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Abstract：
BACKGROUND: 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).
METHODS: 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.
RESULTS: 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 t1/2 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.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov identifier: NCT03334851.
METHODS: 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.
RESULTS: 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 t1/2 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.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov identifier: NCT03334851.
摘要：
背景：这项研究的目的是评估安全性，耐受性,药代动力学，和药效学PF‑06835375，一种有效的选择性无岩藻糖免疫球蛋白G1抗体，靶向C-X-C趋化因子受体5型（CXCR5），可能耗尽B细胞，滤泡辅助性T（Tfh）细胞，和循环Tfh样（cTfh）细胞，在系统性红斑狼疮（SLE）和类风湿性关节炎（RA）患者中。
方法：这是人类第一，多中心，双盲,赞助商开放，安慰剂对照的1期研究招募了18-70岁的SLE或RA患者。在A部分,患者接受单剂量静脉注射PF-06835375(剂量范围:0.03~6mg)或安慰剂,分为6个连续单剂量递增剂量(SAD)组.在B部分,患者在第1天和第29天接受重复剂量的皮下PF-06835375(剂量范围:0.3-10mg)或安慰剂,分为5个多次递增剂量(MAD)队列.在第4天(Td和MenB)和第8周(仅MenB)施用破伤风/白喉(Td)和脑膜炎球菌B(MenB/Trumenba™)疫苗以评估PF-06835375功能作用。终点包括治疗引起的不良事件（TEAE），药代动力学参数，对B和cTfh细胞的药效学作用，和生物标志物计数，疫苗反应，和探索性差异基因表达分析。安全,药代动力学，和药效学终点进行了描述性总结。使用预先指定的混合效应模型计算B和Tfh细胞特异性基因随时间的基线变化，错误发现率<0.05被认为具有统计学意义。
结果：总计，73例患者接受了治疗（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例（84.9%）患者出现TEAE（安慰剂n=17；PF-06835375n=45）；大多数为轻度或中度。3例（9.7%）患者出现严重不良事件。平均t1/2为3.4-121.4h（SAD队列）和162.0-234.0h（MAD队列，Day29).B和cTfh细胞计数通常在队列中显示出剂量依赖性减少（平均最大消耗范围：67.3-99.3％/62.4-98.7％[SAD]和91.1-99.6％/89.5-98.1％[MAD]，分别)。在用PF-06835375治疗的患者中,B细胞相关基因和途径显著下调。
结论：这些数据支持PF-06835375的进一步发展，以评估B和Tfh细胞耗竭作为自身免疫性疾病治疗的临床潜力。
背景：ClinicalTrials.gov标识符：NCT03334851。
方法：这是人类第一，多中心，双盲,赞助商开放，安慰剂对照的1期研究招募了18-70岁的SLE或RA患者。在A部分,患者接受单剂量静脉注射PF-06835375(剂量范围:0.03~6mg)或安慰剂,分为6个连续单剂量递增剂量(SAD)组.在B部分,患者在第1天和第29天接受重复剂量的皮下PF-06835375(剂量范围:0.3-10mg)或安慰剂,分为5个多次递增剂量(MAD)队列.在第4天(Td和MenB)和第8周(仅MenB)施用破伤风/白喉(Td)和脑膜炎球菌B(MenB/Trumenba™)疫苗以评估PF-06835375功能作用。终点包括治疗引起的不良事件（TEAE），药代动力学参数，对B和cTfh细胞的药效学作用，和生物标志物计数，疫苗反应，和探索性差异基因表达分析。安全,药代动力学，和药效学终点进行了描述性总结。使用预先指定的混合效应模型计算B和Tfh细胞特异性基因随时间的基线变化，错误发现率<0.05被认为具有统计学意义。
结果：总计，73例患者接受了治疗（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例（84.9%）患者出现TEAE（安慰剂n=17；PF-06835375n=45）；大多数为轻度或中度。3例（9.7%）患者出现严重不良事件。平均t1/2为3.4-121.4h（SAD队列）和162.0-234.0h（MAD队列，Day29).B和cTfh细胞计数通常在队列中显示出剂量依赖性减少（平均最大消耗范围：67.3-99.3％/62.4-98.7％[SAD]和91.1-99.6％/89.5-98.1％[MAD]，分别)。在用PF-06835375治疗的患者中,B细胞相关基因和途径显著下调。
结论：这些数据支持PF-06835375的进一步发展，以评估B和Tfh细胞耗竭作为自身免疫性疾病治疗的临床潜力。
背景：ClinicalTrials.gov标识符：NCT03334851。
