Predefined Equivalence Margin Research Articles

QL1209 (pertuzumab biosimilar) versus reference pertuzumab plus trastuzumab and docetaxel in neoadjuvant treatment for HER2-positive, ER/PR-negative, early or locally advanced breast cancer: A multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial.

This randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab (Perjeta®) each with trastuzumab and docetaxel in neoadjuvant treatment of early or locally advanced breast cancer patients with HER2-positive, ER/PR-negative. Eligible patients were randomly (1:1) assigned to receive 4 cycles of neoadjuvant QL1209 or pertuzumab each with trastuzumab and docetaxel, and adjuvant treatment. The primary endpoint was total pathologic complete response (tpCR), with equivalence margins of 0.76 to 1.32. Among the 585 patients enrolled, 257 and 259 patients were assigned to the QL1209 and pertuzumab groups, respectively. The tpCR rates were comparable in the QL1209 (109/255, 42.75%; 90% CI 37.65 to 47.84) and pertuzumab (117/259, 45.17%; 90% CI 40.09 to 50.26) groups. The tpCR risk ratio was 0.95 (90% CI, 0.80 to 1.11), and the 90% CI fell within the predefined equivalence margin. The most common grade ≥3 treatment-related adverse event was decreased neutrophil count (10. 9% vs. 12.7%) in the QL1209 and pertuzumab groups. QL1209 demonstrated equivalent efficacy and comparable safety profile to the reference pertuzumab in neoadjuvant treatment of HER2-positive, ER/PR-negative, early, or locally advanced breast cancer. Chinadrugtrials.org CTR20201073; ClinicalTrials.gov NCT04629846.

Biosimilar Candidate CT-P42 in Diabetic Macular Edema: 24-Week Results from a Randomized, Active-Controlled, Phase III Study

ObjectiveTo demonstrate the therapeutic similarity of CT-P42 compared to reference aflibercept (Eylea®) in adult patients with diabetic macular edema (DME). DesignRandomized, active-controlled, double-masked, Phase III clinical trial ParticipantsPatients with a diagnosis of either type 1 or 2 diabetes mellitus (DM) with DME involving the center of the macula. MethodsPatients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 mL) by intravitreal injection every 4 weeks (5 doses) then every 8 weeks (4 doses) in the main study period. Results up to Week 24 are reported herein. Main Outcome MeasuresThe primary endpoint was mean change from baseline at Week 8 in best corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the two-sided 95% confidence interval (CI) (global assumptions) and two-sided 90% CI (US Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set. ResultsOverall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). BCVA improved from baseline to Week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the pre-defined equivalence margin of ±3 letters (95% CI −0.73, 1.88 [global]; 90% CI −0.52, 1.67 [FDA]). Through Week 24, other efficacy results for the two groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing at least one treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups. ConclusionsThis study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 mL) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Growth and gut comfort of healthy term infants exclusively fed with a partially hydrolysed protein-based infant formula: a randomized controlled double-blind trial.

This study aimed to investigate growth and gut comfort of healthy infants fed with a partially hydrolysed cow's milk protein-based infant formula (pHF) compared to a standard intact cow's milk protein-based formula (IPF). A double-blind, multi-center, randomized, controlled trial was performed. Healthy full-term, exclusively formula-fed infants (n = 345), aged ≤28 days were allocated to consume either a pHF (n = 173) or an IPF (n = 172) until the age of 17 weeks. The primary outcome was equivalence of weight gain (g/d) until the age of 17 weeks. The secondary outcomes were equivalence of other growth parameters, i.e., infants' weight, length, head circumference, body mass index (BMI) and anthropometric Z-scores, while tertiary outcomes were gut comfort, formula intake, and adverse events (AEs). Overall, 288 infants completed the study (pHF group: 138, IPF group: 150). No differences were observed between the two groups in weight gain (g/d) during the three-months intervention [p = 0.915 for the Per Protocol (PP) population]. The 90% CI was [-1.252 to 1.100] being within the pre-defined equivalence margin of ±3.0 g/d. Similar findings were observed in the Full Analysis Set (FAS) and the sensitivity analysis. Regarding the secondary outcomes, no differences over the intervention period were shown between the two groups in both the PP and FAS analysis sets. Average Z-scores were in the normal range based on World Health Organization (WHO) growth standards for both groups at all time points in both analysis sets. Stool consistency, amount, and colour were different in the two groups. No differences were observed in gut comfort, stool frequency, and formula intake, between the two groups. In total 14 AEs and 22 serious adverse events (SAEs) were reported of which 15 (12%) and 1 (5%) were considered as (possibly) related to the study product, respectively. The study demonstrates that the consumption of pHF results in adequate infant growth, equivalent to that of infants consuming IPF. Furthermore, the overall gut comfort was comparable between the two groups. Therefore, it can be concluded that the pHF is safe for and well tolerated by healthy infants. https://clinicaltrials.gov/study/NCT05757323?id=NCT05757323&rank=1, identifier (NCT05757323).

