Sutharsan Sivagurunathan, Fischer Rainald, Gleiber Wolfgang, Horsley Alex, Crosby Jeff, Guo Shuling, Xia Shuting, Yu Rosie, Newman Kenneth B, Elborn J Stuart
Division of Cystic Fibrosis, Department of Pulmonary Medicine, University Medicine Essen - Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany.
Mukoviszidose-Zentrum München-West, Munich, Germany.
ERJ Open Res. 2024 Sep 16;10(4). doi: 10.1183/23120541.00986-2023. eCollection 2024 Jul.
Hyperactivity of epithelial sodium channel (ENaC) with increased sodium absorption is a feature of cystic fibrosis (CF). ION-827359 is a 2.5-generation antisense oligonucleotide targeted to reduce ENaC protein. This study evaluated ION-827359 safety, pharmacokinetics and pharmacodynamics.
In this three-part phase 1/2a, double-blind, randomised study, healthy volunteers received single doses of placebo or ION-827359 (3, 10, 37.5 or 100 mg; Part 1) or multiple doses of placebo or ION-827359 (5×10 mg, 5×37.5 mg, 5×75 mg or 10×37.5 mg; Part 2). People with CF (pwCF) received multiple doses of placebo or ION-827359 (5×10 mg, 5×37.5 mg, 5×75 mg and 5×100 mg; Part 3). Treatments were administered Pari eFlow mesh nebuliser. The primary outcome was safety; pharmacokinetic and pharmacodynamic parameters were also assessed.
64 healthy volunteers and 34 pwCF were enrolled. ION-827359 was well tolerated with an acceptable safety profile. There were no clinically relevant changes in laboratory values, ECG or vital signs. Systemic drug exposure was low (plasma half-life ∼2 weeks). Multiple doses of ION-827359 were associated with dose-dependent reductions in ENaC mRNA in bronchial epithelium. After multiple dosing, forced expiratory volume in 1 s was slightly higher in pwCF receiving ION-827359 (+2.9% with ION-827359 100 mg placebo; p=0.27).
The tolerability and safety of ION-827359 appear favourable at this stage of investigation. Reduction in ENaC mRNA supports mechanistic efficacy at the doses and regimens tested, and supports further investigation of ION-827359 in pwCF.
上皮钠通道（ENaC）活性亢进伴钠吸收增加是囊性纤维化（CF）的一个特征。ION-827359是一种第二代半反义寡核苷酸，旨在降低ENaC蛋白水平。本研究评估了ION-827359的安全性、药代动力学和药效学。
在这项三部分的1/2a期双盲随机研究中，健康志愿者接受单剂量安慰剂或ION-827359（3、10、37.5或100毫克；第1部分）或多剂量安慰剂或ION-827359（5×10毫克、5×37.5毫克、5×75毫克或10×37.5毫克；第2部分）。CF患者（pwCF）接受多剂量安慰剂或ION-827359（5×10毫克、5×37.5毫克、5×75毫克和5×100毫克；第3部分）。治疗通过Pari eFlow网状雾化器给药。主要结局是安全性；还评估了药代动力学和药效学参数。
招募了64名健康志愿者和34名pwCF。ION-827359耐受性良好，安全性可接受。实验室检查值、心电图或生命体征无临床相关变化。全身药物暴露较低（血浆半衰期约2周）。多剂量ION-827359与支气管上皮中ENaC mRNA的剂量依赖性降低相关。多次给药后，接受ION-827359的pwCF的1秒用力呼气量略高（ION-827359 100毫克组比安慰剂组高2.9%；p=0.27）。
在本研究阶段，ION-827359的耐受性和安全性似乎良好。ENaC mRNA的降低支持了在测试剂量和方案下的机制有效性，并支持对pwCF患者进一步研究ION-827359。
