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A randomised Phase 3 study comparing the efficacy and safety of proposed denosumab biosimilar RGB-14-P and reference denosumab in women with postmenopausal osteoporosis
Open Access
14.10.2025
Original Article
Erschienen in:
Verfasst von
Lothar Seefried
Lothar Seefried
Lothar Seefried and Serge Ferrari contributed equally to the work.
Musculoskeletal Center Würzburg, University of Würzburg, Würzburg, Germany
Serge Ferrari
Serge Ferrari
Lothar Seefried and Serge Ferrari contributed equally to the work.
Division of Bone Diseases, Geneva University Hospital, Geneva, Switzerland
Dénes Páll
Dénes Páll
Department of Medical Clinical Pharmacology, University of Debrecen, Debrecen, Hungary
Ombretta Viapiana
Ombretta Viapiana
Rheumatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
Jan Rosa
Jan Rosa
Osteoporosis and Metabolic Bone Disease Center Affidea, Prague, Czech Republic
Jerzy Supronik
Jerzy Supronik
NZOZ Centrum Medyczne Artur Racewicz, Bialystok, Poland
• In women with postmenopausal osteoporosis, proposed denosumab biosimilar RGB-14-P demonstrated equivalent efficacy and pharmacodynamics, and similar immunogenicity and safety to reference denosumab.
• RGB-14-P comprehensively replicates the therapeutic benefit of denosumab in a clinical setting.
• Denosumab biosimilars, such as RGB-14, have potential to provide lower-cost alternatives to denosumab with comparable efficacy and safety.
Purpose
To demonstrate the equivalence of the proposed denosumab biosimilar RGB-14-P and the reference denosumab (hereafter denosumab) in women with postmenopausal osteoporosis.
Methods
In this multicentre, double-blind, Phase 3 study (EudraCT 2020-006017-38; NCT05087030), participants were randomised 1:1 to subcutaneous RGB-14-P or denosumab 60 mg every 6 months, on Day 1 and Week 26, with follow-up to Week 52. Primary endpoints were percentage change from baseline (%CfB) in lumbar spine bone mineral density (BMD) at Week 52 and area under the effective curve (AUEC) of %CfB serum C-terminal telopeptide of type 1 collagen (CTX) to Week 26. Secondary endpoints included %CfB in total hip and femoral neck BMD, vertebral and non-vertebral fragility fractures, immunogenicity, and safety to Week 52.
Results
Overall, 473 participants were randomised and received study drug (RGB-14-P, n = 242; denosumab, n = 231). Both primary endpoints demonstrated equivalence of RGB-14-P and denosumab. Adjusted mean (95% CI) %CfB in lumbar spine BMD at Week 52 was 4.89 (3.55, 6.24) for RGB-14-P and 4.55 (3.22, 5.87) for denosumab (estimated difference, 0.34; 95% CI, − 0.40, 1.09). Geometric mean ratio in AUEC of %CfB in CTX concentration was 1.01 (95% CI, 0.98, 1.05; P = 0.494). There were no statistical differences in %CfB in total hip and femoral neck BMD. Incidence of vertebral or non-vertebral fragility fractures was comparable between treatments. Anti-drug antibody incidence was < 1% in both arms. Safety was comparable between groups.
Conclusion
In women with postmenopausal osteoporosis, RGB-14-P demonstrated equivalent efficacy and pharmacodynamics, and similar immunogenicity and safety to denosumab.
Lothar Seefried and Serge Ferrari contributed equally to the work.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Introduction
Antiresorptive therapies for osteoporosis increase bone mineral density (BMD) and reduce fracture risk by limiting bone resorption by osteoclasts, decreasing bone remodelling, and increasing the degree of bone mineralisation while reducing mineralisation heterogeneity for up to 5 years of treatment [1‐3]. Currently, the most commonly used antiresorptive osteoporosis treatments are bisphosphonates [1]. They bind to bone mineral, particularly at sites of active bone remodelling [4]. During bone resorption, bisphosphonates are taken up by osteoclasts, resulting in osteoclast apoptosis and a reduction in overall resorptive capacity, leading to a decrease in fracture rates [5].
Denosumab is a monoclonal antibody that reduces osteoclastic bone resorption by binding receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting the development, function and survival of osteoclasts [1, 2]. Denosumab has been shown to significantly reduce the risk of vertebral, hip and nonvertebral fractures in multiple settings [2, 6‐11]. Based on this body of evidence, denosumab has been approved for the treatment of osteoporosis in males and postmenopausal females in the United States (US) and Europe in 2010, and is also approved for the treatment of bone loss in people at high risk of fracture due to androgen deprivation therapy for non-metastatic prostate cancer (European Medicines Agency [EMA], Food and Drug Administration [FDA]), adjuvant aromatase inhibitor therapy for breast cancer (FDA) and long-term systemic glucocorticoid therapy (EMA, FDA) [12, 13].
