Daien Claire, Krogulec Marek, Gineste Paul, Steens Jean-Marc, Desroys du Roure Laurence, Biguenet Sophie, Scherrer Didier, Santo Julien, Ehrlich Hartmut, Durez Patrick
Montpellier University, CHU de Montpellier, Inserm U1046, CNRS UMR 9214, Montpellier, France
NZOZ Lecznica MAK-MED S.C, Nadarzyn, Poland.
Ann Rheum Dis. 2022 Jul 12;81(8):1076-1084. doi: 10.1136/annrheumdis-2022-222228.
This phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy.
The primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission.
ABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464.
ABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA.
Phase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy.EUDRACT number: 2018-004677-27 TRIAL REGISTRATION NUMBER: NCT03813199.
本2a期随机、双盲、安慰剂对照、平行组研究评估了一种一流候选药物ABX464（奥贝法莫德，每日50毫克和100毫克）的安全性和有效性，该药物可上调mRNA抑制剂微小RNA（miR）-124的生物合成，与甲氨蝶呤（MTX）联合用于60例对MTX或/和抗肿瘤坏死因子α（TNFα）治疗反应不足的中重度活动性类风湿关节炎（RA）患者（比例为1:1:1）。
主要终点是ABX464的安全性；疗效终点包括达到美国风湿病学会（ACR）20/50/70反应的患者比例、疾病活动评分（DAS）28、简化疾病活动评分、临床疾病活动评分）、欧洲抗风湿病联盟反应、DAS28低疾病活动或缓解。
ABX464 50毫克安全且耐受性良好。报告了两例严重不良事件（一例在安慰剂组，一例在ABX464 100毫克组）。11名患者因不良事件退出（9名患者服用100毫克，1名患者服用50毫克，1名患者服用安慰剂）。停药主要是由于胃肠道疾病。未报告机会性感染、恶性肿瘤和死亡病例。与安慰剂相比，ABX464 50毫克在第12周时达到ACR20和ACR50反应的患者比例显著更高。在第12周时，ABX464组的DAS28-C反应蛋白（CRP）和DAS28-红细胞沉降率显著降低，分类DAS28-CRP反应或临床疾病活动指数（CDAI）缓解率显著提高。在每例服用ABX464的患者血液中均观察到miR-124显著上调。
ABX464 50毫克安全、耐受性良好且显示出有前景的疗效。轻度至中度胃肠道不良事件导致服用ABX464 100毫克的患者退出率较高，这可能不是一个合适的使用剂量。这些发现值得探索每日50毫克或更低剂量的ABX464用于治疗RA患者。
ABX464与MTX联合用于对MTX或/和抗TNFα治疗反应不足或对抗TNFα治疗不耐受的中重度活动性RA患者的IIa期随机、双盲、安慰剂对照、平行组、多剂量研究。欧盟临床试验编号：2018-004677-27。试验注册号：NCT03813199。
