类风湿关节炎患者从参照利妥昔单抗转换为生物类似药利妥昔单抗（DRL_RI）后的免疫原性和安全性比较：一项随机、双盲、3期研究。
Comparing immunogenicity and safety following transition from reference rituximab to biosimilar rituximab (DRL_RI) in patients with rheumatoid arthritis: a randomized, double-blind, phase 3 study.
作者信息
Maharaj Narendra, Uppada Dharma Rao, Reddy Naveen, Reddy Pramod, Batalov Anastas, Lvanova Delina, Staykova Nedyalka, Baranauskaite Asta, Hassan Laila Amirali
机构信息
Clinical Development - Biologics, Dr. Reddy's Laboratories Ltd., Bachupally, Hyderabad, 500090, India.
Medical Faculty, Medical University of Plovdiv, University Hospital "Kaspela", Clinic of Rheumatology, Plovdiv, 4000, Bulgaria.
出版信息
Arthritis Res Ther. 2024 Dec 21;26(1):225. doi: 10.1186/s13075-024-03456-w.
OBJECTIVES
To assess immunogenicity and safety in patients with active rheumatoid arthritis (RA) transitioning from rituximab [US-licensed rituximab: Reference Product (RP); EU-approved rituximab: Reference Medicinal Product (RMP)] to DRL_RI (proposed rituximab biosimilar), in comparison to those continuing on RP/RMP.
METHODS
This double-blind, randomized, Phase 3 study included 140 RA patients having prior exposure to RP/RMP; transitioned to DRL_RI (n = 70) or continued with RP/RMP (n = 70) for two 1000 mg infusions on Days 1 and 15. Assessments included Time-matched Rituximab Concentration (TMRC), anti-drug antibodies (ADAs), neutralizing antibodies (NAbs) and ADA titre over 12 weeks, and safety follow-up till 26 weeks.
RESULTS
The mean age of subjects was 59.8 years (range: 24, 86) and the mean BMI was 27.76 kg/m (range: 17.5, 52.0). Incidence of ADA after dosing was low in both groups: 1.4% in DRL_RI group on Day 15, Week 8, and Week 12; and 2.9% in RP/RMP group at Week 12. Only 1 patient in DRL_RI group was positive for NAbs at Week 8. ADA titre values did not significantly differ between the two groups. The time-matched rituximab concentration was comparable between groups, indicating no interference for immunogenicity assessment. Treatment-emergent adverse events (TEAEs) were reported by 34.3% and 38.6% patients, respectively, in DRL_RI and RP/RMP groups. Incidences of TEAEs that were drug-related, leading to treatment discontinuation, grade ≥ 3, or serious, were also comparable.
CONCLUSION
Immunogenicity was low and comparable in RA patients transitioning to DRL_RI or continuing on RP/RMP. The overall safety profile in patients transitioning to DRL_RI did not appear to differ in frequency, severity, or quality from patients continuing on RP/RMP and was in line with the known safety profile of rituximab.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT0426877 EudraCT:2019-002810-37 US IND 112766.
目的
评估活动性类风湿关节炎（RA）患者从利妥昔单抗[美国获批的利妥昔单抗：参比产品（RP）；欧盟获批的利妥昔单抗：参比药品（RMP）]转换为DRL_RI（拟用的利妥昔单抗生物类似药）时的免疫原性和安全性，并与继续使用RP/RMP的患者进行比较。
方法
这项双盲、随机、3期研究纳入了140例曾使用过RP/RMP的RA患者；转换为DRL_RI（n = 70）或继续使用RP/RMP（n = 70），分别于第1天和第15天进行两次1000mg静脉输注。评估内容包括12周内的时间匹配利妥昔单抗浓度（TMRC）、抗药物抗体（ADA）、中和抗体（NAb）及ADA滴度，并进行26周的安全性随访。
结果
受试者的平均年龄为59.8岁（范围：24至86岁），平均体重指数为27.76kg/m（范围：17.5至52.0）。两组给药后的ADA发生率均较低：DRL_RI组在第15天、第8周和第12周时为1.4%；RP/RMP组在第12周时为2.9%。DRL_RI组仅1例患者在第8周时NAb呈阳性。两组间ADA滴度值无显著差异。两组间时间匹配的利妥昔单抗浓度相当，表明对免疫原性评估无干扰。DRL_RI组和RP/RMP组分别有34.3%和38.6%的患者报告了治疗中出现的不良事件（TEAE）。与药物相关、导致治疗中断、≥3级或严重的TEAE发生率也相当。
结论
转换为DRL_RI或继续使用RP/RMP的RA患者免疫原性较低且相当。转换为DRL_RI的患者总体安全性在频率、严重程度或性质方面与继续使用RP/RMP的患者似乎没有差异，且与已知的利妥昔单抗安全性特征一致。
试验注册
ClinicalTrials.gov标识符NCT0426877；EudraCT：2019 - 002810 - 37；美国IND 112766。
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