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Evidence of the efficacy and safety profile of denosumab in osteoporosis has been demonstrated in numerous clinical and real-world studies [2, 6‐8], with long-term data over 10 years showing that it retains a favourable benefit:risk ratio [14]. Denosumab has been shown to offer significantly greater improvements than bisphosphonates in overall BMD [7, 15, 16] and cortical BMD [5, 17]. Furthermore, several studies have confirmed that transitioning from different bisphosphonate pretreatments to denosumab is associated with an acceptable safety profile and leads to further reductions in markers of bone turnover and a significant further increase in BMD compared with continued bisphosphonate treatment [18]. Denosumab has also been shown to not only maintain, but to further increase BMD in patients previously treated with osteoanabolic agents [19, 20]. However, the higher costs of biologic therapies as compared with bisphosphonates may be a limiting factor for patient access [21, 22].
Denosumab biosimilars have the potential to improve treatment access for people with osteoporosis by providing high-quality, lower-cost alternatives to originator denosumab, with the same mechanism of action and a comparable efficacy and safety profile.
This study was part of a global development programme by Gedeon Richter for the biosimilar RGB-14, which is intended for global use, including in the US and Europe, and is manufactured within Europe. In light of differing indications, the compound is referred to as RGB-14-P and RGB-14-X for the treatment of osteoporosis and oncology indications, respectively. A comprehensive quality comparability programme has demonstrated the structural and functional similarity of RGB-14 and denosumab [23]. Furthermore, a Phase 1 study in healthy volunteers has established PK and PD equivalence between the biosimilar and the reference denosumab.
Purpose
This Phase 3 study aimed to demonstrate the clinical equivalence in efficacy of RGB-14-P and US-licensed reference denosumab (hereafter denosumab) and to compare the pharmacodynamic, immunogenicity and safety of the two treatments in women with postmenopausal osteoporosis.
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Methods
Study design
This was a multicentre, randomised, double-blind, two-arm parallel-group, Phase 3 study (EudraCT: 2020–006017−38; NCT05087030 [registered 8 October 2021]) conducted at 76 sites in Bulgaria, Czech Republic, Hungary, Italy, Poland, Spain, Ukraine and the US between September 2021 and November 2023. The full study protocol and statistical analysis plan are available at ClinicalTrials.gov [24]. Participants were randomised 1:1 and received subcutaneous RGB-14-P (Gedeon Richter) or denosumab (Prolia®, Amgen) 60 mg every 6 months (on Day 1 and Week 26) with follow-up to Week 52 (Fig. S1). At Week 52, a subset of participants (188) entered a transition period and were followed to Week 78. Here we report outcomes from the main study period.
Randomisation was performed using interactive response technology and was stratified by geographical region (US and Europe) and prior bisphosphonate use (yes/no). RGB-14-P and denosumab were administered subcutaneously by pre-filled syringe into the thigh, abdomen, or upper arm. In addition, all participants received at least 1 g of elemental calcium daily and at least 800 IU of vitamin D daily. The sponsor, all participants, investigators, and other study personnel who performed clinical assessments were blinded to assigned treatment; as the pre-filled syringes were not blinded, the pharmacy staff and monitor responsible for checking study drug accountability were unblinded but did not perform any clinical assessments.
Study participants
The study included women who were postmenopausal (defined as 12 months of spontaneous amenorrhoea with serum follicle-stimulating hormone levels in the postmenopausal range at screening, or having undergone bilateral oophorectomy [with or without hysterectomy] at least 6 weeks prior to screening), who were ≥ 60 and ≤ 90 years of age, had osteoporosis, BMD consistent with a lumbar spine T-score ≤ − 2.5 and ≥ − 4.0 as per dual energy X-ray absorptiometry (DXA) and body weight between ≥ 50 and ≤ 90 kg. Key exclusion criteria included a history or presence of severe vertebral fractures, more than 2 moderate vertebral fractures, hip fracture or atypical femur fracture. People with active healing fractures, bilateral hip replacement, hypocalcaemia, hypercalcaemia or vitamin D deficiency were not eligible. Patients who had received intravenous bisphosphonates (within 5 years prior to screening) or oral bisphosphonates (more than 3 years of cumulative use prior to screening or any dose within 1 year prior to screening) were excluded. The full list of eligibility criteria is included in the Supplementary Information, including additional exclusion criteria for a history of related comorbidities or receipt of relevant concomitant treatments. Written informed consent was obtained from each participant before any study-related procedures.
Study endpoints
The co-primary endpoints were the percentage change from baseline (%CfB) in lumbar spine BMD at Week 52 and the area under the effective curve (AUEC) of %CfB in serum C-terminal telopeptide of type 1 collagen (CTX) to Week 26. The latter was required as a co-primary endpoint for the EMA submission and included as a secondary endpoint for the US FDA submission.
