Eloxx Pharmaceuticals Presents Positive New Data for Lead Investigational Drug, ELX-02, at the North American Cystic Fibrosis Conference (NACFC)
ELX-02 shows significant increases in CFTR function in Cystic Fibrosis patient-derived
organoids bearing nonsense mutations in the CFTR gene
ELX-02 demonstrated significant increases in CFTR mRNA, with elevations above wild-
type, that correlated to the organoid response
“We are extremely pleased with the emerging profile of ELX-02, as the first read-through agent to demonstrate increases in CFTR function and mRNA in organoids derived from cystic fibrosis patients with nonsense mutations,” said
Recent work with cystic fibrosis patient-derived organoids have extended the potential applications of the FIS assay to include use in stratifying patient disease severity (1) and as a potential predictor of CF patient response to drug therapy (2).
Eloxx plans to initiate a Phase 2 study in cystic fibrosis patients carrying at least one G542X mutation. The European Cystic Fibrosis Society-Clinical Trial Network has reviewed the program and assigned a “high priority” rating. Eloxx expects to report top-line data from the Phase 2 study in 2019.
In a Poster presentation titled “Measuring mRNA levels in cystic fibrosis organoids with nonsense mutations following treatment with ELX-02,” presented by
- ELX-02 demonstrated dose responsive increase in CFTR function and mRNA expression when tested in a correlative assay using organoids from cystic fibrosis patients with homozygous and heterozygous nonsense mutations. The FIS swelling was consistent across a range of concentrations of the swelling inducing agent, forskolin, and did not saturate in the timeframe of the assay. Additionally, the swelling response was demonstrated to be dependent on CFTR activity and the presence of a nonsense mutation. The response demonstrated is consistent with levels potentially predictive of clinical efficacy.
- Using nanoString™ technology, ELX-02 mediated organoid swelling was found to correlate with increased CFTR mRNA, with elevations above wild-type. ELX-02 appears to increase the steady state concentrations of CFTR mRNA suggesting that ELX-02 may be modulating nonsense mediated decay.
- The increased CFTR function demonstrated with ELX-02 was further enhanced with the addition of a potentiator and corrector in some organoids derived from patients with heterozygous nonsense mutations.
- These data demonstrate that ELX-02 promotes translation of functional CFTR and support continuing development of ELX-02 in patients with cystic fibrosis.
ELX-02 is an investigational agent not approved by any regulatory agency for therapeutic use.
Organoids are derived from stem cells isolated from cystic fibrosis patients and are differentiated into cell types found in organs of interest. Because organoids are made from stem cells, they contain the same mutations as the person from whom the biopsies originated. As CFTR functional activity is measurable in organoids, this model system is used to evaluate drug candidates across a range of mutations found in the cystic fibrosis patient population. Since some therapeutic candidates target the basic defect of cystic fibrosis, organoids are being evaluated as a potential biomarker to help identify which treatments can affect specific mutations.
1) de Winter-de Groot KM, Janssens HM, van Uum RT, et.al. (2018). “Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function” Eur Respir J. Sep 17;52(3). pii: 1702529.
2) Dekkers JF, Berkers G, Kruisselbrink E. et.al. (2016) “Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis” Sci Transl Med,
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Source: Eloxx Pharmaceuticals