Abstract PO1-29-03: Efficacy, Safety, and Immunogenicity of TQ-B211 (a Trastuzumab Biosimilar) Plus Docetaxel versus Herceptin® Plus Docetaxel for HER2-positive Metastatic Breast Cancer: a Double-blind, Randomised, Multicenter, Phase 3 Trial

Abstract Background: Breast cancer is one of the most common malignant tumors in women worldwide. In China, the incidence of breast cancer has been steadily increasing. Approximately 30% of human breast cancers exhibit human epidermal growth factor receptor 2 (HER2) positivity, which is closely associated with tumor aggressiveness, high recurrence rate and high mortality. This study aimed to evaluate the efficacy, safety, and immunogenicity of TQ-B211 (a trastuzumab biosimilar) compared to the reference trastuzumab in combination with docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer. Methods: This randomized, multicenter, double-blind phase III equivalence study enrolled HER2+ metastatic breast cancer patients aged 18-75, ECOG PS ≤1, no prior systemic chemotherapy, biologic, or targeted therapy for recurrent or metastatic disease, and at least one measurable lesion (RECIST 1.1). The patients were randomly assigned to two groups: the experimental group received TQ-B211 (8 mg/kg iv on day 1, cycle 1, followed by 6 mg/kg q3w for cycles 2-8) in combination with docetaxel (75 mg/m2 on day 2, cycle1, followed by 75 mg/m2 on day 1 for cycles 2-8), while the control group received Herceptin® in combination with docetaxel. For subjects who completed 8 cycles of treatment without disease progression and demonstrated tolerability, they were subsequently administered TQ-B211 as monotherapy until disease progression or unsuitable for further treatment. The primary efficacy endpoint was ORR up to week 24 (ORR24w). Equivalence was declared if the 90% confidence interval (CI) of relative ratio (RR) value was within the range of 0.8 to 1.25. Secondary efficacy endpoints included duration of response (DoR); progression-free survival (PFS); disease control rate (DCR); overall survival (OS), safety and immunogenicity. Results: Between December 6, 2018 and July 31, 2021, a total of 386 patients (pts) were enrolled (192 pts in the TQ-B211 group and 194 pts in the Herceptin® group). In the intention-to-treat (ITT) population, the ORR24w of the TQ-B211 group was 67.19% (95% CI: 60.55, 73.83), while the ORR24w of the Herceptin® group was 65.98% (95% CI: 59.31, 72.65). The RR of the confirmed ORR24w between the two groups was 1.02 (90%CI, 0.90, 1.15), which fell entirely in the predefined equivalence margins (0.8, 1.25), indicating comparable efficacy of the two drugs. In the ITT population, the DCR of the TQ-B211 group and the Herceptin® group were 83.85% (78.65, 89.06) and 78.35% (72.56, 84.15) respectively, with no statistically significant difference between the two groups (P=0.1940). By the data cutoff date of October 31, 2021, the median PFS was not statistically different (P=0.6834); the median OS was not reached in both groups (P=0.9246). Additionally, the data results of the per-protocol (PP) population were similar to those of the ITT population. In total, similar rates of treatment-related grade ≥3 adverse events (41.05% vs. 46.39%) occurred in the TQ-B211 and Herceptin® groups, respectively. The incidence and magnitude of immunogenicity were low in both of the two groups (ADA: 0.53% vs. 0%, Nab: both negative). Conclusion: Equivalence for efficacy was demonstrated between TQ-B211 and Herceptin® on the basis of ORR24w. Safety and immunogenicity were comparable. Citation Format: Xichun Hu, Qingyuan Zhang, Shusen Wang, Tao Sun, Xiaohua Zeng, Weimin Xie, Zhongsheng Tong, Hui Cao, Huihua Xiong, Xiuwen Wang, Jin Yang, Shuqun Zhang, Ying Wang, Chunhong Hu, Kaijian Lei, Binlin Ma, Wei Liu, Zhiyong Yu, PeiJian Peng, Hongwei Yang, Zhijun Yuan, Xiaojia Wang, Xujuan Wang, Hong Wang, Yongqian Shu, Nanlin Li, Wenbin Yue, Jingfen Wang, Daqing Wang, Zhiguo Luo, Junyang Mo, Yarong Li, Lili Sheng. Efficacy, Safety, and Immunogenicity of TQ-B211 (a Trastuzumab Biosimilar) Plus Docetaxel versus Herceptin® Plus Docetaxel for HER2-positive Metastatic Breast Cancer: a Double-blind, Randomised, Multicenter, Phase 3 Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-29-03.

Comparative Effectiveness and Persistence of SB4 and Reference Etanercept in Patients With Psoriatic Arthritis in Norway.

We aim to compare drug effectiveness and persistence between the reference etanercept (ETN) and ETN biosimilar SB4 in patients with psoriatic arthritis (PsA) naive to ETN and to investigate drug effectiveness and persistence in those undergoing a mandatory nonmedical switch from ETN to SB4. We used a retrospective comparative database study including 1,138 patients with PsA treated with ETN or SB4 (years 1999-2021) in Norway. Disease activity score in 28 joints (DAS28) and drug persistence were compared between unmatched ETN (n = 644) and SB4 (n = 252) cohorts and in matched analyses (n = 144, both cohorts) at baseline using a propensity score (PS) to adjust for confounders. Drug persistence was analyzed with the Kaplan-Meier method. In unmatched analyses, difference in change from baseline between ETN (n = 140) and SB4 (n = 132) for DAS28 at one year was mean 0.67 (95% confidence interval [CI] 0.38-0.96) in favor of ETN. In PS-matched analyses, the difference in change from baseline between ETN (n = 54) and SB4 (n = 54) was mean 0.09 (95% CI -0.33 to 0.50), and the mean difference assessed with an analysis of covariance model was 0.01 (95% CI -0.38 to 0.40), both within predefined equivalence margin (±0.6). Drug persistence at one year was mean 0.75 (95% CI 0.71-0.78) for ETN, mean 0.58 (95% CI 0.51-0.63) for SB4, hazard ratio (HR) 2.45 (95% CI 2.02-2.97) in unmatched analysis, and mean 0.55 (95% CI 0.46-0.63) for ETN, mean 0.60 (95% CI 0.51-0.67) for SB4, HR 1.29 (95%CI 0.94-1.76) in PS-matched cohorts. At one year, outcomes for PsA disease activity and drug persistence were comparable for patients treated with either ETN or SB4. In patients undergoing a mandatory nonmedical switch from ETN to SB4, drug effectiveness was maintained during a two-year period.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 administered by auto-injector or pre-filled syringe: a randomized, open‑label, single-dose phase I study