The secondary endpoints included %CfB in lumbar spine BMD at Week 26, total hip and femoral neck BMD at Week 26 and Week 52, incidence of vertebral and non-vertebral fragility fractures up to Week 52, %CfB in serum procollagen type 1 N-terminal pro-peptide (P1NP) and serum CTX up to Week 52, immunogenicity (incidence of binding anti-drug antibodies [ADA] and neutralising antibodies [NAb] up to Week 52) and safety (AEs, clinical laboratory assessments, vital signs, physical examination and electrocardiograms).
Study assessments
BMD and X-ray
DXA scans were used to confirm participant eligibility and to determine changes in BMD; they were performed at screening and Weeks 26 and 52. BMD criteria for participant eligibility were confirmed by central independent review. For all participants, BMD was measured at the lumbar spine, total hip and femoral neck. Hologic (Marlborough, MA, USA) and Lunar (GE Healthcare, Chicago, IL, USA) scanners were used, and all scans were centrally analysed by Calyx International (now Perceptive; Billerica, MA, USA). Monthly instrument quality control and cross-calibration ensured the reliability of DXA measurements. Lateral spine X-rays were performed at screening and Week 52 to confirm participant eligibility and determine the occurrence of fractures and were centrally analysed by Calyx using the Genant score [25].
Markers of bone turnover
Serum samples were collected for measurement of serum concentrations of CTX and P1NP and analysed at a central laboratory (Eurofins Central, Breda, Netherlands). Participants were required to fast for a minimum of 8 h and refrain from extensive physical exercise for a period of 24 h prior to serum collection. Serum samples were collected from 07:30 to 10:00.
Immunogenicity
Antibodies to denosumab (anti-RGB-14-P antibodies and anti-denosumab antibodies) were evaluated in serum samples collected from participants. Samples were screened for the presence of binding ADAs, and positive samples were analysed to detect the neutralising potency of the antibodies. Immunogenicity analyses were performed centrally (Gedeon Richter PLC, Budapest, Hungary). Details of the immunogenicity assay methodology used in this study have been published elsewhere [26]. Participants were defined as ADA positive if they were ADA negative at baseline and subsequently tested positive at ≥1 post-baseline time point, or were positive at baseline with a significant ADA titre increase post-baseline. In participants who were ADA positive at baseline, a significant ADA titre increase was defined as a ≥fourfold increase in titre ratio (corresponding to a 75% increase).
Safety
All safety laboratory tests relevant for enrolment and endpoint assessment were performed at a central lab (Eurofins Central Laboratory, Lancaster, PA, USA, and Breda, Netherlands). Safety was monitored throughout the trial. AEs were coded with the Medical Dictionary for Regulatory Activities, and severity was evaluated with the Common Terminology Criteria for Adverse Events v5.0.
Statistical methods
The sample size calculation was based on data from prior studies conducted with denosumab and assumed that: the two-sided 95% confidence interval (CI) of the difference between the study arms in %CfB in lumbar spine BMD was contained within the equivalence margin of ± 1.45, the expected value in the reference arm was equal to 5.35, the expected difference between the study arms was equal to − 0.2675 (i.e. 5% of the expected reference arm value), and the expected common standard deviation (SD) was 3.44. Based on these assumptions, the total evaluable sample size required for evaluation of the primary efficacy endpoint with a margin of 1.45% and power of 90% was 362 (181 per arm). As such, approximately 434 women with postmenopausal osteoporosis were planned to be enrolled (217 per arm), accounting for a 17% drop-out in the study to have 362 evaluable participants.
For analysis of the co-primary endpoint of %CfB in lumbar spine BMD at Week 52, the treatment difference was estimated using an analysis of covariance (ANCOVA) model, with the following covariates: treatment arm, stratification factors at randomisation (previous use of bisphosphonates [yes/no] and geographical region [Europe, US]), baseline BMD value in the lumbar spine, machine type, and machine type*baseline BMD value interaction. Three separate analyses were performed on the full analysis set: an equivalence analysis (requested by the EMA) and non-inferiority and non-superiority analyses (both requested by the FDA). Equivalence was declared if the two-sided 95% CI of the mean difference was within the pre-defined equivalence margin of − 1.45 to 1.45%. The non-inferiority and non-superiority analyses were performed as two separate one-sided tests, each with an alpha of 0.05. Non-inferiority was declared if the lower limit of the 90% CI was greater than − 1.45; non-superiority was claimed if the upper limit of the 90% CI was less than 1.45. For the equivalence analysis, missing data were assumed to be missing completely at random and were not imputed. For the non-inferiority and non-superiority analyses, missing data in the denosumab arm were assumed to be missing at random and imputed accordingly, while missing data in the RGB-14-P group were assumed to be missing not at random and imputed under the null hypothesis (assumed to worsen by the equivalence margin [delta = − 1.45 when testing for non-inferiority and delta = 1.45 when testing for non-superiority]). Analysis methods for sensitivity, supplemental, and secondary analyses of the primary endpoint are described in the Supplementary Information.
