Denosumab Biosimilar KN012 Matches Reference Drug in Phase 3 Osteoporosis Trial

A denosumab (Prolia; Amgen) biosimilar candidate, KN012, demonstrated clinical equivalence to US-reference denosumab for the treatment of postmenopausal osteoporosis (PMO) in a 12-month, double-blind, randomized, active-controlled phase 3 trial conducted across 25 centers in China.¹ The findings, published in Bone Reports, support KN012 as a viable lower-cost alternative for patients at high fracture risk.

KN012 achieved BMD equivalence with US-approved denosumab in postmenopausal women in China. | Image credit: Art_spiral - stock.adobe.com

“The primary objective was to establish equivalence for the mean percent change from baseline in lumbar spine BMD [bone mineral density] at month 12,” wrote the researchers of the study. “Secondary objectives included assessment of additional efficacy endpoints, safety, bone turnover markers, population pharmacokinetics, and immunogenicity, aiming to provide high-quality evidence for the clinical value and accessibility of a denosumab biosimilar in the Chinese PMO population.”

Trial Design Directly Compared Biosimilar With Reference Product

Denosumab, a fully human monoclonal antibody that targets RANKL, inhibits osteoclast-mediated bone resorption and has been a mainstay PMO therapy since the pivotal FREEDOM (NCT00089791) trial demonstrated reductions in vertebral and nonvertebral fracture risk. Despite its established efficacy, cost has remained a persistent barrier to access, prompting biosimilar development efforts worldwide.

The study enrolled 279 Chinese women aged 50 to 80 years with a T-score between −2.5 and −4.0 at the total hip or lumbar spine, plus at least one additional fracture risk factor. Participants were randomized 1:1 to receive 60 mg of KN012 or US-denosumab subcutaneously at baseline and month 6, with all patients also receiving daily calcium and vitamin D supplementation. Unlike 2 earlier Chinese denosumab biosimilar trials that used placebo controls, this study was the first head-to-head, active-controlled comparison against the reference product in this population, a design intended to yield more direct equivalence evidence.

Primary End Point Met With Narrow Margins

The primary efficacy analysis indicated that the least squares mean difference between the KN012 group and the US-denosumab group was 0.22% (95% CI, −0.78, 1.23) in the full analysis set and 0.11% (95% CI, −0.92, 1.14) in the per-protocol set. Both confidence intervals fell entirely within the predefined equivalence margin (±1.75%), confirming clinical equivalence between KN012 and US-denosumab. Secondary efficacy end points, safety, bone turnover markers, population pharmacokinetics, and immunogenicity results were comparable between the 2 groups up to month 12.

Secondary bone mineral density end points at the total hip, femoral neck, and trochanter also improved similarly in both arms, and bone turnover markers (s-CTX and P1NP) followed comparable suppression-and-recovery patterns across the dosing interval.

Safety and Immunogenicity Profiles Were Comparable

Treatment-emergent adverse events occurred in 85.7% of the KN012 group and 86.3% of the US-denosumab group. Adverse drug reactions—most commonly hypocalcemia, hypophosphatemia, and urinary tract infection—occurred at similar rates, and all were grade 1 or 2. Serious adverse events were reported in 8.6% of the KN012 group vs 13.7% of the reference group, with no events attributed to the study drug except a single case of liver enzyme elevation in the US-denosumab arm, later judged unrelated to treatment. No cases of osteonecrosis of the jaw, atypical femoral fracture, or serious infection—risks flagged in the denosumab label—were observed in either arm.

Immunogenicity was low across both products. By month 12, no KN012 recipients tested positive for anti-drug antibodies, compared with 2.3% of US-denosumab recipients; no neutralizing antibodies were detected in either group at any time point.

Biologic pricing has long constrained broader use of denosumab despite its favorable long-term benefit-risk profile, and biosimilars are positioned to expand access without compromising outcomes.² In the US, where multiple denosumab biosimilars have launched following FDA approval, payer modeling has projected measurable savings from conversion: one recent analysis estimated per-member-per-month savings of $0.59 under a base-case scenario assuming majority conversion to biosimilars for osteoporosis and oncology indications within 5 years. As additional denosumab biosimilars like KN012 generate further equivalence data, managed care organizations may find further support for formulary strategies favoring biosimilar-first approaches, potentially easing cost barriers for patients at high fracture risk while preserving the clinical benefits associated with RANKL inhibition.

“Comparable efficacy in terms of bone mineral density gains, along with similar safety and pharmacokinetic profiles, was observed between the 2 treatments,” wrote the researchers.^{1 “}The study employed a parallel-group design without crossover. These findings collectively support KN012 as a well-tolerated and effective biosimilar alternative in this patient population.”

References

1. Zhu X, Liu J, Mao Y, et al. Comparison of KN012, a denosumab biosimilar, versus reference denosumab in Chinese postmenopausal women with osteoporosis: efficacy, safety, and population pharmacokinetics in a 12-month phase III study. Bone Reports. 2026;29:101916. doi:10.1016/j.bonr.2026.101916
2. Myshko D. Biosimilar denosumab could save $0.59 per member per month. Managed Healthcare Executive^®. December 3, 2025. Accessed July 31, 2026. https://www.managedhealthcareexecutive.com/view/biosimilar-denosumab-could-save-0-59-per-member-per-month