Preclinical Work Supports ELX-02, Potential Treatment for Nonsense Mutations

Eloxx Pharmaceuticals presented preclinical safety and efficacy data supporting ELX-02, its investigational treatment for cystic fibrosis (CF) caused by nonsense mutations that is also being evaluated in two enrolling, Phase 2 trials.

The data were presented as two posters at this year’s virtual North American Cystic Fibrosis Virtual Conference (NACFC). Poster abstracts were also electronically published as a supplement to the journal Pediatric Pulmonology.

“We were pleased to have the opportunity to present additional preclinical study results,” Gregory Williams, PhD, CEO of Eloxx, said in a press release. “We believe that these results de-risk the current Phase 2 proof of concept clinical trials for ELX-02 in cystic fibrosis.”

ELX-02 is designed to restore the production of the working CFTR protein that is defective in CF. Without this protein, cells of the lungs and other organs produce a thick and sticky mucus that affects their function and promotes infections.

Specifically, ELX-02 targets nonsense mutations in the CFTR gene. These mutations create an early stop signal in the gene, resulting in the production of a shorter, and non-functional CFTR protein. ELX-02 helps the ribosome — the cellular machinery that synthesizes proteins — ignore the early stop signal (read-through process) to generate healthy, full-length CFTR protein.

The first poster, “ELX-02 Generates Protein Via Premature Stop Codon Read-through Without Inducing Native Stop Codon Read-through Proteins,” was presented by Dan Crawford, PhD, a senior principal scientist at Eloxx.

Researchers tested the read-through ability of ELX-02 by targeting a nonsense mutation called R213X in the TP53 gene found in cultured lung cells. Treating the cells with ELX-02 led to a significant uptick of full-length proteins, indicating that its read-through capability worked as intended, results showed.

The study found no evidence that ELX-02 caused ribosomes to read through the wanted — so-called “native” — stop signal. Doing so would result in an abnormally long protein.

Results of this work were also consistent with the acceptable tolerability profile of ELX-02 seen in preclinical and clinical studies so far, supporting its safety.

The second poster, “CFTR Restoration By ELX-02 Across CF Nonsense Genotypes: Utilizing Patient-Derived Organoids to Survey Responsive Alleles,” was presented by Matthew Goddeeris, PhD, vice president of research at Eloxx.

In this study, patient-derived organoids — a type of lab-grown “mini-organs” that better mimic three-dimensional tissue — were used to find CFTR mutations that responded to ELX-02 treatment. Researchers reported being able to screen over 75% of nonsense CFTR mutations with these organoids.

ELX-02 succeeded in boosting the level of CFTR mRNA (mRNA molecules are the templates cells use to produce proteins) in cells carrying the W1282X mutation. The amount of CFTR mRNA could be increased even more by simultaneously blocking nonsense-mediated decay in these cells, the work found. (Nonsense-mediated decay refers to the elimination of mRNAs that contain premature stop codons.)

Overall, data presented demonstrated “ELX-02’s selectivity for read-through of premature stop codons [stop signals] versus native stop codons and its ability to restore production of functional CFTR in patient-derived organoids,” Williams said.

ELX-02 is currently being tested in two open-label Phase 2 clinical trials — EL-004 (NCT04126473) and EL-012 (NCT04135495) — both evaluating the therapy’s safety, tolerability, and pharmacological properties, at ascending doses, in CF patients with at least one G542X mutation in the CFTR, the most common CF-causing nonsense mutation.

EL-004 is enrolling eligible adults, ages 18 and older, at sites in Germany and Israel; sites in Australia, which may allow patients starting at age 16, are due to open. More information can be found here.

EL-012 is enrolling adult patients at sites across the U.S.; more information is available here.

Earlier this year, ELX-02 was designated an orphan drug in the U.S., which supports its development through financial incentives.

“We are continuing to advance our trials in Europe, Israel and the U.S., and we look forward to reporting top line data from the Phase 2 clinical trial program as quickly as possible,” Williams said.