Abuqayyas Lubna, Cheng Laurence E, Teixeira Dos Santos Marcia, Sullivan Barbara A, Ruiz-Santiago Norma, Wang Hui, Zhou Yanchen, Chindalore Vishala, Cohen Stanley, Kivitz Alan J, Posch Maximilian G, Parnes Jane R
Amgen Inc., Thousand Oaks, California.
Amgen Inc., South San Francisco, California.
ACR Open Rheumatol. 2022 Oct;4(10):903-911. doi: 10.1002/acr2.11487. Epub 2022 Jul 27.
To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA).
This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow-up. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28-CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease).
TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t = 4.6-9.5 days) and dose-related, reversible PD (>90% ICOSL receptor occupancy in 210- and 420-mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti-rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210- and 420-mg cohorts.
Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.
评估rozibafusp alfa（一种靶向诱导性共刺激配体（ICOSL）和B细胞活化因子（BAFF）的首创双特异性抗体 - 肽偶联物）在类风湿性关节炎（RA）患者中的安全性和生物学活性。
这项1b期、双盲、安慰剂对照、多剂量递增研究纳入了34例（年龄18 - 75岁；82.4%为女性）活动性RA患者（28个关节疾病活动评分 - C反应蛋白[DAS28 - CRP] > 2.6，甲氨蝶呤治疗稳定），按3:1随机分组，接受rozibafusp alfa（n = 26，分70、140、210和420 mg四个剂量递增队列）或安慰剂（n = 8），每2周皮下注射一次，共注射10周（总计6次剂量），并进行24周的随访。主要终点是治疗中出现的不良事件（TEAE）的发生率。其他评估包括血清药代动力学（PK）、药效学（PD）、免疫原性以及RA疾病活动指标（DAS28 - CRP、患者疾病整体评估和医生疾病整体评估）。
接受rozibafusp alfa和安慰剂的患者中，TEAE的发生率分别为96.2%和87.5%；大多数为轻度或中度严重程度。两名（7.7%）接受rozibafusp alfa治疗的患者报告了严重TEAE；均不认为与治疗相关。多次剂量的rozibafusp alfa显示出非线性PK（平均t = 4.6 - 9.5天）以及与剂量相关的、可逆的PD（在210和420 mg队列中ICOSL受体占有率> 90%；所有队列中幼稚B细胞减少，记忆B细胞增加）。五名（20%）患者产生了抗rozibafusp alfa抗体，对安全性无明显影响。在210和420 mg队列中，与安慰剂相比，rozibafusp alfa使RA疾病活动从基线有更大的数值改善。
rozibafusp alfa多剂量递增给药耐受性良好，PK和PD反映了对ICOSL和BAFF的双重阻断。研究结果支持对rozibafusp alfa在自身免疫性疾病中的进一步临床评估。
