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<h2>Abstract</h2><h3>Background:</h3> Biosimilars offer significant advantages for patients over originator products by reducing medication costs and improving access to treatments. Consequently, there is considerable interest in transitioning therapies from originator biologics to biosimilars. FKS518 is a candidate biosimilar to denosumab, a RANKL inhibitor used in patients with osteoporosis. This phase study (LUMIADE-3, NCT04934072) aimed to demonstrate therapeutic equivalence between FKS518 and reference denosumab in postmenopausal women with osteoporosis, and to evaluate whether a single treatment transition from the reference denosumab to FKS518 had any impact on efficacy, safety and immunogenicity. <h3>Objectives:</h3> LUMIADE-3 study demonstrated therapeutic equivalence between FKS518 and reference denosumab [1]. The impact of the single treatment transition from the reference denosumab to FKS518 on efficacy, safety and immunogenicity is presented here. <h3>Methods:</h3> The study was a randomized, double-blind, multicenter, multiple-dose, 2-arm, parallel-group trial in osteoporotic women aged 55-85 with confirmed postmenopausal status and centrally determined lumbar spine bone mineral density (LS-BMD) T-scores between -2.5 and -4.0, measured by dual energy X-ray absorptiometry (DXA). Patients were randomized 1:1 for three 60 mg administrations, stratified by age and prior bisphosphonate use. At week 52 (W52), those on reference denosumab were re-randomized 1:1 to continue or switch to FKS518, while those on FKS518 continued their treatment. The primary objective was to show equivalence in efficacy (percentage change from baseline (%CfB) in LS-BMD at W52) and pharmacodynamics (PD, Area under the effect curve (AUEC) of serum C-terminal cross-linking telopeptide of type 1 collagen (CTX) up to W26). Efficacy and safety endpoints at W52 and up to W78 included LS-BMD, BMD at femoral neck and total hip, occurrence of adverse events (AE), serious adverse events (SAE), local tolerability and immunogenicity. A repeated measures analysis of %CfB was performed, and safety parameters were reported descriptively for the three post-switch groups (continuous reference denosumab, switch to FKS518, and continuous FKS518). <h3>Results:</h3> A total of 553 patients were randomized to FKS518 (276) or reference denosumab (277). Efficacy and PD equivalence were demonstrated [1]. At W52, patients on reference denosumab were re-randomized to continue their treatment (125) or switch to FKS518 (124). Clinically relevant increases in LS-BMD, femoral neck BMD, and total hip BMD were seen at W52 in both treatment groups. At W78 after re-randomization changes from baseline in these BMD measures were similar between those who continued on reference denosumab and those who switched to FKS518 (Figure 1). Consistently, results from the repeated measures analysis of the %CfB in LS-BMD, femoral neck BMD and total hip BMD at W78 showed that the 95% CI for the difference between the continued group and the switched group were narrowed around zero. No clinically meaningful differences in safety, tolerability or immunogenicity were observed after switching from reference denosumab to FKS518 compared to patients who continued with either treatment (Table 1). During the Transition Period the most frequently reported TEAEs were Nasopharyngitis and Upper respiratory tract infection. Only 5 patients experienced injection site reactions during whole 78 week study, with no differences between treatments. None of the ISR was serious. The number of patients with anti-drug antibodies was low. <h3>Conclusion:</h3> The results of this study demonstrated therapeutic equivalence between FKS518 and the originator and showed sustained efficacy after transitioning from the originator to FKS518, with no impact on safety or immunogenicity. <h3>REFERENCES:</h3> [1] Sadek, J., Valter, I., de Souza, A., Szeles, P., Monnet, J. "A randomized, double-blind study to evaluate the efficacy, pharmacodynamics, safety and immunogenicity of FKS518 proposed biosimilar to denosumab with the originator in postmenopausal woman with Osteoporosis" <i>ASCO</i>, 2024. <b>Table 1.</b> Overview of adverse events during the Transition Period (TP-Safety Analysis Set) and the Overall Period (Safety Analysis Set). Figure 1<b>LS-BMD, BMD at femoral neck and total hip (g/cm2) by DXA over time in patients receiving FKS518, reference denosumab and patients who transitioned from reference denosumab to FKS518 at W52 (ITT Analysis set</b>) <h3>Acknowledgements:</h3> <b>NIL</b>. <h3>Disclosure of Interests:</h3> Serge Ferrari Fresenius Kabi Biopharma, Ewa Krecipro-Nizinska Fresenius Kabi Biopharma, Wojciech Pluskiewicz Fresenius Kabi Biopharma, Peter Szeles Fresenius Kabi Biopharma, Adriano de Souza Fresenius Kabi Biopharma, Joëlle Monnet Fresenius Kabi Biopharma, Ivo Valter Fresenius Kabi Biopharma. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.