Background/Objectives: To assess the clinical similarity in terms of efficacy, pharmacodynamics (PD), pharmacokinetics (PK), safety, and immunogenicity between MB09 (denosumab biosimilar) and the reference product [RP, (Prolia®)] up to 18 months in women with postmenopausal osteoporosis (PMO). Methods: Women with PMO received three doses of 60 mg of MB09 or RP subcutaneously, every 6 months [two doses in the main treatment period and one dose in the transition period (TP)]. The primary efficacy endpoint was the percent change from baseline (%CfB) in lumbar spine bone mineral density (BMD). Secondary endpoints included other efficacy parameters and PD, PK, safety, and immunogenicity assessments. Results: A total of 555 subjects received MB09 (N = 278) or RP (N = 277). At month 12, %CfB in lumbar spine BMD was comparable between groups (MB09 versus Prolia) and met the predefined equivalence margins. Secondary efficacy endpoints—%CfB in lumbar spine BMD at 6 months and %CfB in hip and femoral neck BMD at 6 and 12 months—were similar between groups. PD marker (serum carboxy terminal cross linking telopeptide of type I collagen) was similarly suppressed in both groups, and the inhibition was maintained in the TP. PK results showed similar denosumab systemic exposure for MB09 and the RP. Both study treatments were well tolerated with similar safety profiles throughout the study period. The incidence of anti-denosumab antibodies was very low. Conclusions: MB09 demonstrated equivalent efficacy to the reference denosumab in women with PMO. All secondary efficacy endpoints, together with PD, PK, safety, and immunogenicity assessments, supported MB09 as a denosumab biosimilar (NCT05338086, EudraCT No. 2021-003609-24).

To establish the therapeutic equivalence of RGB-14-P and reference denosumab (RD) in postmenopausal women with osteoporosis through demonstrating equivalent efficacy and similar safety, pharmacodynamics (PD), and immunogenicity when transitioning from RD to RGB-14-P. Patients (n = 188) who had received two 60-mg doses of RGB-14-P or RD (day 1 and week 26) in a randomised, blinded, controlled phase 3 study were re-randomised 1:1:1 at week 52 to continue RGB-14-P (n = 63) or RD (n = 63) or transition from RD to RGB-14-P (n = 62) and followed to week 78. Gains in lumbar spine, hip, and femoral neck bone mineral density (BMD) observed in the first 52 weeks of treatment were further improved up to week 78 in all three groups, including patients who transitioned from RD to RGB-14-P. Incidences of new fragility fractures were comparable. Changes from baseline in serum PD markers (serum C-telopeptide of type I collagen and procollagen type I N-terminal propeptide) were maintained. The transition did not induce a discernible immunological reaction, and there were no clinically meaningful between-group differences in safety. Treatment responses to RGB-14-P or RD seen during the first 52 weeks of treatment further improved to week 78; transitioning from RD to RGB-14-P had no discernible impact on efficacy, PD, immunogenicity, or safety. The totality of the evidence on the proposed biosimilar RGB-14-P available to date demonstrated structural and functional similarity as well as PK, PD, and therapeutic equivalence to reference denosumab, which suggests that RGB-14-P can be considered for long-term treatment, as well as a continuation of denosumab treatment.

Objectives:To demonstrate therapeutic equivalence of the proposed denosumab biosimilar FKS518 to the originator denosumab (US-licensed Prolia®, reference product), a potent antiresorptive biologic that increases bone mineral density (BMD) and reduces the risk of fractures, in women with postmenopausal osteoporosis. Methods:This 78-week double-blind, controlled, randomized, multicenter, multiple-dose, 2-arm, parallel-group study compared the efficacy (BMD), pharmacodynamic (bone biomarkers), safety, tolerability, and immunogenicity profiles of FKS518 with those of reference denosumab in women with postmenopausal osteoporosis. Primary-percentage change from baseline to 52 weeks in lumbar spine BMD and area under the effect curve from baseline to week 26 of serum C-terminal cross-linking telopeptide of type 1 collagen-and secondary results from the 52-week core treatment period are reported here. Results:Postmenopausal women with osteoporosis were randomized to receive 60 mg of FKS518 (n = 277) or reference denosumab (n = 276) every 26 weeks. Demographics, baseline characteristics and medical history were similar between treatment groups. Therapeutic equivalence of FKS518 and reference denosumab was demonstrated for efficacy and pharmacodynamic characteristics. All sensitivity analyses, supportive estimands, secondary efficacy, and pharmacodynamic endpoint analyses consistently showed similarity between the 2 products. Safety outcomes were consistent with the known safety profile of denosumab and were comparable between FKS518 and reference denosumab. Immunogenicity was infrequently observed and similar between the FKS518 and the reference denosumab groups. Conclusion:This study demonstrated therapeutic equivalence of, and comparable pharmacokinetics, safety, and immunogenicity profiles between FKS518 and reference denosumab, completing the clinical evidence to propose FKS518 as a biosimilar to denosumab.

