Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.

Denosumab is a biologic treatment that stops bone breakdown. This clinical trial evaluated how similar GP2411 (a denosumab biosimilar in development) is compared with European-approved reference denosumab in women with post-menopausal osteoporosis. Biosimilars are highly similar to the original treatment (‘reference denosumab’) and may have a lower price. 263 patients were randomly assigned to receive GP2411 and 264 to reference denosumab. Treatment was given at the study beginning, at Week 26 and at Week 52. 124 patients were re-assigned at Week 52 to test the effect of changing from reference denosumab to GP2411. The study showed similarity in how the body interacts with the treatments, what effects the treatment has (both measured over 26 weeks), and bone mineral density (measured over 78 weeks). Antibody responses to GP2411 were detected in similar proportions of patients on each treatment. Reported adverse events were similar between treatments before Week 52, and from Week 52 to 78, and <5% of patients experienced serious adverse events. A change of treatment from reference denosumab to GP2411 did not affect outcomes. These results showed similarity between GP2411 and reference denosumab in this population. In future, GP2411 may enable more patients to benefit from denosumab.

Altoona Center for Clinical Research Duncansville PA 16635 United States

Clinic and Department of Rheumatology and Systemic Diseases of Connective Tissue University Hospital No 2 Bydgoszcz CM UMK 85 168 Bydgoszcz KP Poland

Clinical Development Biopharmaceuticals Hexal AG 83607 Holzkirchen BY Germany

Department of Medicine University Hospital Brugmann Université Libre de Bruxelles 1020 Brussels BE Belgium

Division of Clinical Medicine University of Sheffield Sheffield S10 2TN SYK United Kingdom

Masaryk University Faculty of Pharmacy Department of Pharmaceutical Technology 612 00 Brno JM Czech Republic

Medical Plus s r o 68601 Uherske Hradiste ZL Czech Republic

J Bone Miner Res. 2024 Aug 5;39(7):1042. doi: 10.1093/jbmr/zjae077. PubMed

Zobrazit více v PubMed

Prolia® (Denosumab). European Medicines Agency SmPC. 2022. Breda, The Netherlands: Amgen Europe B.V.; 2022.

Prolia® (Denosumab) [Package Insert]. 2023. Thousand Oaks, CA: Amgen Inc.; 2023.

Xgeva® (Denosumab) [Package Insert]. 2022. Thousand Oaks, CA: Amgen Inc.; 2022.

Xgeva® (Denosumab). European Medicines Agency SmPC. 2020. Breda, The Netherlands: Amgen Europe B.V; 2020.

Kendler DL, Cosman F, Stad RK, Ferrari S. Denosumab in the treatment of osteoporosis: 10 years later: a narrative review. Adv Ther. 2022;39(1):58–74. 10.1007/s12325-021-01936-y PubMed DOI PMC

Canadian Agency for Drugs and Technologies in Health . Common Drug Review Pharmacoeconomic Report for Prolia [Internet]. 2015. Accessed November 6, 2023. https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0414_ProliaMen_PE_Report.pdf

Karnon J, Shafie AS, Orji N, Usman SK. What are we paying for? A cost-effectiveness analysis of patented denosumab and generic alendronate for postmenopausal osteoporotic women in Australia. Cost Eff Resour Alloc. 2016;14(1):11. 10.1186/s12962-016-0060-5 PubMed DOI PMC

Kvien TK, Patel K, Strand V. The cost savings of biosimilars can help increase patient access and lift the financial burden of health care systems. Semin Arthritis Rheum. 2022;52:151939. 10.1016/j.semarthrit.2021.11.009 PubMed DOI

U.S. Food and Drug Administration . Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry [Internet]. 2015; https://www.fda.gov/media/82647/download

Weise M, Bielsky MC, De Smet K, et al. . Biosimilars: what clinicians should know. Blood. 2012;120(26):5111–5117. 10.1182/blood-2012-04-425744 PubMed DOI

European Medicines Agency . Biosimilars in the EU. Information Guide for Healthcare Professionals [Internet]. 2019. Accessed November 6, 2023. https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf.

Vasikaran S, Eastell R, Bruyère O, et al. . Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391–420. 10.1007/s00198-010-1501-1 PubMed DOI

Cummings SR, Martin JS, McClung MR, et al. . Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765. 10.1056/NEJMoa0809493 PubMed DOI

Bone HG, Bolognese MA, Yuen CK, et al. . Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008;93(6):2149–2157. 10.1210/jc.2007-2814 PubMed DOI

McClung MR, Lewiecki EM, Cohen SB, et al. . Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821–831. 10.1056/NEJMoa044459 PubMed DOI

Zheng J, van Schaick E, Wu LS, Jacqmin P, Perez Ruixo JJ. Using early biomarker data to predict long-term bone mineral density: application of semi-mechanistic bone cycle model on denosumab data. J Pharmacokinet Pharmacodyn. 2015;42(4):333–347. 10.1007/s10928-015-9422-4 PubMed DOI

Sutjandra L, Rodriguez RD, Doshi S, et al. . Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50(12):793–807. 10.2165/11594240-000000000-00000 PubMed DOI

Civoli F, Kasinath A, Cai XY, et al. . Recommendations for the development and validation of immunogenicity assays in support of biosimilar programs. AAPS J. 2020;22(1):7. 10.1208/s12248-019-0386-y PubMed DOI

FDA . Immunogenicity Testing of Therapeutic Protein Products — Developing and Validating Assays for Anti-Drug Antibody Detection. Guidance for industry [Internet]. 2019. Accessed November 6, 2023. https://www.fda.gov/media/119788/download

Bone HG, Wagman RB, Brandi ML, et al. . 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. 2017;5(7):513–523. 10.1016/S2213-8587(17)30138-9 PubMed DOI

Niazi SK. Biosimilars: harmonizing the approval guidelines. Biologics. 2022;2(3):171–195. 10.3390/biologics2030014 DOI

Moore TJ, Mouslim MC, Blunt JL, Alexander GC, Shermock KM. Assessment of availability, clinical testing, and US Food and Drug Administration review of biosimilar biologic products. JAMA Intern Med. 2021;181(1):52–60. 10.1001/jamainternmed.2020.3997 PubMed DOI PMC