Suhr Ole B, Grogan Martha, Silva Ana Martins da, Karam Chafic, Garcia-Pavia Pablo, Drachman Brian, Zago Wagner, Tripuraneni Radhika, Kinney Gene G
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
Mayo Clinic, Rochester, MN, USA.
Amyloid. 2025 Mar;32(1):14-21. doi: 10.1080/13506129.2024.2420809. Epub 2024 Oct 29.
The investigational monoclonal antibody PRX004 is designed to specifically target and deplete TTR amyloid. Here, we report on the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical activity of PRX004 in patients with ATTRv amyloidosis.
This global, multicentre, phase 1 trial comprised a 3 + 3 dose-escalation phase and a long-term extension (LTE) phase (NCT03336580). In the dose-escalation phase, patients received PRX004 (0.1, 0.3, 1, 3, 10 or 30 mg/kg), administered intravenously every 28 days for 3 months. In the LTE, eligible patients could receive up to 15 additional doses. Patients who received doses of ≥3 mg/kg for ≥9 months were assessed for Global Longitudinal Strain (GLS) and Neuropathy Impairment Score (NIS). The primary objective was to determine the maximum tolerated dose (MTD) of PRX004.
Overall, 21 patients with ATTRv amyloidosis completed the dose-escalation phase; 17 subsequently enrolled in the LTE. The MTD was not reached. PRX004 was well tolerated at all doses, with dose-proportional exposure. GLS and NIS were improved or maintained over 9 months ( = 7).
PRX004 was well tolerated in patients with ATTRv amyloidosis and demonstrated potential clinical activity. A phase 2 randomised controlled trial in ATTR cardiomyopathy is ongoing (NCT05442047).
研究性单克隆抗体PRX004旨在特异性靶向并清除转甲状腺素蛋白淀粉样蛋白。在此，我们报告PRX004在转甲状腺素蛋白变异型（ATTRv）淀粉样变性患者中的安全性、耐受性、药代动力学、药效学及初步临床活性。
这项全球多中心1期试验包括一个3+3剂量递增阶段和一个长期扩展（LTE）阶段（NCT03336580）。在剂量递增阶段，患者接受PRX004（0.1、0.3、1、3、10或30mg/kg），每28天静脉注射一次，共3个月。在LTE阶段，符合条件的患者可额外接受多达15剂治疗。对接受≥3mg/kg剂量≥9个月的患者进行整体纵向应变（GLS）和神经病变损害评分（NIS）评估。主要目标是确定PRX004的最大耐受剂量（MTD）。
总体而言，21例ATTRv淀粉样变性患者完成了剂量递增阶段；其中17例随后进入LTE阶段。未达到MTD。PRX004在所有剂量下耐受性良好，暴露量与剂量成比例。在9个月内（n=7），GLS和NIS得到改善或维持。
PRX004在ATTRv淀粉样变性患者中耐受性良好，并显示出潜在的临床活性。一项关于ATTR心肌病的2期随机对照试验正在进行中（NCT05442047）。
