A Randomized, Double‐Blind, Placebo‐Controlled, Multiple Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of ELX‐02 in Healthy Subjects

Leubitz, Andi; Vanhoutte, Frédéric; Hu, Ming‐yi; Porter, Kaela M.; Gordon, Efrat; Tencer, Kathleen; Campbell, Kathleen C.M.; Banks, Kate; Haverty, Thomas P.

doi:10.1002/cpdd.914

Cited by 23 publications

(14 citation statements)

References 6 publications

(11 reference statements)

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“…Small molecules that promote translational readthrough of termination codons are also being explored as potential treatments for PTC mutations, including CF (40)(41)(42)(43)(44)(45). However, effects from the long-term use of these drugs has raised concerns (44,46,47). Though these approaches may hold promise, none are specific to CFTR directly, and to date none have been approved for use in CF patients.…”

Section: Discussionmentioning

confidence: 99%

Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

Michaels

Peña‐Rasgado

Kotaria

et al. 2021

Preprint

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CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR mRNA expression as a result of nonsense mediated mRNA decay (NMD), as well as production of a non-functional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations, due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs) designed to induce skipping of exons in order to restore the mRNA open reading frame have shown therapeutic promise pre-clinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the 5th most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from homozygote CFTR-W1282X patients. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein.

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Section: Discussionmentioning

confidence: 99%

Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

Michaels

Peña‐Rasgado

Kotaria

et al. 2021

Preprint

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“… 48 In Phase I clinical studies (NCT02807961, NCT03292302, NCT03309605), 62 healthy volunteers were treated with ELX-02 and no serious adverse events or deaths were reported. 49 Two Phase II clinical studies have been initiated with 24 individuals with CF carrying the G542X mutation in at least one allele (NCT04126473, NCT04135495). Interestingly, ELX-02 demonstrated to rescue CFTR activity in the forskolin-induced swelling assay using intestinal organoids from individuals with CF carrying G542X-CFTR.…”

Section: Cftr Modulator Drugs and Personalized Medicinementioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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“…However, efficacy in many preclinical models was not reproduced [ 4 , 5 ] and clinical trials with Ataluren failed to reach their primary endpoints [6] . A recently chemically-engineered aminoglycosides derivative termed ELX-02 (NB124; Eloxx Pharmaceuticals) is currently in early clinical development [7] and showed to be effective as single treatment in intestinal organoids [8] .…”

Section: Introductionmentioning

confidence: 99%

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Poel

Spelier

Suen

et al. 2022

Journal of Cystic Fibrosis

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Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function.

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A Randomized, Double‐Blind, Placebo‐Controlled, Multiple Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of ELX‐02 in Healthy Subjects

Cited by 23 publications

References 6 publications

Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

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