For the co-primary endpoint of AUEC of the %CfB in serum CTX concentration until Week 26, the treatment difference was estimated using a mixed-effects ANCOVA model, with the following covariates: treatment arm, stratification factors at randomisation, and log of baseline serum CTX. Equivalence was concluded if the 95% CI of the treatment geometric mean ratio was within the 80% and 125% equivalence margin.
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The analysis of %CfB for secondary BMD endpoints was performed using a mixed model for repeated measures, including the same covariates as for the primary endpoint analysis.
Incidence of fractures was reported as the proportion of participants with at least one post-randomisation fracture, and the average treatment difference (95% CI) was computed using the Miettinen–Nurminen (score) method.
Results
Patient population
Of the 1210 screened participants, 473 were randomised (242 participants in the RGB-14-P treatment group and 231 in the denosumab treatment group; refer to the CONSORT flowchart provided in Fig. S2). All randomised participants received study treatment, and 436 (92.2%) participants completed the main period of the study (up to Week 52). The percentage of participants who completed the main period was comparable between the two treatment groups (RGB-14-P, 225 [93%] participants; denosumab, 211 [91.3%] participants).
At baseline, the overall population had a mean age (SD) of 66.7 (5.06) years and most participants (99.4%) were White. Demographics were well balanced between the two treatment groups (Table 1). Around 10% of participants in each arm had a history of fracture in the year prior to enrolment.
Table 1
Baseline characteristics (full analysis set)
RGB-14-P N = 242
Denosumab N = 231
Age, years, mean (SD)
66.7 (5.2)
66.8 (4.9)
Race, n (%)
White
241 (99.6)
229 (99.1)
Black or African American
0
2 (0.9)
Native Hawaiian or Other Pacific Islander
1 (0.4)
0
Height, cm, mean (SD)
159.2 (5.8)
159.3 (6.7)
Weight, kg, mean (SD)
64.0 (9.7)
65.1 (9.0)
BMI, kg/m2, mean (SD)
25.2 (3.5)
25.7 (3.8)
Osteoporosis diagnosis, n (%)
Prior diagnosis
188 (77.7)
163 (70.6)
New diagnosis
54 (22.3)
68 (29.4)
Femoral neck BMD T-Score, mean (SD)a
− 2.08 (0.64)
− 2.05 (0.74)
Total Hip BMD T-Score, mean (SD)a
− 1.80 (0.72)
− 1.78 (0.79)
Lumbar spine BMD T-Score, mean (SD)a
− 3.06 (0.40)
− 3.05 (0.43)
Mean serum P1NP levels, ng/mL (SD)b
60.85 (22.71)
61.36 (23.85)
Mean serum CTX levels, ng/mL (SD)b
0.51 (0.22)
0.51 (0.22)
Vertebral fractures, n (%) [events]c
5 (2.1) [5]
4 (1.7) [6]
Non-vertebral fractures, n (%) [events]c
70 (28.9) [115]
57 (24.7) [90]
Traumatic fractures, n (%) [events]c
2 (0.83) [3]
6 (2.60) [7]
Fractures within 1 year of screening, n (%) [events]c,d
23 (9.50) [27]
16 (6.93) [23]
Fractures within 2 years of screening, n (%) [events]c,d
25 (10.30) [31]
23 (9.96) [35]
BMI body mass index, BMD bone mineral density, CTX C-terminal telopeptide of type 1 collagen, P1NP type 1 N-terminal propeptide, SD standard deviation
aInstrument quality control- and cross calibration-corrected; bRGB-14-P, n = 240; denosumab, n = 228; cbased on participants’ medical history; dimputation performed in the case of incomplete medical history dates
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Efficacy
BMD
For the equivalence analysis of the BMD co-primary endpoint, the adjusted mean (95% CI) %CfB in lumbar spine BMD at Week 52 was 4.89% (3.55, 6.24) for RGB-14-P and 4.55% (3.22, 5.87) for denosumab (estimated difference, 0.34; 95% CI, − 0.40, 1.09). The 95% CI of the mean difference was within the pre-defined equivalence margin of − 1.45 to 1.45%, demonstrating that RGB-14-P was equivalent to denosumab.
For the non-inferiority analysis of the BMD co-primary endpoint, the adjusted mean (90% CI) %CfB in lumbar spine BMD at Week 52 was 4.70% (3.63, 5.77) for RGB-14-P and 4.52% (3.45, 5.59) for denosumab (estimated difference, 0.18; 90% CI, − 0.47, 0.83). As the lower limit of the 90% CI was greater than − 1.45, non-inferiority criteria were met.
For the non-superiority analysis of the BMD co-primary endpoint, the adjusted mean (90% CI) %CfB in lumbar spine BMD at Week 52 was 5.28% (4.21, 6.35) for RGB-14-P and 4.73% (3.66, 5.80) for denosumab (estimated difference, 0.55; 90% CI, − 0.10, 1.19). As the upper limit of the 90% CI was lower than 1.45, non-superiority criteria were met.
