Eloxx Pharmaceuticals presented new positive preclinical data for ELX-02, its lead treatment candidate for cystic fibrosis (CF), demonstrating that the therapy increases the levels of CFTR protein and its correct placement at the cell’s surface in patient-derived organoids.
Findings were presented by Shira Landskroner-Eiger, PhD, Eloxx’s principal scientist at the 2019 European Cystic Fibrosis Society (ECFS) Basic Science Conference, taking place March 27-30 in Croatia. The data were presented in a poster titled “CFTR protein detection in organoids from healthy and CF patients with nonsense mutations support using organoid model to test ELX-02 mediated CFTR read-through restoration.”
ELX-02 is an experimental therapy to treat CF caused by nonsense mutations, in which a premature stop signal is inserted in the CFTR gene, which is defective in CF. This signal causes the cellular machinery to stop making the CFTR protein midway, forming an incomplete version of the protein that is rapidly degraded by the cell.
ELX-02 is a eukaryotic ribosomal selective glycoside (ERSG) that binds to ribosomes, complexes that serve as factories to produce proteins inside cells. The therapy is designed to increase ribosome’s skipping over nonsense mutations, and enable the production of sufficient amounts of full-length CFTR protein and lessen CF burden.
Eloxx has been evaluating the effect of ELX-02 on patient-derived organoids, a type of “mini-organs” that are grown in the lab based on biopsied patient cells. These organoids mimic diseased tissues, and they have been regarded as a potentially valuable tool to predict clinical benefit.
Potential applications of organoids include determining disease severity and predicting a patient’s response to therapy.
In February, Eloxx joined the European HIT-CF project, an EU-funded preclinical and clinical research program evaluating the efficacy and safety of several therapeutic candidates for CF patients with rare genetic mutations. The goal of the project is to investigate whether a positive response in organoids can be predictive of a positive response in patients in clinical trials.
In their most recent findings, Eloxx researchers report that ELX-02 increased the production and correct localization of CFTR proteins in CF patient-derived organoids with two of the most common nonsense mutations, G542X and W1282X.
This is the first demonstration that ELX-02 works in CF patient-derived organoids.
Prior preclinical studies in the organoid model showed that ELX-02 increased the activity of the CFTR channel, as well as the activity of the CFTR gene, in a dose-dependent manner.
Those findings are now complemented with the current data, demonstrating an accompanying increase in CFTR protein levels.
“ELX-02 is the first read-through agent to demonstrate significant increases in CFTR protein expression, localization on the apical surface, and functional activity in a dose responsive manner in organoids derived from cystic fibrosis patients with nonsense mutations,” Matthew Goddeeris, PhD, research director at Eloxx, said in a press release.
Eloxx is conducting a Phase 2 trial after completing an ongoing Phase 1 dosing study in healthy volunteers (NCT03309605). The trial will evaluate the safety and tolerability of ELX-02 in CF patients carrying the G542X mutation, which accounts for about 5 percent of the CF population. Results are expected this year.
The ECFS Clinical Trial Network has assigned “high priority” to the ELX-02 clinical development program.
“We believe these ground-breaking new data establish a solid basis for understanding the activity of ELX-02 and it’s potential for development in the treatment of the high unmet medical need cystic fibrosis patients with nonsense mutations. We look forward to reporting top line data in 2019 from our planned Phase 2 cystic fibrosis clinical trial,” said Robert Ward, Eloxx’s chairman and CEO.
According to the company, it is continuing to study ELX-02’s activity in a growing number of patient-derived organoids, covering the top five nonsense mutations in CF, which represent about 75 percent of nonsense mutation-carrying patients.