ABSTRACT Background This study compared the pharmacokinetics (PK), immunogenicity, and safety of candidate tocilizumab biosimilar, CT-P47, administered via auto-injector (CT-P47 AI) or pre-filled syringe (CT-P47 PFS), in healthy Asian adults. Research design and methods In this phase I, multicenter, open-label study, participants were randomized 1:1 to receive a single 162 mg/0.9 mL dose of CT-P47 via AI or PFS. Primary endpoints were area under the concentration – time curve from time zero to infinity (AUC0–inf) and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the predefined 80–125% equivalence margin. Secondary PK parameters, immunogenicity, and safety outcomes were also assessed. Results Of 314 participants randomized (155 CT-P47 AI; 159 CT-P47 PFS), 310 received the study drug (153 CT-P47 AI; 157 CT-P47 PFS). Primary and secondary PK results, immunogenicity and safety were similar between groups. Ninety percent CIs for the ratio of gLSMs were within the predefined equivalence margin for AUC0–inf (85.87–102.94) and Cmax (82.98–98.16). Conclusions PK equivalence between CT-P47 AI and CT-P47 PFS was demonstrated in healthy Asian adults, with comparable immunogenicity and safety between the two devices. Trial registration ClinicalTrials.gov: NCT05617183.

A randomized, double-blind, single-dose, phase 1 study comparing the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of denosumab biosimilar CT‑P41 and reference denosumab in healthy males

ABSTRACT Background This study’s objective was to demonstrate pharmacokinetic (PK) similarity and safety of denosumab biosimilar, CT‑P41, and United States–licensed reference denosumab (US-denosumab) in healthy male Asian adults, considering also pharmacodynamic (PD) outcomes. Research design and methods This double-blind, two-arm, parallel-group, Phase 1 study randomized (1:1) healthy males to a single (60-mg) subcutaneous dose of CT‑P41 or US-denosumab. Primary endpoints were area under the concentration – time curve (AUC) from time zero to infinity (AUC0–inf), AUC from time zero to the last quantifiable concentration (AUC0–last), and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for ratios of geometric least-squares means (gLSMs) were within the predefined 80–125% equivalence margin. Secondary PK, PD, safety, and immunogenicity outcomes were also evaluated. Results Of 154 participants randomized (76 CT‑P41; 78 US-denosumab), 151 received study drug (74 CT‑P41; 77 US-denosumab). Primary and secondary PK results, PD results, safety, and immunogenicity were comparable between groups. Ninety percent CIs for ratios of gLSMs were within the predefined equivalence margin for AUC0–inf (100.4–114.7), AUC0–last (99.9–114.3), and Cmax (95.2–107.3). Conclusions Following a single dose in healthy males, CT‑P41 demonstrated PK equivalence with US-denosumab. Trial registration ClinicalTrials.gov: NCT06037395

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial

Biosimilars provide an opportunity to address unmet medical need by expanding access to biological treatments. This study aimed to show equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles of a proposed tocilizumab biosimilar BAT1806/BIIB800, to reference tocilizumab, in participants with rheumatoid arthritis with an inadequate response to methotrexate. This phase 3, multicentre, randomised, double-blind, active-controlled, equivalence study comprised a 24-week initial treatment period (results reported here) and a 24-week secondary treatment period. Participants were recruited at 54 centres across five countries (China, Ukraine, Poland, Georgia, and Bulgaria). Patients with active rheumatoid arthritis with an inadequate response to methotrexate were randomly assigned (1:1:2) to receive reference tocilizumab up to week 48, or reference tocilizumab up to week 24 followed by BAT1806/BIIB800 up to week 48 (the two reference tocilizumab groups were analysed as a single group in this analysis), or BAT1806/BIIB800 up to week 48 (the BAT1806/BIIB800 group), administered by intravenous infusion once every 4 weeks at a starting dose of 8 mg/kg. The primary endpoint was the proportion of participants who had a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 (for the European Medicines Agency [EMA]) or week 24 (for the US Food and Drug Administration [FDA] and China National Medical Products Administration [NMPA]) using prespecified equivalence margins (95% CI -14·5 to +14·5 [EMA], 90% CI -12·0 to +15·0 [FDA], and 95% CI -13·6 to +13·6 [NMPA]). The International Council for Harmonisation E9(R1) estimand framework, with strategies for addressing intercurrent events, was implemented for the efficacy evaluations with expected differences as per the predefined equivalence margins. This trial is registered at ClinicalTrials.gov (NCT03830203) and EudraCT (2018-002202-31), and is closed to new participants. Between Dec 19, 2018, and Jan 5, 2021, we randomly assigned 621 participants: 309 to the reference tocilizumab group and 312 to the BAT1806/BIIB800 group. The mean age was 50·5 years (SD 12·0), 534 (86%) were women, 87 (14%) were men, and 368 (59%) were White. For the primary estimands, estimated ACR20 response rates were 64·8% in the reference tocilizumab group and 69·0% in the BAT1806/BIIB800 group (treatment difference 4·1% [95% CI -3·6 to 11·9]) at week 12, and 67·9% in the reference tocilizumab group and 69·9% in the BAT1806/BIIB800 group (treatment difference 1·9% [90% CI -4·0 to 7·9; 95% CI -5·2 to 9·1]) at week 24. All confidence intervals were contained within the predefined equivalence margins. Comparable pharmacokinetic and immunogenicity profiles were observed for the reference tocilizumab and BAT1806/BIIB800 groups. Adverse events were reported by 201 (65%) participants in the reference tocilizumab group and 206 (66%) in the BAT1806/BIIB800 group; 196 (63%) participants in the reference tocilizumab group and 201 (64%) participants in the BAT1806/BIIB800 group reported a treatment-emergent adverse event. Five participants had a fatal event (reference tocilizumab n=1; BAT1806/BIIB800 n=4). BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab. Bio-Thera Solutions and Biogen.