Sensitivity, supplemental, and secondary analyses further supported the equivalence, non-inferiority, and non-superiority findings for the co-primary endpoint of %CfB in lumbar spine BMD at Week 52 (Table S1).
There were no statistically significant differences between treatments for the secondary BMD endpoints of %CfB in lumbar spine, total hip, and femoral neck BMD up to Week 52 (Fig. 1).
Fig. 1
Adjusted mean percentage change from baseline (95% CI) in BMD at Week 26 and 52 (full analysis set)a. BMD bone mineral density, CfB change from baseline, CI confidence interval. aMixed model for repeated measures used to estimate %CfB (95% CI) and P-values
For the co-primary endpoint of AUEC of %CfB in serum CTX concentration to Week 26 (Fig. 2), the geometric mean ratio between the RGB-14-P and denosumab groups was 1.01 (95% CI 0.98 to 1.05; P = 0.494); the 95% CIs were within the pre-defined 80% to 125% margin for equivalence.
Fig. 2
Percentage change from baseline in serum CTX to Week 26 (PD analysis set)a. Error bars represent the SD. ANCOVA analysis of covariance, AUEC area under the effective curve, CfB change from baseline, CI confidence interval, CTX C-terminal telopeptide of type 1 collagen, PD pharmacodynamic, SD standard deviation. aThe large SD in the denosumab arm was the result of two outlier patients. bPerformed with a mixed-effects model ANCOVA with natural log-transformed AUEC data as the dependent variable and treatment arm, stratification factors (previous use of bisphosphonates [yes/no] and geographical region [Europe, US]), and log of baseline serum CTX as covariates. Log-scale fitted mean and treatment group differences (RGB-14-P – denosumab), together with associated 95% CIs, were back-transformed. The delta method was applied to back transform the geometric mean standard error used for the computation of corresponding 95% CIs
Serum P1NP and CTX levels both decreased up to Week 52, with comparable reductions between treatment groups, supporting the similar effect of RGB-14-P and denosumab on bone turnover (Table 2).
Table 2
Serum P1NP and CTX concentrations (PD analysis set)
RGB-14-P
Denosumab
P1NP
Baseline
Mean, ng/mL (SD) [n]
60.85 (22.71) [240]
61.36 (23.85) [228]
Week 4
Mean, ng/mL (SD)
46.96 (18.68) [235]
47.68 (17.22) [221]
Reduction from baseline, % (SD) [n]
22.10 (14.91) [234]
20.22 (15.09) [220]
Week 26
Mean, ng/mL (SD) [n]
18.94 (11.67) [217]
19.49 (9.49) [212]
Reduction from baseline, % (SD) [n]
65.92 (17.83) [216]
62.89 (29.29) [211]
Week 52
Mean, ng/mL (SD)
19.62 (10.30) [205]
19.57 (8.99) [198]
Reduction from baseline, % (SD) [n]
65.04 (19.13) [204]
63.82 (21.71) [198]
CTX
Baseline
Mean, ng/mL (SD) [n]
0.51 (0.22) [240]
0.51 (0.22) [228]
Week 4
Mean, ng/mL (SD) [n]
0.06 (0.02) [235]
0.06 (0.02) [221]
Reduction from baseline, % (SD) [n]
85.87 (9.57) [234]
85.38 (15.50) [220]
Week 26
Mean, ng/mL (SD) [n]
0.13 (0.09) [217]
0.15 (0.12) [212]
Reduction from baseline, % (SD) [n]
69.74 (23.21) [216]
61.51 (83.76) [211]
Week 52
Mean, ng/mL (SD) [n]
0.17 (0.14) [205]
0.17 (0.12) [198]
Reduction from baseline, % (SD) [n]
62.90 (29.00) [204]
58.26 (63.93) [198]
CTX C-terminal telopeptide of type 1 collagen, P1NP procollagen type 1 N-terminal propeptide, PD pharmacodynamic, SD standard deviation
Vertebral and non-vertebral fragility fractures
The incidence of vertebral and non-vertebral fragility fractures was similar between the RGB-14-P and denosumab groups at Week 52 (Table 3).
Table 3
Fragility fractures to Week 52 (full analysis set)
RGB-14-P N = 242
Denosumab N = 231
Vertebral fragility fractures
Number of fractures
7
9
Participants with fractures, n (%)
4 (1.7)
8 (3.5)
% difference between treatments (95% CI)a
−1.8% (−5.2 to 1.2)
Non-vertebral fragility fractures
Number of fractures
6
12
Participants with fractures, n (%)
4 (1.7)
10 (4.3)
% difference between treatments (95% CI)a
−2.7% (−6.3 to 0.4)
Location of non-vertebral fragility fractures, number of fractures
Foot
2
2
Rib
2
Forearm
1
Radius
1
Tooth
2
2
Hand
2
Humerus
2
1
Lower limb including ankle
1
CI confidence interval
aDifference equals the percentage of participants with fractures in the RGB-14-P group minus the denosumab group
Immunogenicity
There was no clinically meaningful difference in immunogenicity between the two treatment groups.
