From Northwell Health, Great Neck, NY (R.A.F.); Amsterdam University Medical Centers, Amsterdam (R.F.V.); the University of California San Diego, La Jolla (K.K.); the University of Santo Tomas, Manila, Philippines (S.N.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (J.R.-D.); the University of Pennsylvania and Corporal Michael J. Crescenz Veterans Affairs Medical Center - both in Philadelphia (V.P.W.); Biogen, Cambridge, MA (X.H., G.C., H.C., A.M., C.M., N.F.); and Biogen, Baar, Switzerland (C.B.).
N Engl J Med. 2022 Sep 8;387(10):894-904. doi: 10.1056/NEJMoa2118025.
Antibody-binding of blood dendritic cell antigen 2 (BDCA2), which is expressed exclusively on plasmacytoid dendritic cells, suppresses the production of type I interferon that is involved in the pathogenesis of systemic lupus erythematosus (SLE). The safety and efficacy of subcutaneous litifilimab, a humanized monoclonal antibody that binds to BDCA2, in patients with SLE have not been extensively studied.
We conducted a phase 2 trial of litifilimab involving participants with SLE. The initial trial design called for randomly assigning participants to receive litifilimab (at a dose of 50, 150, or 450 mg) or placebo administered subcutaneously at weeks 0, 2, 4, 8, 12, 16, and 20, with the primary end point of evaluating cutaneous lupus activity. The trial design was subsequently modified; adults with SLE, arthritis, and active skin disease were randomly assigned to receive either litifilimab at a dose of 450 mg or placebo. The revised primary end point was the change from baseline in the total number of active joints (defined as the sum of the swollen joints and the tender joints) at week 24. Secondary end points were changes in cutaneous and global disease activity. Safety was also assessed.
A total of 334 adults were assessed for eligibility, and 132 underwent randomization (64 were assigned to receive 450-mg litifilimab, 6 to receive 150-mg litifilimab, 6 to receive 50-mg litifilimab, and 56 to receive placebo). The primary analysis was conducted in the 102 participants who had received 450-mg litifilimab or placebo and had at least four tender and at least four swollen joints. The mean (±SD) baseline number of active joints was 19.0±8.4 in the litifilimab group and 21.6±8.5 in the placebo group. The least-squares mean (±SE) change from baseline to week 24 in the total number of active joints was -15.0±1.2 with litifilimab and -11.6±1.3 with placebo (mean difference, -3.4; 95% confidence interval, -6.7 to -0.2; P = 0.04). Most of the secondary end points did not support the results of the analysis of the primary end point. Receipt of litifilimab was associated with adverse events, including two cases of herpes zoster and one case of herpes keratitis.
In a phase 2 trial involving participants with SLE, litifilimab was associated with a greater reduction from baseline in the number of swollen and tender joints than placebo over a period of 24 weeks. Longer and larger trials are required to determine the safety and efficacy of litifilimab for the treatment of SLE. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).
血树突状细胞抗原 2（BDCA2）的抗体结合物，仅表达于浆细胞样树突状细胞上，可抑制参与系统性红斑狼疮（SLE）发病机制的 I 型干扰素的产生。利替利单抗是一种与人源化单克隆抗体结合的 BDCA2，其在 SLE 患者中的安全性和疗效尚未得到广泛研究。
我们进行了一项利替利单抗治疗 SLE 患者的 2 期试验。最初的试验设计要求参与者随机接受利替利单抗（剂量为 50、150 或 450mg）或安慰剂皮下注射，分别在第 0、2、4、8、12、16 和 20 周进行，主要终点是评估皮肤狼疮活动。随后修改了试验设计；患有 SLE、关节炎和活动性皮肤疾病的成年人被随机分配接受 450mg 利替利单抗或安慰剂。修订后的主要终点是第 24 周时活跃关节总数（定义为肿胀关节和压痛关节的总和）与基线相比的变化。次要终点是皮肤和整体疾病活动的变化。还评估了安全性。
共有 334 名成年人接受了合格性评估，其中 132 人接受了随机分组（64 人接受 450mg 利替利单抗，6 人接受 150mg 利替利单抗，6 人接受 50mg 利替利单抗，56 人接受安慰剂）。主要分析在接受 450mg 利替利单抗或安慰剂且至少有 4 个压痛关节和至少 4 个肿胀关节的 102 名参与者中进行。利替利单抗组和安慰剂组的基线活跃关节数分别为 19.0±8.4 和 21.6±8.5。从基线到第 24 周时活跃关节总数的最小二乘均数（±SE）变化为利替利单抗组-15.0±1.2，安慰剂组-11.6±1.3（平均差异-3.4；95%置信区间-6.7 至-0.2；P=0.04）。大多数次要终点并不支持主要终点分析的结果。利替利单抗治疗与不良反应有关，包括 2 例带状疱疹和 1 例单纯疱疹性角膜炎。
在一项涉及 SLE 患者的 2 期试验中，与安慰剂相比，利替利单抗在 24 周内可更显著减少肿胀和压痛关节的数量。需要更长和更大规模的试验来确定利替利单抗治疗 SLE 的安全性和疗效。（由 Biogen 资助；LILAC ClinicalTrials.gov 编号，NCT02847598。）