Efficacy of SB12 (Eculizumab Biosimilar) in Asian and Non-Asian Patients with Paroxysmal Nocturnal Hemoglobinuria: Subgroup Analysis of a Global Phase III Randomized Controlled Trial

Background SB12 is a humanized monoclonal antibody biosimilar to reference eculizumab (ECU) which received marketing authorization in Europe in May 2023 after a comprehensive biosimilarity demonstration including non-clinical and clinical assessments. The pivotal SB12 Phase III study demonstrated equivalent clinical efficacy by evaluating lactate dehydrogenase (LDH) and comparable safety, pharmacokinetics, pharmacodynamics, and immunogenicity between SB12 and ECU in patients with paroxysmal nocturnal hemoglobinuria (PNH) (Jun Ho Jang et al., eJHaem 2022). Objective To analyze the efficacy of SB12 in Asian and non-Asian patients with PNH from the pivotal phase III study. Methods A total of 50 adult patients with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor (naïve) were randomized. All patients provided written informed consents and were randomized (1:1) to treatment sequence I (TS1: SB12 to ECU, n=25) or II (TS2: ECU to SB12, n=25), to receive 600 mg of SB12 or ECU intravenously every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter (maintenance phase). Patients were switched to ECU or SB12 at Week 26, and switched treatment was provided until Week 50. The primary endpoints included LDH level at Week 26 and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52. Equivalence was declared for LDH level at Week 26 if the two-sided 95% confidence interval (CI) of the mean difference in between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L. In addition, equivalence was declared for time-adjusted AUEC of LDH if the two-sided 90% CI of the ratio of geometric means between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]. Secondary endpoints included the LDH profile over time. Overall, post-hoc analysis in Asian and Non-Asian (based on race) patients who received either ECU or SB12 during the study period was conducted for the aforementioned efficacy endpoints. Results Asian patients were 27 (54.0%) of total 50. Overall, 15 (60%) Asian patients and 10 (40%) Non-Asian patients were randomized to TS1 and 12 (48%) Asian patients and 13 (52%) Non-Asian patients were randomized to TS2. Baseline demographic and disease characteristic were comparable between the two treatment sequences, with no significant differences between the treatment sequences by race between Asian and Non-Asian patients. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU in Asian (SB12 − ECU: -12.02, 95% CI [−126.87, 102.83]) and Non-Asian patients (SB12 − ECU: 76.12, 95% CI [−56.75, 208.99]) lied within the pre-defined equivalence margins (Table). The 90% CI of ratio of time-adjusted AUEC of LDH between SB12 and ECU in Asian patients (SB12/ECU: 1.01, 90% CI [0.92, 1.10]) lied within the pre-defined equivalence margin and was also comparable in Non-Asian patients (SB12/ECU: 1.15, 90% CI [0.90, 1.46]). The overall LDH profile during the study period was also comparable between Asian and Non-Asian patients. No patient developed anti-drug antibodies during the study period and no patient discontinued due to lack of efficacy. While the limited sample size suggests for caution, the comparable efficacy results by Asian and Non-Asian subgroups are also comparable to previously published results in the overall population (Jun Ho Jang et al., eJHaem 2022), with no significant differences identified. Conclusion SB12 showed comparable efficacy to ECU in complement-inhibitor naïve PNH patients in both Asian and Non-Asian subgroups. No patient developed anti-drug antibodies nor discontinued due to lack of efficacy during the study period.

A phase I, randomized, double-blind, single-dose pharmacokinetic study to evaluate the biosimilarity of SB16 (proposed denosumab biosimilar) with reference denosumab in healthy male subjects

ABSTRACT Background SB16 is a biosimilar to reference denosumab (DEN). This study assessed pharmacokinetic (PK) equivalence and evaluated pharmacodynamic (PD), safety, tolerability, and immunogenicity between SB16, European Union-sourced DEN (EU-DEN), and United States-sourced DEN (US-DEN). Research design and methods In this double-blind, parallel group, and single-dose study, healthy male subjects were randomized 1:1:1 to receive a single 60 mg dose of either SB16, EU-DEN, or US-DEN subcutaneously. PK, PD, safety, and immunogenicity were evaluated for 197 days. Primary PK endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration (Cmax). Equivalence was determined if 90% confidence intervals (CIs) for the ratio of geometric least squares means (LS Means) were within the equivalence margin of 0.80 to 1.25. Results A total of 168 subjects (56 per treatment group) were randomized. All of the corresponding 90% CI of geometric LS Means ratio of primary PK parameters were within the pre-defined equivalence margin. PD, safety, and immunogenicity profiles were also comparable between the treatment groups. Conclusion This study demonstrated PK bioequivalence between SB16, EU-DEN, and US-DEN in healthy male subjects. TrialRegistration CT.gov identifier: NCT04621318

Efficacy and Safety of the Aflibercept Biosimilar SB15 in Neovascular Age-Related Macular Degeneration

Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy. To establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD). This was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up. Participants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56. The primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of -3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity. The mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, -1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, -110.4 μm vs AFL, -115.7 μm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable. In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD. ClinicalTrials.gov Identifier: NCT04450329.

Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration

To evaluate the efficacy, safety, and immunogenicity of a ranibizumab biosimilar candidate (XSB-001) versus reference product (Lucentis) for neovascular age-related macular degeneration (nAMD). Phase III, multicenter, randomized, double-masked, parallel-group study. Patients with nAMD. Eligible patients were randomized (1:1) to receive intravitreal injections of XSB-001 or reference ranibizumab (0.5 mg [0.05 ml]) in the study eye once every 4 weeks for 52 weeks. Efficacy and safety assessments continued through 52 weeks of treatment. Primary end point was change from baseline in best-corrected visual acuity (BCVA) by ETDRS letters at week 8. Biosimilarity was concluded if the 2-sided 90% confidence interval (CI) (United States) or 95% CI (rest of world) for the difference in least-squares (LS) mean change in BCVA at week 8 between treatment groups was within the predefined equivalence margin of ± 3.5 letters. In total, 582 patients (n= 292 XSB-001, n= 290 reference ranibizumab) were randomized. Mean age was 74.1 years, most patients (85.2%) were White, and 55.8% were women. Mean BCVA score at baseline was 61.7 and 61.5 ETDRS letters in the XSB-001 and reference ranibizumab groups, respectively. At week 8, the LS mean (standard error [SE]) change in BCVA from baseline was 4.6 (0.5) ETDRS letters in the XSB-001 group and 6.4 (0.5) letters in the reference ranibizumab group (LS mean [SE] treatment difference:-1.8 [0.7] ETDRS letters; 90% CI,-2.9 to-0.7; 95% CI,-3.1 to-0.5). The 90% CI and 95% CI for LS mean difference in change from baseline were within the predefined equivalence margin. At week 52, LS mean (SE) change in BCVA was 6.4 (0.8) and 7.8 (0.8) letters, respectively (LS mean [SE] treatment difference,-1.5 [1.1] ETDRS letters; 90% CI,-3.3 to 0.4; 95% CI,-3.6 to 0.7). There were no clinically meaningful differences between treatments in anatomical, safety, or immunogenicity end points through week52. XSB-001 demonstrated biosimilarity to reference ranibizumab in patients with nAMD. Treatment with XSB-001 for 52 weeks was generally safe and well tolerated, with a safety profile similar to the reference product. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Replacement of the Mouse LD50 Assay for Determination of the Potency of AbobotulinumtoxinA with a Cell-Based Method in Both Powder and Liquid Formulations.

Botulinum neurotoxins (BoNTs) are important therapeutic agents. The in vivo median lethal dose (LD50) assay has been commonly used to measure the potency of BoNT commercial preparations. As an alternative, we developed cell-based assays for abobotulinumtoxinA in both powder (Dysport®, Azzalure®) and liquid (Alluzience®) formulations using the in vitro BoCell® system. The assays demonstrated linearity over 50-130% of the expected relative potency, with a correlation coefficient of 0.98. Mean recoveries of 90-108% of the stated potency were observed over this range. The coefficients of variation for powder and liquid formulations, respectively, were 3.6% and 4.0% for repeatability and 8.3% and 5.0% for intermediate precision. A statistically powered comparability assessment of the BoCell® and LD50 assays was performed. Equivalence was demonstrated between the assays for the liquid formulation at release and end of shelf life using a paired equivalence test with predefined equivalence margins. For the powder formulation, the assays were also shown to be equivalent for release samples and when determining loss of potency following thermal degradation. The BoCell® assay was approved for establishing the potency of abobotulinumtoxinA for both powder and liquid formulations in Europe and for the powder formulation only in the USA.

Bevacizumab biosimilar candidate TAB008 compared to Avastin® in patients with locally advanced, metastatic EGFR wild-type non-squamous non-small cell lung cancer: a randomized, double-blind, multicenter study.

Bevacizumab (Avastin®) is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Used alone or in combination with chemotherapy and/or immunotherapy, Avastin® has shown promising efficacy in many cancers. This study compared the efficacy and safety of TAB008 with Avastin® sourced from the EU (bevacizumab-EU), in patients with non-squamous non-small cell lung cancer (nsNSCLC). In this randomized, double-blind, multicenter, phase III similarity study, treatment naïve for metastatic lung cancer., EGFR wild-type, locally advanced, metastatic, or recurrent non-squamous, non-small cell, lung cancer (nsNSCLC) patients were enrolled and randomized (1:1) into TAB008 or Avastin® groups. Patients received TAB008 or Avastin® 15mg/kg intravenously plus paclitaxel/carboplatin for 4-6 cycles followed by TAB008 or Avastin® 7.5mg/kg until disease progression, unacceptable toxicity or death. The primary endpoint compared the objective response rate (ORR) within 6 cycles as read by an independent radiological review committee (IRRC). Secondary endpoints compared disease control rate (DCR) Within 6 cycles, duration of response (DoR), progression-free survival (PFS), a year overall survival rate (OSR), overall survival (OS), safety, immunogenicity, and steady-state pharmacokinetics. A total of 549 nsNSCLC patients were enrolled (277 in TAB008 group and 272 in Avastin® group). In the full analysis set, ORRs were 55.957% for TAB008 and 55.720% for Avastin®, and the ORR ratio was 1 (90% CI 0.89-1.14), well within the predefined equivalence margin of 0.75-1.33. No significant differences were found in DCR within 6 cycles (95.703% vs 95.367%, p = 0.8536), DoR (8.17 vs 7.3months, p = 0.3526), PFS (9.10 vs. 7.97months, p = 0.9457), 1year overall survival rate (66.2% vs 68%, p = 0.6793), or OS (20.4 vs 17.6months, p = 0.6549). Serious adverse events (SAEs) occurred in 37.55% (104/277) of patients in the TAB008 group and 34.32% (93/271) in the Avastin® group. Anti-drug antibodies were reported in 3 of 277 (1.08%) TAB008 patients, and 5 of 271 (1.85%) Avastin® patients, neutralizing antibody (Nab) was positive in 1 patient on Avastin®, which became negative upon follow-up. The steady-state trough concentrations (Cssmin) were 106.13μg/mL in TAB008 group and 96.03μg/mL in Avastin® groups, with the treatment group ratio of LS geometric means fully contained within the bioequivalence limits of 80.00-125.00% (90% CI was 101.74-120.05%). TAB008 is similar to Avastin® in terms of efficacy, safety, and pharmacokinetic parameters, with comparable immunogenicity. ClinicalTrials.gov number; NCT05427305.

