Denosumab Biosimilar CT-P41 Demonstrates Pharmacokinetic Equivalence

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A single dose of denosumab biosimilar, CT-P41, showed pharmacokinetic equivalence and comparable safety and immunogenicity among a cohort of healthy male Asian participants, according to a study published in Expert Opinion on Biological Therapy.¹

Denosumab was originally approved in the United States and Europe in 2010 for the treatment of postmenopausal women with osteoporosis and to increase bone mass in patients with high fracture risk. The drug is currently used as an initial treatment in this patient population and a part of sequential treatment for those with severe osteoporosis coupled with a very high risk of fracture.²

“The high cost of biologic therapies can limit widespread patient access to treatment, particularly considering that prolonged therapy may be required to treat chronic conditions such as osteoporosis,” wrote a group of Korean investigators. “Biosimilars can improve global patient access to effective treatments and significantly reduce the associated costs for healthcare systems. For instance, the introduction of infliximab and etanercept biosimilars gave rise to cost savings of £38.8 billion over a 2-year period.”

To evaluate the pharmacokinetic similarity of the biosimilar compared with the reference product, the double-blind, 2-arm, parallel-group, phase 1 study randomized healthy males 1:1 to receive a single 60 mg subcutaneous dose of CT-P41 or denosumab.

The primary outcomes were area under the concentration - time curve (AUC) from time zero to infinity (AUC0-inf), AUC from time zero to the last quantifiable concentration (AUC0-last), and maximum serum concentration (Cmax). Pharmacokinetic equivalence was achieved if 90% confidence intervals (CIs) for ratios of geometric least-squares means (gLSMs) were within the predefined 80-125% equivalence margin. Other endpoints of interest included pharmacodynamics, safety, and immunogenicity.

A total of 151 patients were enrolled in the trial, of which 74 received CT-P41 and 77 received the reference drug. Demographics and characteristics at baseline were similar across groups, with a median age of 38 (range 28 — 55) years. The overall median body mass index (BMI) was 24.5 kg/m2 and the overall median body weight was 74.8 kg.

The primary endpoint was achieved, with CT-P41 demonstrating comparable pharmacokinetics. The 90% CIs for ratios of gLSMs were within the equivalence margin for AUC0-inf (100.4-114.7), AUC0-last (99.9-114.3), and Cmax (95.2-107.3).

The safety, immunogenicity, and pharmacodynamics were also similar across treatment arms. All patients had ≥ 1 post-treatment positive anti-drug antibody (ADA) result, the proportion of which peaked on day 85 and were comparable between groups (CT P41: n = 72 [97.3%]; denosumab: n = 73 [94.8%]).

A total of 282 treatment-emergent adverse events (TEAEs) were reported in 114 subjects, most of which were labeled as mild or moderate in intensity. No new safety signals were identified during the trial, with the most frequent TEAE among both treatment groups being decreased blood calcium (< 8.5 mg/dL; n = 63). Infection was reported in 26.5% of participants (n = 40), although most were considered unrelated to treatment. The most common infection was nasopharyngitis, which aligns with previous studies evaluating denosumab.

Investigators noted the sampling period of 253 days as a strength of the study, as it allowed the pharmacokinetic parameters to be adequately described. However, generalizability of results was limited as patients with chronic conditions are generally treated with denosumab every 6 months, as opposed to the single dose administered in this trial.

“Further studies to establish biosimilarity between CT‑P41 and US-denosumab include an ongoing phase 3 multidose study comparing efficacy, pharmacokinetics, pharmacodynamics, and safety in patients with postmenopausal osteoporosis,” investigators concluded.

References

1. ^{Kim A, Hong JH, Shin W, et al. A randomized, double-blind, single-dose, phase 1 study comparing the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of denosumab biosimilar CT‑P41 and reference denosumab in healthy males. Expert Opin Biol Ther. Published online February 22, 2024. doi:10.1080/14712598.2024.2316846}
2. ^{Curtis EM, Reginster JY, Al-Daghri N, et al. Management of patients at very high risk of osteoporotic fractures through sequential treatments. Aging Clin Exp Res. 2022;34(4):695–714. doi: 10.1007/s40520-022-02100-4}