Efficacy and safety of candidate biosimilar CT-P41 versus reference denosumab: a double-blind, randomized, active-controlled, Phase 3 trial in postmenopausal women with osteoporosis

Abstract

This 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles.

Purpose: To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis.

Methods: This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80-125% (for 95% CIs associated with geometric LS mean ratios).

Results: Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: - 0.139 [- 0.826, 0.548] in the full analysis set and - 0.280 [- 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab.

Conclusions: CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.

Keywords: Biosimilar; CT-P41; Denosumab; Equivalence; Osteoporosis.

Fig. 1

Patient disposition (ITT set and ITT set – TPII subset). ^aOne patient in each of the CT-P41 and US-denosumab groups who did not meet eligibility criteria were mistakenly randomized by study center staff. The patients terminated their study participation before first study drug administration. ^bOne patient in the CT-P41 maintenance group discontinued treatment at Week 52 owing to an ongoing adverse event; however, the patient continued to participate in the study (without study treatment) and completed TPII. ITT, intent-to-treat; TPII, Treatment Period II; US-denosumab, US-licensed reference denosumab

Fig. 2

Mean ± SD percent change from baseline in BMD for lumbar spine (a), total hip (b), and femoral neck (c) from baseline through Week 78 (FAS and FAS – TPII subset). BMD, bone mineral density; FAS, full analysis set; SD, standard deviation; TP, treatment period; US-denosumab, US-licensed reference denosumab

Fig. 3

Median (Q1, Q3) percent change from baseline in serum concentrations of s-CTX (a) and PINP (b) during TPI (PD set) and TPII (PD set – TPII subset). Serum concentrations below the LLoQ were set to the LLoQ, and values above the ULoQ were set to the ULoQ. EOS, end of study; LLoQ, lower limit of quantification; PD, pharmacodynamic; PINP, procollagen type I N-terminal propeptide; Q, quartile; s-CTX, serum carboxy-terminal cross-linking telopeptide of type I collagen; TP, treatment period; ULoQ, upper limit of quantification; US-denosumab, US-licensed reference denosumab