• 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. To demonstrate the equivalence of the proposed denosumab biosimilar RGB-14-P and the reference denosumab (hereafter denosumab) in women with postmenopausal osteoporosis. 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 (

PURPOSE:This study evaluated the efficacy, safety, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of SB16 versus reference denosumab (DEN) up to 18 months in postmenopausal osteoporosis (PMO) patients, and assessed outcomes after switching from DEN to SB16 compared to those who continued with DEN or SB16. METHODS:457 PMO patients were initially randomized, with 407 re-randomized at Month 12 to either continue DEN (DEN+DEN), switch to SB16 (DEN+SB16), or continue SB16 (SB16 + SB16) through Month 18. Efficacy was assessed by the percent change from baseline in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck. Safety, PD, PK, and immunogenicity were evaluated throughout the study period. RESULTS:Mean percent changes from baseline in lumbar spine, total hip, and femoral neck BMD at Month 18 were comparable across treatment groups, indicating comparable efficacy between SB16 and DEN. The mean percent change in lumbar spine BMD was 6.8 % (SB16 + SB16), 6.2 % (DEN+SB16), and 6.8 % (DEN+DEN). Total hip BMD increased by 4.4 %, 3.5 %, and 4.0 %, and femoral neck BMD by 3.4 %, 3.1 %, and 2.7 % for SB16 + SB16, DEN+SB16, and DEN+DEN, respectively. Safety profiles were similar among groups, with no new safety concerns identified after switching. Only one patient in the DEN+SB16 group developed non-neutralizing anti-drug antibodies by Month 18, indicating a low immunogenicity risk for SB16. CONCLUSION:Switching from DEN to SB16 demonstrated comparable efficacy, safety, PD, PK, and immunogenicity in PMO patients relative to those who continued DEN. SB16 was well tolerated over 18 months, demonstrating comparable outcomes to DEN.

Context SB16 is a proposed biosimilar to reference denosumab (DEN; brand name: Prolia).Objective This phase 3 randomized, double-blind, multicenter study evaluated the biosimilarity of SB16 to DEN in women with postmenopausal osteoporosis (NCT04664959).Design The study included 457 postmenopausal osteoporosis patients who had a lumbar spine or total hip T-score between -2.5 and -4. Patients were randomized in a 1:1 ratio to receive either 60 mg of SB16 or DEN subcutaneously at month 0 and month 6. At month 12, patients were rerandomized to continue with the assigned treatment or switch from DEN to SB16 up to month 18. This report includes results up to month 12.Methods The primary endpoint was the percent change from baseline in lumbar spine bone mineral density (BMD) at month 12. Secondary endpoints including the percent change from baseline in BMD of the lumbar spine (except for month 12), total hip, and femoral neck; pharmacokinetic, pharmacodynamic (serum C-telopeptide of type I collagen, and procollagen type I N-terminal propeptide), safety, and immunogenicity profiles were measured up to month 12.Results The least-squares mean differences in percent change from baseline in lumbar spine BMD at month 12 were 0.33% (90% CI, -0.25 to 0.91) in the full analysis set and 0.39% (95% CI, -0.36 to 1.13) in the per-protocol set; both within the predefined equivalence margin. The secondary endpoints were comparable between the 2 treatment groups.Conclusion The reported efficacy, pharmacokinetic, pharmacodynamic, safety, and immunogenicity data support the biosimilarity of SB16 to DEN.

Objective. Our goal was to assess the efficacy and safety of intravenous (IV) secukinumab for the treatment of adults with active axial spondyloarthritis (axSpA) in INVIGORATE-1. Methods. INVIGORATE-1 (NCT04156620) was a randomized, double-blind, parallel-group, phase 3 trial in patients with active axSpA (either radiographic or nonradiographic). Patients were randomized one to one to receive IV secukinumab (6 mg/kg at baseline followed by 3 mg/kg every four weeks) or IV placebo for 16 weeks. After week 16, patients randomized to placebo were switched to IV secukinumab (3 mg/kg every four weeks), and patients randomized to secukinumab continued treatment through week 52. The primary endpoint was the Assessment of SpondyloArthritis International Society (ASAS40) response at week 16. Safety was evaluated through week 60. Results. Among patients initially randomized to IV secukinumab (n = 264) or placebo (n = 262), 86.0% and 88.9% completed the entire 60-week study period, respectively. A higher proportion of patients receiving secukinumab versus placebo met the primary endpoint (ASAS40 response) at week 16 (40.9% vs 22.9%; P < 0.0001). By week 24, patients who switched from placebo to secukinumab at week 16 achieved ASAS40 response rates comparable to those in patients originally randomized to secukinumab. All secondary efficacy endpoints were met at week 16, and responses were sustained through week 52. No new or unexpected safety signals were observed with IV secukinumab. Conclusion. IV secukinumab was effective for the treatment of adults with active axSpA over 52 weeks. The safety profile was consistent with that in previous reports on subcutaneous secukinumab.

