Internal Medicine, University of Texas Southwestern Medical School Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 800, Dallas, TX, 75231, USA.
Pfizer Inc, Cambridge, MA, USA.
Arthritis Res Ther. 2024 Jun 6;26(1):117. doi: 10.1186/s13075-024-03337-2.
The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant.
In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375.
These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases.
ClinicalTrials.gov identifier: NCT03334851.
本研究旨在评估 PF-06835375 的安全性、耐受性、药代动力学和药效学，PF-06835375 是一种强效的选择性去岩藻糖基免疫球蛋白 G1 抗体，可靶向 C-X-C 趋化因子受体 5 (CXCR5)，潜在地耗竭 B 细胞、滤泡辅助 T (Tfh) 细胞和循环 Tfh 样 (cTfh) 细胞，用于治疗系统性红斑狼疮 (SLE) 和类风湿关节炎 (RA) 患者。
这是一项首次在人体中进行的、多中心、双盲、研究者发起、安慰剂对照的 1 期研究，招募了年龄在 18-70 岁之间的 SLE 或 RA 患者。在第 A 部分中，患者接受了静脉注射 PF-06835375（剂量范围：0.03-6mg）或安慰剂的单次递增剂量（SAD），共分为六个连续的 SAD 队列。在第 B 部分中，患者在第 1 天和第 29 天接受了重复的皮下 PF-06835375（剂量范围：0.3-10mg）或安慰剂的多次递增剂量（MAD），共分为五个 MAD 队列。在第 4 天（Td 和 MenB）和第 8 周（仅 MenB）接种破伤风/白喉（Td）和脑膜炎球菌 B（MenB/Trumenba™）疫苗，以评估 PF-06835375 的功能效应。主要终点包括治疗期间出现的不良事件（TEAEs）、药代动力学参数、B 和 cTfh 细胞的药效学效应、生物标志物计数、疫苗反应和探索性差异基因表达分析。安全性、药代动力学和药效学终点均采用描述性方法进行总结。使用预设的混合效应模型计算 B 和 Tfh 细胞特异性基因随时间的变化，假发现率<0.05 被认为具有统计学意义。
共有 73 名患者接受了治疗（SAD 队列：SLE，n=17；RA，n=14；MAD 队列：SLE，n=22；RA，n=20）。平均年龄为 53.3 岁。62 名（84.9%）患者发生了 TEAEs（安慰剂，n=17；PF-06835375，n=45），多数为轻度或中度。3 名（9.7%）患者发生了严重不良事件。平均 t 范围为 3.4-121.4 h（SAD 队列）和 162.0-234.0 h（MAD 队列，第 29 天）。B 和 cTfh 细胞计数通常表现出剂量依赖性减少（SAD 队列中，平均最大耗竭率范围为 67.3-99.3%/62.4-98.7%；MAD 队列中，平均最大耗竭率范围为 91.1-99.6%/89.5-98.1%）。PF-06835375 治疗的患者 B 细胞相关基因和途径显著下调。
这些数据支持进一步开发 PF-06835375，以评估 B 和 Tfh 细胞耗竭作为治疗自身免疫性疾病的临床潜力。
ClinicalTrials.gov 标识符：NCT03334851。
Zotero 插件
