products Administration in 2022. An ongoing phase 3 study is currently comparing LY01011's efficacy, safety, and immunogenicity with reference denosumab in patients with bone metastases (搜索) from solid tumors (搜索).