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. 2024 Sep 16;10(4):00986-2023.
doi: 10.1183/23120541.00986-2023. eCollection 2024 Jul.

Randomised, phase 1/2a trial of ION-827359, an antisense oligonucleotide inhibitor of ENaC

Sivagurunathan Sutharsan  1 , Rainald Fischer  2 , Wolfgang Gleiber  3 , Alex Horsley  4 , Jeff Crosby  5 , Shuling Guo  5 , Shuting Xia  5 , Rosie Yu  5 , Kenneth B Newman  5 , J Stuart Elborn  6
Affiliations

Randomised, phase 1/2a trial of ION-827359, an antisense oligonucleotide inhibitor of ENaC

Sivagurunathan Sutharsan et al. ERJ Open Res. .

Abstract

Background: 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.

Methods: 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 via Pari eFlow© mesh nebuliser. The primary outcome was safety; pharmacokinetic and pharmacodynamic parameters were also assessed.

Results: 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 versus placebo; p=0.27).

Conclusions: 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.

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Conflict of interest statement

Conflict of interest: S. Sutharsan received personal fees or grants from Galapagos, Proteostasis Therapeutics, Celtaxsys, Vertex Pharmaceuticals, Boehringer Ingelheim, Corbus Pharmaceuticals and Ionis Pharmaceuticals, Inc. outside the submitted work. Conflict of interest: R. Fischer received personal fees or grants from Galapagos, Proteostasis Therapeutics, Celtaxsys, Berlin-Chemie, AstraZeneca, Novartis Pharma GmbH, Vertex Pharmaceuticals, Teva GmbH, Chiesi GmbH, Boehringer Ingelheim, Inamed, Pari Pharma GmbH and Ionis Pharmaceuticals, Inc. outside the submitted work. Conflict of interest: W. Gleiber has no conflict of interest. Conflict of interest: A. Horsley is supported by the NIHR Manchester BRC, and has received grants from the CF Trust, CF Foundation, NIHR and EPSRC, and personal fees from Vertex Pharmaceuticals, Boehringer Ingelheim and Genentech outside the submitted work. Conflict of interest: J. Crosby, S. Guo, S. Xia, R. Yu and K.B. Newman are employees of Ionis Pharmaceuticals, Inc., and may own stock or stock options in that company. Conflict of interest: J.S. Elborn has received grants from Novartis, Polyfor, the European Commission and NIHR (all direct to Queen's University Belfast), and consultancy fees from ProQR, Vertex and Viatris.

Figures

FIGURE 1
FIGURE 1
Patient flow chart. AE: adverse event; CF: cystic fibrosis; SAE: serious adverse event; PK: pharmacokinetics; PD: pharmacodynamics.
FIGURE 2
FIGURE 2
Epithelial sodium channel (ENaC) mRNA expression, shown as the mean±se of the mean percentage of baseline (pretreatment screening), in cells from bronchial brushings at Day 23 after multiple doses of ION-827359 in healthy volunteers.
FIGURE 3
FIGURE 3
Relationship between the trough plasma concentration of ION-827359 (Cmin) and epithelial sodium channel (ENaC) mRNA expression in cells from bronchial brushings.
FIGURE 4
FIGURE 4
Change from baseline in % predicted forced expiratory volume in 1 s (FEV1) in the multiple-dose cystic fibrosis cohort (safety population; n=33). Note: doses refer to those of ION-827359.
See this image and copyright information in PMC

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