Denosumab Biosimilar LY01011 Demonstrates Therapeutic Equivalence in Phase 3 Bone Metastases Trial
核心洞察
LY01011, a denosumab biosimilar developed by Shandong Boan Biotechnology, met its primary endpoint by demonstrating equivalent efficacy to reference denosumab in reducing bone metabolism biomarker NTX in patients with bone metastases (搜索) from solid tumors (搜索).
The multicenter, randomized, double-blind phase 3 trial enrolled 850 patients and showed comparable safety profiles between LY01011 and denosumab, with no unexpected adverse reactions reported during the study period.
Both treatments achieved significant and sustained decreases in bone turnover markers, with maximum median reductions of approximately 80% in uNTX/uCr ratios within one week of treatment initiation.
A phase 3 clinical trial has demonstrated that LY01011, a biosimilar to denosumab developed by Shandong Boan Biotechnology Co, Ltd (搜索), shows equivalent efficacy and safety to the reference product Xgeva (Amgen) in treating patients with bone metastases (搜索) from solid tumors (搜索). The study, published in the Journal of Bone Oncology, met its primary endpoint with no unexpected adverse reactions reported.
Clinical Trial Design and Patient Population
The multicenter, randomized, double-blind phase 3 trial (NCT04859569) enrolled 850 eligible patients with bone metastases (搜索) from solid tumors (搜索). Participants were randomized at a 1:1 ratio into LY01011 (n = 424) and denosumab (n = 426) treatment groups. The study population had a mean age of 57.2 years, with 42.5% identifying as men and 54.2% having lung cancer (搜索).
Patients received either 120 mg of LY01011 or denosumab subcutaneously every 4 weeks during a 12-week double-blind treatment period. Following this phase, all patients received LY01011 until week 53. The trial's primary endpoint was the natural logarithm of change in urinary N-terminal crosslinked telopeptide of type 1 collagen level normalized to urine creatinine level (uNTX/uCr) at week 13 from baseline.
Primary Efficacy Results
The study successfully established equivalence between LY01011 and denosumab groups. The least-squares mean difference of the logarithmic change in uNTX/uCr ratios was well within the prespecified equivalence margins for the full analysis set at week 13 from baseline (LY01011 group, −1.810 [0.0404]; denosumab group, −1.791 [0.0406]). The difference between the two arms was approximately −0.019 (90% CI −0.110, 0.073) within the equivalence margins (90% CI −0.135, 0.135).
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. Subgroup analyses confirmed this equivalence across different patient demographics and tumor types.
Secondary Endpoints and Biomarker Analysis
Both treatment groups exhibited continuous reduction in serum bone-specific alkaline phosphatase (s-BALP) levels throughout the study. At weeks 13, 25, and 53, the median percent change in s-BALP levels from baseline was comparable between the two 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 skeletal-related events was comparable between the two groups, with no statistically significant difference observed. No significant differences were found between treatment groups regarding the time frame from baseline to weeks 25 and 53 for uNTx/uCr ratios and the time frame from baseline to weeks 13, 25, and 53 for s-BALP levels.
Safety Profile
During the double-blind treatment period, 91.3% of all patients experienced at least one treatment-emergent adverse event (TEAE), with comparable proportions in the LY01011 (91.7%) and denosumab (90.8%) groups. The most frequent TEAEs (≥ 20%) were decreased white blood cell count (32.5% vs 34.8%), 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). Hypocalcemia was the most common treatment-related adverse event (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.
Pharmacokinetic and Immunogenicity Analysis
A two-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). 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.
All patients were antidrug antibody (ADA) negative at study initiation. In the LY01011 group, one patient tested positive for ADAs with a titer of 80 at week 5, but subsequent tests were negative. Similarly, one 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.
Clinical Context and Implications
Bone metastases (搜索) cause an estimated 35,000 deaths in the US each year and present a significant socioeconomic burden. Denosumab received FDA approval in 2010 for the treatment of skeletal-related events in patients with bone metastases, and the first US biosimilars referencing denosumab were recently approved for treating osteoporosis (搜索) and hypercalcemia (搜索), in addition to preventing skeletal-related events.
The study authors noted that "switching therapeutic drugs after week 13 did not affect the efficacy, safety, or immunogenicity profiles of either group." However, they acknowledged limitations including the absence of long-term follow-up data and the exclusion of non-Chinese participants, which provides no data on LY01011's safety and efficacy in a global patient population.