A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis

IF 4.9 2区 医学 Q1 Medicine Arthritis Research & Therapy Pub Date : 2024-06-06 DOI:10.1186/s13075-024-03337-2
Stanley Cohen, Jean S. Beebe, Vishala Chindalore, Shunjie Guan, Mina Hassan-Zahraee, Madhurima Saxena, Li Xi, Craig Hyde, Sarita Koride, Robert Levin, Shannon Lubaczewski, Mikhail Salganik, Abigail Sloan, Erin Stevens, Elena Peeva, Michael S. Vincent, David A. Martin, Myron Chu
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Abstract

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 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. 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.
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一项 1 期随机、双盲、安慰剂对照、单剂量和多剂量递增研究,旨在评估 PF-06835375 (一种 C-X-C 趋化因子受体 5 型定向抗体)在系统性红斑狼疮或类风湿性关节炎患者中的安全性和药代动力学/药效学特性
PF-06835375是一种靶向C-X-C趋化因子受体5型(CXCR5)的强效选择性阿夫糖基免疫球蛋白G1抗体,可消耗系统性红斑狼疮(SLE)和类风湿性关节炎(RA)患者的B细胞、滤泡T辅助细胞(Tfh)和循环Tfh样细胞(cTfh)。这项首次进行的人体多中心、双盲、赞助商开放、安慰剂对照的 1 期研究招募了 18-70 岁的系统性红斑狼疮或类风湿关节炎患者。在 A 部分,患者在六个连续的单剂量递增(SAD)队列中接受单剂量静脉注射 PF-06835375(剂量范围:0.03-6 毫克)或安慰剂。在 B 部分中,患者在第 1 天和第 29 天重复接受皮下注射 PF-06835375(剂量范围:0.3-10 毫克)或安慰剂,共分为 5 个多剂量组。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。终点包括治疗突发不良事件 (TEAE)、药代动力学参数、对 B 细胞和 cTfh 细胞的药效学效应、生物标记物计数、疫苗应答和探索性差异基因表达分析。对安全性、药代动力学和药效学终点进行了描述性总结。B细胞和Tfh细胞特异性基因随时间推移的基线变化采用预设的混合效应模型进行计算,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%)患者出现了TEAEs(安慰剂 n = 17;PF-06835375 n = 45);大多数为轻度或中度。3名(9.7%)患者出现严重不良事件。平均 t1/2 为 3.4-121.4 小时(SAD 组)和 162.0-234.0 小时(MAD 组,第 29 天)。各组的 B 细胞和 cTfh 细胞计数普遍呈剂量依赖性下降(平均最大消耗范围:67.3%-99.3%):分别为 67.3-99.3%/62.4-98.7% [SAD] 和 91.1-99.6%/89.5-98.1% [MAD])。在接受 PF-06835375 治疗的患者中,B 细胞相关基因和通路显著下调。这些数据支持进一步开发PF-06835375,以评估B细胞和Tfh细胞耗竭作为自身免疫性疾病治疗方法的临床潜力。ClinicalTrials.gov identifier:NCT03334851。
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来源期刊
CiteScore
8.60
自引率
2.00%
发文量
261
审稿时长
14 weeks
期刊介绍: Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.
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