Up to Week 52, the overall incidence of ADAs was 0.8% (2/239) for RBG-14-P and 0.4% (1/228) for denosumab, and the overall incidence of NAbs was 0.4% in both groups (1/239 for RBG-14-P and 1/228 for denosumab).
Safety
The percentages of participants experiencing ≥ 1 treatment-emergent AE (TEAE), treatment-related TEAE or TEAE leading to treatment discontinuation were similar between the two treatment groups (Table 4). TEAEs were most frequently reported in the infections and infestations system organ class (incidence: RGB-14-P, 39.3%; denosumab, 38.5%). The most frequently reported TEAEs in the RGB-14-P group (≥ 5% of participants) were COVID-19 (9.9%), nasopharyngitis and upper respiratory tract infection (9.5% each), hypocalcaemia (9.1%), headache (5.4%) and arthralgia (5.0%). The incidences of common TEAEs were generally similar between groups.
Table 4
Treatment-emergent adverse events to Week 52 (safety analysis set)
Patients, n (%)
RGB-14-P N = 242
Denosumab N = 231
≥ 1 TEAE
158 (65.3)
152 (65.8)
≥ 1 TEAE leading to treatment discontinuation
2 (0.8)
2 (0.9)
≥ 1 serious TEAE
7 (2.9)
16 (6.9)
≥ 1 TEAE leading to death
0
1 (0.4)a
≥ 1 treatment-related TEAE
36 (14.9)
32 (13.9)
≥ 1 treatment-related TEAE leading to treatment discontinuation
1 (0.4)
0
≥ 1 serious treatment-related TEAE
0
0
≥ 1 fracture TEAE
9 (3.7)
18 (7.8)
≥ 1 serious fracture TEAE
1 (0.4)
1 (0.4)
Most frequently reported TEAEs, by preferred term (≥ 5% in either treatment arm)
COVID-19
24 (9.9)
24 (10.4)
Nasopharyngitis
23 (9.5)
20 (8.7)
Upper respiratory tract infection
23 (9.5)
10 (4.3)
Hypocalcaemia
22 (9.1)
22 (9.5)
Headache
13 (5.4)
4 (1.7)
Arthralgia
12 (5.0)
10 (4.3)
Hypertension
7 (2.9)
13 (5.6)
Most frequently reported TEAE SOC, by preferred term
Infections and infestations
95 (39.3)
89 (38.5)
Most frequently reported treatment-related TEAEs, by preferred term (≥ 3% in either treatment arm)
Hypocalcaemia
16 (6.6)
16 (6.9)
COVID-19 Coronavirus disease-19, SOC system organ class, TEAE treatment-emergent adverse event
aDeath due to myocardial infarction in a participant with a history of aortic valve incompetence, bundle branch block, cardiac hypertrophy, hypercholesterolaemia and hypertension. Deemed by the investigator to be unrelated to treatment
Discussion
This Phase 3, randomised, double-blind, multicentre clinical study demonstrated that RGB-14-P and denosumab have equivalent efficacy, as assessed by %CfB in lumbar spine BMD at Week 52, and equivalent pharmacodynamics, as assessed by AUEC of %CfB in serum CTX until Week 26, in participants with postmenopausal osteoporosis. Both primary endpoints met their pre-defined equivalence thresholds. Sensitivity and supplemental analyses supported the robustness of the primary efficacy endpoint findings. These results are in line with the FDA and EMA guidance for demonstrating equivalence of biosimilars with reference therapies [27, 28]. Secondary endpoint findings underscored the comparability of RGB-14-P and denosumab, with similar increases in total hip and femoral neck BMD, a comparable incidence of fragility fractures, and similar reductions in the %CfB of bone turnover markers P1NP and CTX between the study groups over 52 weeks of treatment. Immunogenicity was low overall, and the incidence of ADAs and NAbs was similar between groups. Both treatments were well tolerated, with few participants discontinuing due to AEs and a generally similar pattern of TEAEs between groups.
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The efficacy and tolerability of denosumab have been well established in clinical trials and real-world studies in women with postmenopausal osteoporosis [2, 6, 7]. Effectiveness in terms of BMD increase and suppression of bone turnover markers has been demonstrated for denosumab in multiple studies [7, 18]. In addition, reassuring long-term outcomes with denosumab have been demonstrated; notably, a favourable benefit:risk profile has been shown with a follow-up over 10 years in the Phase 3 FREEDOM extension study, with progressive increases in BMD, sustained low rates of vertebral fracture, and reductions in non-vertebral fracture risk, without increases in the risk of infection, cancer, or immunogenicity [2, 14]. Furthermore, modelling studies suggest additional gains in lumbar spine BMD beyond 10 years of treatment with denosumab [29].