A phase III, randomised, double-blind, multi-national clinical trial comparing SB12 (proposed eculizumab biosimilar) and reference eculizumab in patients with paroxysmal nocturnal haemoglobinuria.

Treatment of paroxysmal nocturnal haemoglobinuria (PNH) includes the monoclonal antibody eculizumab. This randomised, double-blind, multi-national cross-over Phase III study in PNH patients aimed to demonstrate the equivalence of the proposed eculizumab biosimilar SB12 and reference eculizumab (Soliris, ECU). PNH patients with lactate dehydrogenase (LDH) ≥1·5× upper limit of normal were randomised into treatment sequences SB12-ECU or ECU-SB12. Four weekly infusions of 600mg eculizumab were followed by fortnightly infusions of 900mg until week 50 (ECU/SB12 cross-over at week 26). Primary endpoints were LDH at week 26 and the time-adjusted area under the effect curve (AUEC) of LDH over weeks 14‒26 and 40‒52. Among 46 patients (92%) who completed the study, the least squares mean (LSM) difference in LDH at week 26 (34·48; 95% confidence interval [CI] -47·66‒116·62U/l) and geometric LSM ratio of time-adjusted AUEC of LDH (1·08; 90% CI 0·95‒1·23) were within pre-defined equivalence margins. Mean numbers of transfused red blood cell units, other secondary endpoints, pharmacokinetics, and pharmacodynamics were comparable. No patients developed anti-drug antibodies. Treatment-emergent adverse events were reported in 72% and 68% of patients in the SB12 and ECU treatment groups, respectively. The results demonstrate equivalence of SB12 to ECU and support SB12-use in PNH patients.

Comparison of recombinant human FSH biosimilar QL1012 with Gonal-f® for ovarian stimulation: a phase-three trial

Research questionAre QL1012 and Gonal-f® equivalent in women undergoing ovarian stimulation for assisted reproductive technology (ART)? DesignThis multicentre, randomized, assessor-blinded, phase-three trial was conducted at 13 centres in China. Eligible patients were infertile women; age 20–39 years; body mass index 18–30 kg/m2; regular menstrual cycles; and indication for ART. After successful pituitary downregulation, patients were randomly assigned (1:1) to receive QL1012 or Gonal-f®, stratified by age (initial dose of 75–150 IU for women younger than 30 years, 150–225 IU for women aged 30–34 years and 225–300 IU for women aged ≥35 years, subcutaneously, once daily). The primary end point was the number of oocytes retrieved. ResultsBetween October 2018, and June 2019, 341 patients were included in the per-protocol set. The mean numbers of oocytes retrieved were 14.7 ± 7.0 in the QL1012 group (n = 169) and 13.4 ± 6.1 in the Gonal-f® group (n = 172). Adjusted by analysis of covariance model, the least-squares mean difference was 1.3 oocytes (95% CI –0.1 to 2.7; P = 0.0650), within the pre-defined equivalence margins of ±3.0. Similar results were observed in the full analysis set. Additionally, no statistical differences were found in secondary end points except oestradiol concentration (median 3948.0 pg/ml versus 3545.3 pg/ml; P = 0.0015). Ovarian hyperstimulation syndrome (12.4% versus 13.1 %) and other adverse events were similar between the two groups. ConclusionsTherapeutic equivalence and similar safety profiles were demonstrated between QL1012 and Gonal-f® in women undergoing ovarian stimulation for ART.

SGLT-2 inhibition by empagliflozin exerts neutral effects on experimental arterial thrombosis in a murine model of low-grade inflammation

Abstract Introduction Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular disease (ASCVD). Selective sodium-glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of glucose-lowering. Yet, its mechanism of action remains largely undetermined. Purpose We aimed to test whether empagliflozin affects arterial thrombus formation in baseline conditions or low-grade inflammation, a systemic milieu shared among patients with ASCVD. Methods Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg BW) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg BW), before carotid thrombosis was induced by photochemical injury. The translational value of these findings was investigated in primary human aortic endothelial cells (HAECs) and plasma samples of patients randomized to empagliflozin therapy. Results The between-group difference in doppler-flow probe detected time-to-occlusion (TTO) remained within the predefined equivalence margin (Δ=|10.50|), irrespective of low-grade inflammation (95% confidence interval [CI], −9.82 to 8.85 and −9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmol/l, respectively (Fig. 1). Ex vivo platelet aggregometry suggests similar platelet activation status, corroborated by unchanged circulating platelet-factor 4 (PF4) plasma levels. In concert, carotid PAI-1 expression and TF activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity (Fig. 1). In HAECs pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression (Fig. 2). Accordingly, among patients with established ASCVD or at high cardiovascular (CV) risk randomized to 10 mg empagliflozin daily signatures of thrombotic (i.e., TF) and fibrinolytic activity (i.e., PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up (Fig. 2). Conclusion SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under baseline conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating thrombosis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science FoundationSwiss Heart FoundationFoundation for Cardiovascular Research–Zurich Heart House

