Abstract：
To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA).
In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria.
Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported.
Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.
In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria.
Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported.
Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.
摘要：
目的：为了评估ABBV-3373的疗效和安全性，ABBV-3373是一种新型抗体药物偶联物（ADC），由抗肿瘤坏死因子（TNF）单克隆抗体阿达木单抗与糖皮质激素受体调节剂（GRM）连接，类风湿关节炎（RA）患者与阿达木单抗的比较。
方法：在本随机分组中，双盲,主动控制概念验证试验(NCT03823391)，在甲氨蝶呤背景下患有中度/重度RA的成年人每隔一周（EOW）接受静脉注射ABBV-3373100mg，持续12周，随后服用安慰剂12周，或皮下阿达木单抗80mgEOW24周。
方法：第12周时DAS28（CRP）与基线的变化，进行ABBV-3373与历史阿达木单抗（80mgEOW或等效剂量）以及与联合试验中/历史阿达木单抗的两个预先指定的主要比较。次要终点：CDAI从基线的变化，SDAI,和DAS28（ESR）；达到DAS28（CRP）≤3.2和ACR50的患者比例。
结果：48例患者被随机分为ABBV-3373（n=31）或阿达木单抗（n=17）。在第12周，ABBV-3373与历史阿达木单抗相比降低了DAS28（CRP）（-2.65对-2.13；P=0.022），以及联合试验中/历史阿达木单抗（-2.65对-2.29；概率=89.9％），数值上比试验中的阿达木单抗有更大的改善（-2.51）。对于次要端点，ABBV-3373的疗效优于历史阿达木单抗;根据试验中/历史阿达木单抗的综合数据,ABBV-3373的预测概率为79.3-99.5%,优于阿达木单抗.在ABBV-3373治疗的患者中，在第12周达到DAS28（CRP）≤3.2，70.6％的患者在第24周保持这种反应，尽管改用安慰剂。ABBV-3373（非心源性胸痛，肺炎,上呼吸道感染,和过敏性休克）和两个SAE与阿达木单抗（乳腺脓肿和支气管炎）。将ABBV-3373IV给药的持续时间从3分钟增加到15-30分钟后，未报告类似的过敏性休克事件.
结论：来自概念验证试验的数据支持TNF-GRM-ADC用于治疗RA的持续发展，与目前可用的治疗方法相比，有可能获得更好的结果。
方法：在本随机分组中，双盲,主动控制概念验证试验(NCT03823391)，在甲氨蝶呤背景下患有中度/重度RA的成年人每隔一周（EOW）接受静脉注射ABBV-3373100mg，持续12周，随后服用安慰剂12周，或皮下阿达木单抗80mgEOW24周。
方法：第12周时DAS28（CRP）与基线的变化，进行ABBV-3373与历史阿达木单抗（80mgEOW或等效剂量）以及与联合试验中/历史阿达木单抗的两个预先指定的主要比较。次要终点：CDAI从基线的变化，SDAI,和DAS28（ESR）；达到DAS28（CRP）≤3.2和ACR50的患者比例。
结果：48例患者被随机分为ABBV-3373（n=31）或阿达木单抗（n=17）。在第12周，ABBV-3373与历史阿达木单抗相比降低了DAS28（CRP）（-2.65对-2.13；P=0.022），以及联合试验中/历史阿达木单抗（-2.65对-2.29；概率=89.9％），数值上比试验中的阿达木单抗有更大的改善（-2.51）。对于次要端点，ABBV-3373的疗效优于历史阿达木单抗;根据试验中/历史阿达木单抗的综合数据,ABBV-3373的预测概率为79.3-99.5%,优于阿达木单抗.在ABBV-3373治疗的患者中，在第12周达到DAS28（CRP）≤3.2，70.6％的患者在第24周保持这种反应，尽管改用安慰剂。ABBV-3373（非心源性胸痛，肺炎,上呼吸道感染,和过敏性休克）和两个SAE与阿达木单抗（乳腺脓肿和支气管炎）。将ABBV-3373IV给药的持续时间从3分钟增加到15-30分钟后，未报告类似的过敏性休克事件.
结论：来自概念验证试验的数据支持TNF-GRM-ADC用于治疗RA的持续发展，与目前可用的治疗方法相比，有可能获得更好的结果。
