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

IF 5.2 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Amyloid-Journal of Protein Folding Disorders Pub Date : 2024-10-29 DOI:10.1080/13506129.2024.2420809

Ole B Suhr, Martha Grogan, Ana Martins da Silva, Chafic Karam, Pablo Garcia-Pavia, Brian Drachman, Wagner Zago, Radhika Tripuraneni, Gene G Kinney

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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).

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PRX004治疗变异型淀粉样转甲状腺素（ATTRv）淀粉样变性病：1期开放标签剂量递增研究结果。

研究背景正在研究的单克隆抗体PRX004旨在特异性靶向和清除TTR淀粉样蛋白。我们在此报告 PRX004 在 ATTRv 淀粉样变性患者中的安全性、耐受性、药代动力学、药效学和初步临床活性：这项全球性、多中心、1期试验包括3 + 3剂量递增期和长期延长期（LTE）（NCT03336580）。在剂量递增阶段，患者接受PRX004（0.1、0.3、1、3、10或30毫克/千克），每28天静脉注射一次，持续3个月。在LTE阶段，符合条件的患者最多可再接受15个剂量的治疗。接受剂量≥3 mg/kg、持续时间≥9个月的患者将接受全球纵向应变（GLS）和神经病变损害评分（NIS）评估。主要目的是确定PRX004的最大耐受剂量（MTD）：共有21名ATTRv淀粉样变性患者完成了剂量递增阶段的治疗，其中17人随后加入了LTE。未达到MTD。PRX004在所有剂量下的耐受性都很好，暴露量与剂量成正比。GLS和NIS在9个月内得到改善或维持（n = 7）：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。ATTR心肌病的2期随机对照试验正在进行中（NCT05442047）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学

CiteScore

10.60

自引率

10.90%

发文量

审稿时长

6-12 weeks

期刊介绍： Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.