Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab.
BACKGROUND: Bio-Thera Solutions and Biogen.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab.
BACKGROUND: Bio-Thera Solutions and Biogen.
摘要：
背景：生物仿制药提供了一个机会，通过扩大获得生物治疗来解决未满足的医疗需求。这项研究旨在显示等效的疗效，和可比的安全性，免疫原性,和拟议的托珠单抗生物仿制药BAT1806/BIIB800的药代动力学特征，参考托珠单抗，类风湿性关节炎患者对甲氨蝶呤反应不足。
方法：此阶段3，多中心，随机化，双盲,主动控制，等效性研究包括24周的初始治疗期(此处报告结果)和24周的二次治疗期.参与者在五个国家的54个中心招募(中国，乌克兰,波兰,格鲁吉亚,和保加利亚)。对甲氨蝶呤反应不足的活动性类风湿关节炎患者被随机分配（1：1：2）至48周接受参考托珠单抗，或至24周接受参考托珠单抗，然后BAT1806/BIIB800至48周（在本分析中将两个参考托珠单抗组作为单个组进行分析），或BAT1806/BIIB800至第48周（BAT1806/BIIB800组），以8mg/kg的起始剂量每4周一次静脉输注给药。主要终点是在第12周（对于欧洲药品管理局[EMA]）或第24周（对于美国食品和药物管理局[FDA]和中国国家医疗产品管理局[NMPA]），在美国风湿病学会标准（ACR20）中改善了20％的参与者比例，使用预定的等效性边缘（95％CI-14·5至14·5[EMA]，90%CI-12·0至+15·0[FDA]，和95%CI-13·6至+13·6[NMPA])。国际协调理事会E9(R1)评估和框架，有了解决并发事件的策略，根据预定义的等效裕度，实施了具有预期差异的疗效评估。该试验已在ClinicalTrials.gov（NCT03830203）和EudraCT（2018-002202-31）注册，并对新参与者关闭。
结果：在2018年12月19日至2021年1月5日之间，我们随机分配了621名参与者：309名为参考托珠单抗组，312名为BAT1806/BIIB800组。平均年龄为50·5岁(SD12·0)，534（86%）是女性，87（14%）是男性，和368（59％）是白人。对于主要资产，12周时,参考托珠单抗组为64·8%,BAT1806/BIIB800组为69·0%(治疗差异4·1%[95%CI-3·6~11·9]),参考托珠单抗组为67·9%,BAT1806/BIIB800组为69·9%(治疗差异4·90%~7·9);24周·9·9所有置信区间均包含在预定义的等效裕度内。对于参考托珠单抗和BAT1806/BIIB800组观察到相当的药代动力学和免疫原性谱。参考托珠单抗组201名（65%）参与者和BAT1806/BIIB800组206名（66%）参与者报告了不良事件；参考托珠单抗组196名（63%）参与者和BAT1806/BIIB800组201名（64%）参与者报告了因治疗引起的不良事件。五名参与者发生了致命事件（参考托珠单抗n=1；BAT1806/BIIB800n=4）。
结论：BAT1806/BIIB800具有同等疗效，和可比的安全性，免疫原性,和药代动力学曲线作为参考托珠单抗。
背景：Bio-Thera解决方案和Biogen。
方法：此阶段3，多中心，随机化，双盲,主动控制，等效性研究包括24周的初始治疗期(此处报告结果)和24周的二次治疗期.参与者在五个国家的54个中心招募(中国，乌克兰,波兰,格鲁吉亚,和保加利亚)。对甲氨蝶呤反应不足的活动性类风湿关节炎患者被随机分配（1：1：2）至48周接受参考托珠单抗，或至24周接受参考托珠单抗，然后BAT1806/BIIB800至48周（在本分析中将两个参考托珠单抗组作为单个组进行分析），或BAT1806/BIIB800至第48周（BAT1806/BIIB800组），以8mg/kg的起始剂量每4周一次静脉输注给药。主要终点是在第12周（对于欧洲药品管理局[EMA]）或第24周（对于美国食品和药物管理局[FDA]和中国国家医疗产品管理局[NMPA]），在美国风湿病学会标准（ACR20）中改善了20％的参与者比例，使用预定的等效性边缘（95％CI-14·5至14·5[EMA]，90%CI-12·0至+15·0[FDA]，和95%CI-13·6至+13·6[NMPA])。国际协调理事会E9(R1)评估和框架，有了解决并发事件的策略，根据预定义的等效裕度，实施了具有预期差异的疗效评估。该试验已在ClinicalTrials.gov（NCT03830203）和EudraCT（2018-002202-31）注册，并对新参与者关闭。
结果：在2018年12月19日至2021年1月5日之间，我们随机分配了621名参与者：309名为参考托珠单抗组，312名为BAT1806/BIIB800组。平均年龄为50·5岁(SD12·0)，534（86%）是女性，87（14%）是男性，和368（59％）是白人。对于主要资产，12周时,参考托珠单抗组为64·8%,BAT1806/BIIB800组为69·0%(治疗差异4·1%[95%CI-3·6~11·9]),参考托珠单抗组为67·9%,BAT1806/BIIB800组为69·9%(治疗差异4·90%~7·9);24周·9·9所有置信区间均包含在预定义的等效裕度内。对于参考托珠单抗和BAT1806/BIIB800组观察到相当的药代动力学和免疫原性谱。参考托珠单抗组201名（65%）参与者和BAT1806/BIIB800组206名（66%）参与者报告了不良事件；参考托珠单抗组196名（63%）参与者和BAT1806/BIIB800组201名（64%）参与者报告了因治疗引起的不良事件。五名参与者发生了致命事件（参考托珠单抗n=1；BAT1806/BIIB800n=4）。
结论：BAT1806/BIIB800具有同等疗效，和可比的安全性，免疫原性,和药代动力学曲线作为参考托珠单抗。
背景：Bio-Thera解决方案和Biogen。