P829: A PHASE III RANDOMIZED CLINICAL TRIAL COMPARING SB12 (PROPOSED ECULIZUMAB BIOSIMILAR) WITH REFERENCE ECULIZUMAB IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Background: SB12, a proposed eculizumab biosimilar, is a humanized monoclonal antibody that blocks complement C5 cleavage, thereby inhibits terminal complement-mediated intravascular hemolysis. Aims: The randomized, double-blind, multicenter, cross-over study was aimed to demonstrate comparable clinical efficacy by evaluating the lactate dehydrogenase (LDH), safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SB12 and reference eculizumab (ECU) in paroxysmal nocturnal hemoglobinuria (PNH) patients (NCT04058158). Methods: A total of 50 patients aged ≥ 18 years with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor were included. All patients provided written informed consents and were randomized (1:1) to treatment sequence I (TS1: SB12 to ECU, n=25) or II (TS2: ECU to SB12, n=25). Patient received 600 mg of SB12 (TS1) or ECU (TS2) intravenously every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter (maintenance phase). The treatment was switched to ECU (TS1) or SB12 (TS2) at Week 26, and switched treatment was provided until Week 50. Primary endpoints were LDH level at Week 26 and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52. Equivalence was declared for LDH level at Week 26 if the two-sided 95% confidence interval (CI) of the mean difference in between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L. Equivalence was declared for time-adjusted AUEC of LDH if the two-sided 90% CI of the ratio of geometric means between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]. Secondary endpoints were LDH profile over time and number of units of packed red blood cells (pRBCs) transfused throughout the study period, safety, PK, PD, and immunogenicity. Results: Of the 50 randomized patients, 49 patients received the study treatment and 46 patients completed the study. Baseline demographic and disease characteristic were comparable between the two treatment sequences. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU (SB12 − ECU: 34.48, 95% CI [−47.66, 116.62]) lied within the pre-defined equivalence margin. The 90% CI of ratio of time-adjusted AUEC of LDH between SB12 and ECU (SB12/ECU: 1.08, 90% CI [0.95, 1.23]) lied within the pre-defined equivalence margin. The overall LDH profile during the study period was also comparable. The mean number of units of pRBCs transfused during Period 1 (TS1: 1.1 U; TS2: 0.9 U, respectively) and Period 2 (TS1: 1.1 U; TS2: 1.0 U, respectively) was comparable. Treatment-emergent adverse events (TEAEs) was reported in 72.3% for SB12 and 68.1% in ECU. Three patients in SB12 and 2 patients in ECU had serious TEAEs. None of three serious TEAEs reported in SB12 were related to the treatment. Two of three TEAEs (cellulitis; infusion site hypersensitivity) reported in ECU were treatment-related, and 1 death due to major adverse vascular event (portal vein thrombosis) not related to the treatment was reported in ECU. The mean eculizumab serum trough concentrations and the mean terminal complement activities in both treatment sequences were comparable. No patient developed anti-drug antibodies during the study period. Image:Summary/Conclusion: SB12 showed clinical equivalence to ECU measured by LDH. SB12 and ECU were comparable in terms of safety, PK, PD, and immunogenicity.

TX05-03e: Adjuvant treatment following neoadjuvant treatment and surgical resection in TX05-03, a trial comparing the safety, efficacy, and immunogenicity of trastuzumab biosimilar candidate (TX05) with originator trastuzumab in HER2+ EBC.

LBA511 Background: TX05 is being developed as a biosimilar to trastuzumab. We previously reported results of a Phase III study (TX05-03) comparing the efficacy and safety of TX05 to originator trastuzumab (TRA) in patients with HER2+ early breast cancer (EBC). The rate of pathologic complete response for subjects treated with TX05 compared to TRA in the TX05-03 study were within pre-defined equivalence margins, supporting the therapeutic equivalence of TX05 and TRA. This is an extension study to further assess and characterize the safety, immunogenicity, and efficacy of TX05 and TRA as single agents. Methods: TX05-03e was a randomized double-blinded, parallel group Phase III trial with patients enrolled at 82 centers in 10 countries. Adjuvant treatment included single agent trastuzumab (TX05 or TRA) for up to thirteen 3-week cycles. Subjects originally assigned to TX05 in the neoadjuvant phase of treatment received TX05, while subjects randomized to TRA in the neoadjuvant phase were randomized (1:1) to receive either TX05 or TRA. Efficacy endpoints include assessment of disease-free survival and overall survival. DFS is defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) to the documentation of a first failure. OS is defined as the time from randomization in the neoadjuvant study until death from any cause. Safety parameters assessed include treatment emergent adverse events (TEAE) and serious adverse events (SAE), death, clinical laboratory parameters, vital signs, 12-Lead ECG, LVEF and Physical examination. Immunogenicity was also assessed. Results: Of the 338 subjects randomized, 256 received TX05 while 82 received TRA. 81 of the TX05 patients received TRA in the neoadjuvant treatment phase. Demographic and baseline characteristics were well balanced between the three arms (TX05/TX05, TRA/TRA, or TRA/TX05 in neoadjuvant/adjuvant treatment phases). There was one death reported (TRA/TX05 group due to disease progression). DFS events occurred in only 3.4% of the TX05/TX05 group, 6.1% of the TRA/TRA group and 3.7% of the TRA/TX05 group. The number of subjects with any AE was 53.1% in the TX05/TX05, 56.1% in the TRA/TRA group and 37% in the TRA/TX05 groups. Frequency, type and severity of adverse events related to study drug were similar between the three groups and no new safety signals were detected. Conclusions: The rates of DFS, OS, AEs and immunogenicity were comparable in subjects randomized to TX05/TX05, TRA/TRA or TRA/TX05 for neoadjuvant/adjuvant treatment and continue to support the conclusion of biosimilarity of TX05 to the reference product. The change from TRA to TX05 for adjuvant treatment has no detectable impact on safety or treatment outcome. Clinical trial information: NCT04109391.