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

To evaluate the efficacy and safety of secukinumab 150 mg, with or without a loading regimen, using a self-administered prefilled syringe in patients with ankylosing spondylitis (AS) over 104 weeks from the MEASURE 4 study.Patients (N = 350) with active AS were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with loading dose (150 mg), without loading dose (150 mg no load), or placebo. All patients received secukinumab or placebo at baseline, weeks 1, 2, and 3 and every 4 weeks starting at week 4. The primary endpoint was the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) at week 16.A total of 96.9% of patients (339/350) completed 16 weeks and 82.6% (289/350) completed 104 weeks of treatment. The ASAS20 response rate at week 16 was 59.5% and 61.5% with 150 and 150 mg no load groups, respectively, versus placebo (47%; P = 0.057 and 0.054, respectively); the primary endpoint was not met. Increases in response rates achieved with secukinumab for ASAS20 at week 16 were sustained through week 104. The safety profile of secukinumab 150 mg, with or without a loading regimen, showed no new or unexpected safety signals.Secukinumab 150 mg, with or without loading regimen, provided rapid and sustained decreases in the signs and symptoms of patients with AS, but the differences were not statistically significant at week 16 due to higher than expected placebo responses. The responses and safety profile were consistent with previous phase 3 studies and sustained through 2 years.ClinicalTrials.gov identifier, NCT02159053.Novartis Pharma AG, Basel, Switzerland.

OBJECTIVE:To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis.METHODS:In this 52-week, double-blind, placebo-controlled (up to Week 20) study (NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs (DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from Week 20 to 60 are presented.RESULTS:Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52 (ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ≤ 2.6: Week 16 = 25%, Week 52 = 40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60.CONCLUSION:Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.

Objective To assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA).Methods In this 12-week, double-blind, placebo-controlled study, patients with active RA (n=350) were randomised 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing RA disease-modifying antirheumatic drug (DMARD) treatment. The primary end point was the percentage of patients achieving a 20% improvement in RA signs and symptoms according to American College of Rheumatology criteria (ie, an ACR20 response) at week 12. Changes in morning pain, duration of morning stiffness, 28-joint Disease Activity Score and health-related quality of life were also assessed.Results MR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% vs 29%, p<0.001) and ACR50 (22% vs 10%, p<0.006) and a greater median relative reduction from baseline in morning stiffness (55% vs 35%, p<0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28) (p<0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score) (p=0.003) as well as a greater improvement in physical function (36-item Short-Form Health Survey score) (p<0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%).Conclusion Low-dose MR prednisone added to existing DMARD treatment produced rapid and relevant improvements in RA signs and symptoms. ClinicalTrials.gov, number NCT00650078

Objective To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA).Methods Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16.Results Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one).Conclusions ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

the most frequent side effects (84.21%). First visit before age 60 years ensures a better adherence during the FU (p=0.018). Co-morbidities reduce adherence (p=0.047). Weekly bisphosponates absuntion presents better compliance rates than daily (p=0.005). Patients with history of fractures have better adherence (p<0.001). Adherence results higher since the first year post-fracture (p=0.048) and remain higher during FU (p=0.004). Dividing population in adherent and non-adherent at the 85% MPR cut-off results that non-adherent have an RR=1.75 of fracture. Considering the 3 periods of FU, adherence seems to increase over time (84.53% – 87,64% – 91.19%; p=0.025) Major determinants of adherence already described in clinical trials and relationship between adherence and fracture risk are confirmed in this real life study. An adherence rate increase is also detected with fractures history (more motivation) and in patients in therapy from many years. Conflict of interest: None declared.

In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained.Introduction: In the HORIZON pivotal fracture trial (PIT), enrolling 7736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum 11, n = 1652).Materials and Methods: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for mu CT analysis and histomorphometry.Results: Analysis of bone structure by mu LCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63 % median (71 % mean) reduction of the activation frequency (Ac.f; p < 0.0001) and reduced mineralizing surface (MS/BS; p < 0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p < 0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid.Conclusions: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.