Previous studies have demonstrated the cost effectiveness of denosumab versus other types of osteoporosis treatment [22, 30]. However, cost may still be a factor limiting patient access to denosumab treatment [21, 30]. Biosimilars to denosumab, such as RGB-14-P, offer the prospect of improving access by providing an alternative to originator denosumab at a lower cost [31].
It is well established that improvements in BMD and mitigation of bone resorption are only maintained for the duration of denosumab treatment and that discontinuation of therapy without transitioning to alternative interventions is associated with a large increase in bone resorption and the risk of fracture in at-risk patients [5, 32‐34]. It is therefore critical that treatment adherence to scheduled doses is maintained [5], and that appropriate long-term treatment strategies are applied. This may consist of either continued treatment with that compound or, alternatively, warrant appropriate follow-up treatment following denosumab discontinuation [32, 35] in order to prevent a ‘rebound effect’ and minimise fracture risk. Improved access to a broader range of approved denosumab biosimilars with decreased costs may facilitate continuation of treatment by reducing the risk of discontinuation for cost-related reasons.
Limitations
The incidence of fractures was relatively low in this study. Low fracture rates can present a challenge for the assessment of efficacy in trials of therapy for osteoporosis. In these cases, BMD measurements are a well-established surrogate for fracture rates [36‐41]. For example, meta-regression analyses of pooled randomised controlled trial data performed for the Study to Advance BMD as a Regulatory Endpoint (SABRE) project have shown that treatment-related changes in BMD are significantly associated with decreased fractures [39, 41]. Therefore, the improvements in BMD observed in this study are expected to translate into robust reductions in fracture risk.
Additional limitations include that the study population was homogeneous with respect to race and the study duration was only 1 year. Although this study was carried out in women with postmenopausal osteoporosis, it is reasonable to anticipate that the findings can be extrapolated with confidence to the other licensed indications of originator denosumab [12, 13, 42‐44].
Conclusion/Summary
In this Phase 3 study in women with postmenopausal osteoporosis, RGB-14-P and denosumab demonstrated similar improvements in lumbar spine, total hip and femoral neck BMD and similar reductions in the bone turnover biomarkers serum CTX and P1NP during 52 weeks of treatment. Fracture incidence, immunogenicity and safety were also comparable between treatment groups.
These results provide robust data for the comparability of RGB-14-P and denosumab, demonstrating that RGB-14-P effectively replicates the therapeutic benefit of licensed denosumab in a clinical setting. These data build on the findings of a comprehensive quality comparability programme that has demonstrated the structural and functional similarity between RGB-14-P and denosumab [23], as well as equivalent PK/PD demonstrated in the Phase I study. These findings provide additional supporting evidence for the broader application of denosumab biosimilars in clinical practice. Additional outcomes from the transition phase of this study showing results to Week 78 are anticipated.
Acknowledgements
The authors would like to thank the participating patients and their families, clinicians and study investigators. Medical writing support was provided by Timothy Davies, PhD, from Avalere Health Group Limited, and was funded by Gedeon Richter.
Declarations
Ethical approval
The conduct of this clinical study met all local legal and regulatory requirements and was in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board or Independent Ethics Committee for each study site before the start of the study (see Supplementary Information for details).
Informed consent
Informed consent was obtained from all individual participants included in the study.
Conflicts of interest
LS, SF and IT report receiving consulting and lecture fees from Gedeon Richter; JK, NJ, KH-K and EJ are employees at Gedeon Richter; DP, JR, JS, OV and RNL have no conflicts of interest to disclose.
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A randomised Phase 3 study comparing the efficacy and safety of proposed denosumab biosimilar RGB-14-P and reference denosumab in women with postmenopausal osteoporosis
Verfasst von
Lothar Seefried
Serge Ferrari
Dénes Páll
Ombretta Viapiana
Jan Rosa
Jerzy Supronik
Rodina Nestorova Licheva
Joachim Kiefer
Norbert Jeszenői
Károly Horvát-Karajz
Enikő Jókai
István Takács
Cummings SR, San Martin J, McClung MR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765. https://doi.org/10.1056/NEJMoa0809493CrossRefPubMed
7.
Brown JP, Prince RL, Deal C et al (2009) Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 24:153–161. https://doi.org/10.1359/jbmr.0809010CrossRefPubMed
Orwoll E, Teglbjaerg CS, Langdahl BL et al (2012) A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 97:3161–3169. https://doi.org/10.1210/jc.2012-1569CrossRefPubMed
11.
Saag KG, Wagman RB, Geusens P et al (2018) Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol 6:445–454. https://doi.org/10.1016/S2213-8587(18)30075-5CrossRefPubMed
Bone HG, Wagman RB, Brandi ML et al (2017) 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 5:513–523. https://doi.org/10.1016/S2213-8587(17)30138-9CrossRefPubMed
15.