POS0287 A PHASE III, RANDOMISED, DOUBLE-BLIND, ACTIVE-CONTROLLED CLINICAL TRIAL TO COMPARE BAT1806/BIIB800, A PROPOSED TOCILIZUMAB BIOSIMILAR, WITH TOCILIZUMAB REFERENCE PRODUCT IN SUBJECTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE THERAPY

BackgroundBAT1806/BIIB800 is a proposed biosimilar to reference tocilizumab (TCZ). A Phase III randomised, double-blind, active-controlled clinical trial was conducted as part of a biosimilar development programme.ObjectivesTo evaluate the efficacy, pharmacokinetics (PK), safety and immunogenicity of BAT1806/BIIB800 in comparison with EU-sourced TCZ in subjects with moderate to severe rheumatoid arthritis with inadequate response to methotrexate (MTX).MethodsThe study was conducted at 55 centres in China and Europe, between June 2018 and January 2021. Eligible subjects were randomised in a 2:1:1 ratio to one of three treatment groups: (1) BAT1806/BIIB800 up to Week 48, (2) TCZ up to Week 48, or (3) TCZ up to Week 24, followed by BAT1806/BIIB800 from Week 24 to Week 48, administered intravenously every 4 weeks at a dose of 8mg/kg. The primary endpoint was the proportion of subjects achieving an ACR20 response at timepoints pre-specified to meet the requirements of different Regulatory Agencies: Week 12, for EMA; Week 24, for FDA and NMPA. Equivalence margins applied to differences in ACR20 response rates in the BAT1806/BIIB800 and TCZ treatment groups were pre-specified as follows: +/- 14.5% for EMA (95% confidence interval (CI)); -12.0%,15% for FDA (90% CI); +/- 13.6% for NMPA (95% CI). Secondary endpoints included pharmacokinetics, safety and immunogenicity.The ICH E9(R1) estimands framework including intercurrent events (related or unrelated to the COVID19 pandemic) was implemented for the ACR20 evaluation. A logistic regression model including ‘region’ (China and Eastern Europe) and ‘previous biologic or targeted synthetic DMARD use’ (Yes/No) as captured in Interactive Web Response System as stratification factors was utilised to assess equivalence for the primary endpoint. The difference in response rates was estimated and corresponding confidence intervals were derived to assess equivalence for the primary endpoint. This abstract presents results up to Week 24.ResultsIn total, 621 subjects were randomised to receive BAT1806/BIIB800 (N=312), TCZ (N=155), or TCZ followed by BAT1806/BIIB800 (N=154). The groups were comparable in terms of baseline demographics and disease characteristics, including age, gender, disease activity and disease duration. The estimated proportions of subjects achieving an ACR20 response in the BAT1806/BIIB800 vs. the TCZ groups, respectively, were 68.97% vs. 64.82% at Week 12 and 69.89% vs. 67.94% at Week 24. The estimated difference between ACR response rates was 4.15% (95% CI -3.63, 11.93) at week 12, and 1.94% (90% CI -4.04, 7.92; 95% CI -5.18, 9.07) at Week 24. The CIs for the estimated differences between the treatment groups were within the pre-defined equivalence margins (Figure 1). The treatment groups were comparable in terms of serum trough levels, incidence of TEAEs and ADA/NAb positivity (Table 1).Table 1.Safety and Immunogenicity up to Week 24, and Pharmacokinetics at Week 24TCZ (N =309) n (%)BAT1806/BIIB800 (N=312) n (%)TEAE196 (63.4)201 (64.4)Related TEAE151 (48.9)148 (47.4)Serious TEAE13 (4.2)11 (3.5)Related Serious TEAE7 (2.3)2 (0.6)Fatal TEAE1 (0.3)3 (1.0)ADA positive a42 (13.6%)64 (20.5%)NAb positive a42 (13.6%)63 (20.2%)PK, n271276Serum trough level (ug/mL), mean (SD)15.4 (17.1)15.8 (12.3)Serum trough level (ug/mL), geometric mean (CV%)12.3 (140.3)12.9 (121.3)Below limit of quantification, n (%)43 (15.9)28 (10.1)TEAE, treatment emergent adverse eventsa subjects with ≥1 ADA/NAb positive results up to week 24ConclusionBAT1806/BIIB800 has demonstrated equivalent efficacy at Week 12 and Week 24 and a similar PK, safety and immunogenicity profile as reference tocilizumab up to Week 24.Disclosure of InterestsXiaomei Leng: None declared, Piotr Leszczynski: None declared, Sławomir Jeka: None declared, Shengyun Liu: None declared, Huaxiang Liu: None declared, Malgorzata Miakisz: None declared, Jieruo Gu: None declared, Lali Kilasonia Speakers bureau: Sandoz, Amgen, Takeda, Mykola Stanislavchuk Speakers bureau: Pfizer, Orion, Boehringer Ingelheim, Xiaolei Yang Shareholder of: Employee of the Bio-thera Solutions Ltd. with shares as a part of Stock incentive plan., Employee of: Employee of the Bio-thera Solutions Ltd., Yinbo Zhou Shareholder of: Employee of Bio-thera Solutions Ltd. with share as part of Stock incentive plan, Employee of: Employee of Bio-thera Solutions Ltd., Qingfeng Dong Shareholder of: Employee of Bio-thera Solutions Ltd. with shares as part of Stock incentive plan, Employee of: Employee of Bio-thera Solutions Ltd., Marian Mitroiu Shareholder of: Employee of Biogen and may hold stocks, Employee of: Employee of Biogen, Janet Addison Shareholder of: Employee of Biogen and holds stock in Biogen, Employee of: Employee of Biogen, Xiaofeng Zeng: None declared