Denosumab biosimilar HLX14 versus EU-denosumab in postmenopausal women at high fracture risk: a randomized, double-blind, multicenter phase 3 trial

Biosimilars can increase access to efficacious drugs. This randomized, double-blind phase 3 study demonstrated efficacy equivalence between HLX14 and EU-denosumab and comparable safety, pharmacokinetics, and immunogenicity in postmenopausal women with osteoporosis at high risk of fracture. The findings provided direct evidence for HLX14 as a potential denosumab biosimilar. HLX14 is a proposed biosimilar of denosumab. This randomized, double-blind, multicenter, parallel-controlled phase 3 study aimed to compare the equivalence between HLX14 and European Union-sourced denosumab (EU-denosumab). Elderly female subjects with osteoporosis at high risk of fracture were randomized to receive two doses of HLX14 or EU-denosumab. At Week 52, subjects receiving EU-denosumab were re-randomized 1:1 to continue with a third dose of EU-denosumab or switch to HLX14, while those receiving HLX14 continued with a third dose of the drug. The co-primary endpoints were the percent change from baseline in lumbar spine BMD (LS-BMD) at Week 52, and the area under the effect-time curve for percent change of serum type I collagen C-telopeptide from baseline to Week 26 (AUEC 0-26W ). Initially, 514 subjects were enrolled (256 vs. 258) across 40 hospitals in China. An increase in LS-BMD was evident in both groups (6.10% vs. 5.90%) at Week 52. The adjusted mean difference was 0.23% (90% confidence interval [CI]: −0.36%, 0.83%; 95% CI: −0.48%, 0.95%), demonstrating efficacy equivalence as the 95% and 90% CIs fell within the pre-specified equivalence margins of −1.45% to 1.45%. Similarly, pharmacodynamic equivalence was shown with the 95% and 90% CIs for the geometric mean ratio of AUEC 0-26W (1.01, 90% CI: 0.99, 1.04; 95% CI: 0.98, 1.05) fully contained within the equivalence margins of 0.8 to 1.25. The results of all secondary efficacy endpoints also supported the equivalence between HLX14 and EU-denosumab. Safety profiles were comparable and remained similar even after the single switch of treatment. The findings from this phase 3 study support biosimilarity between HLX14 and denosumab. This trial was registered at Clinicaltrials.gov (NCT05352516).