Lyu H, Jundi B, Xu C et al (2019) Comparison of denosumab and bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 104:1753–1765. https://doi.org/10.1210/jc.2018-02236CrossRefPubMed
16.
Li M, Ge Z, Zhang B et al (2024) Efficacy and safety of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in osteoporosis not previously treated with bisphosphonates: a systematic review and meta-analysis of randomized controlled trials. Arch Osteoporos 19:89. https://doi.org/10.1007/s11657-024-01447-7CrossRefPubMedPubMedCentral
17.
Seeman E, Delmas PD, Hanley DA et al (2010) Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate. J Bone Miner Res 25:1886–1894. https://doi.org/10.1002/jbmr.81CrossRefPubMedPubMedCentral
18.
Miller PD, Pannacciulli N, Malouf-Sierra J et al (2020) Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates. Osteoporos Int 31:181–191. https://doi.org/10.1007/s00198-019-05233-xCrossRefPubMed
19.
Cosman F, Crittenden DB, Ferrari S et al (2018) FRAME study: the foundation effect of building bone with 1 year of romosozumab leads to continued lower fracture risk after transition to denosumab. J Bone Miner Res 33:1219–1226. https://doi.org/10.1002/jbmr.3427CrossRefPubMed
Garai AS, Huse D, Fizil A et al (2025) Comprehensive physico-chemical and functional similarity assessment study of RGB-14-P and RGB-14-X drug products as proposed biosimilars to denosumab reference products. BioDrugs 39:697–724. https://doi.org/10.1007/s40259-025-00738-wCrossRefPubMedPubMedCentral
24.
ClinicalTrials.gov (2024) Comparative efficacy and safety study of RGB-14-P and prolia® in women with postmenopausal osteoporosis: NCT05087030. https://clinicaltrials.gov/study/NCT05087030. Accessed 25 Mar 2025
Pap T, Király N, Fekete A, Tóth JP, Kónya A (2025) Target tolerance improvement of the immunogenicity assay developed for analysing samples from clinical trials of RGB-14, a proposed biosimilar to Prolia/Xgeva. J Immunol Methods 541:113878. https://doi.org/10.1016/j.jim.2025.113878CrossRefPubMed
27.
Services USDoHaH, Administration FaD (2016) Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. https://www.fda.gov/media/70958/download Accessed 31 Jan 2025
Kvien TK, Patel K, Strand V (2022) The cost savings of biosimilars can help increase patient access and lift the financial burden of health care systems. Semin Arthritis Rheum 52:151939CrossRefPubMed
32.
Cosman F, Huang S, McDermott M, Cummings SR (2022) Multiple vertebral fractures after denosumab discontinuation: FREEDOM and FREEDOM extension trials additional post hoc analyses. J Bone Miner Res 37:2112–2120. https://doi.org/10.1002/jbmr.4705CrossRefPubMed
33.
Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B (2017) Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 102:354–358. https://doi.org/10.1210/jc.2016-3170CrossRefPubMed
34.
Lu KH, Wang SI, Yang SF (2025) Denosumab withdrawal increases vertebral fracture and mortality risk compared with zoledronate. Eur J Endocrinol 192:180–190. https://doi.org/10.1093/ejendo/lvaf013CrossRefPubMed
Black DM, Cauley JA, Wagman R et al (2018) The ability of a single BMD and fracture history assessment to predict fracture over 25 years in postmenopausal women: the study of osteoporotic fractures. J Bone Miner Res 33:389–395. https://doi.org/10.1002/jbmr.3194CrossRefPubMed
Schini M, Vilaca T, Vittinghoff E et al (2024) Influence of age on the efficacy of pharmacologic treatments on fracture risk reduction and increases in BMD: RCT results from the FNIH-ASBMR-SABRE project. J Bone Miner Res 39:544–550. https://doi.org/10.1093/jbmr/zjae040CrossRefPubMedPubMedCentral
39.
Black DM, Bauer DC, Vittinghoff E et al (2020) Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials. Lancet Diabetes Endocrinol 8:672–682. https://doi.org/10.1016/S2213-8587(20)30159-5CrossRefPubMed
40.
Black DM, Thompson AR, Eastell R, Bouxsein ML (2024) Bone mineral density as a surrogate endpoint for fracture risk reduction in clinical trials of osteoporosis therapies: an update on SABRE. Lancet Diabetes Endocrinol 12:371–373. https://doi.org/10.1016/S2213-8587(24)00092-5CrossRefPubMed
41.
Eastell R, Vittinghoff E, Lui LY et al (2022) Validation of the surrogate threshold effect for change in bone mineral density as a surrogate endpoint for fracture outcomes: the FNIH-ASBMR SABRE project. J Bone Miner Res 37:29–35. https://doi.org/10.1002/jbmr.4433CrossRefPubMed
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