PRX004 in variant amyloid transthyretin (ATTRv) amyloidosis: results of a phase 1, open-label, dose-escalation study

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 (n = 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TTR淀粉样蛋白。本研究报道了PRX004在ATTRv淀粉样变性患者中的安全性、耐受性、药代动力学、药效动力学及初步临床活性。这项全球多中心1期临床试验包含3+3剂量爬坡阶段与长期扩展（LTE）阶段（试验编号：NCT03336580）。在剂量爬坡阶段，患者接受每28天静脉输注1次PRX004，剂量梯度为0.1、0.3、1、3、10或30 mg/kg，持续3个月。在长期扩展阶段，符合入组标准的患者最多可额外接受15次给药。对接受≥3 mg/kg剂量且给药持续≥9个月的患者，评估其整体纵向应变（Global Longitudinal Strain, GLS）与神经病变损害评分（Neuropathy Impairment Score, NIS）。本试验的主要目的为确定PRX004的最大耐受剂量（maximum tolerated dose, MTD）。最终，共21例ATTRv淀粉样变性患者完成剂量爬坡阶段，其中17例后续入组长期扩展阶段。本研究未达到最大耐受剂量。所有剂量下PRX004均具有良好耐受性，其暴露量呈剂量依赖性。在7例随访满9个月的患者中，整体纵向应变与神经病变损害评分均得到改善或维持。PRX004在ATTRv淀粉样变性患者中耐受性良好，且显示出潜在的临床活性。目前，一项针对ATTR心肌病的2期随机对照试验正在进行中（试验编号：NCT05442047）。