The therapy was well-tolerated in single- and multiple-ascending dose studies in those clinical trials, and raised levels of the crucial CFTR protein in patient-derived organoids, data showed. These results were presented at the 42nd European Cystic Fibrosis Society Conference that took place June 5–8 in Liverpool.
Certain mutations in the CFTR gene, the underlying cause of CF, give rise to a premature stop signal called a stop codon, resulting in the production of a protein from messenger RNA with a wrong stop signal. This means the process finishes before the full CFTR protein is made, leaving people with such nonsense mutations with little or none of that protein.
ELX-02 is a eukaryotic ribosomal selective glycoside that binds to ribosomes, which are cellular units that serve as factories to produce proteins inside cells. The therapy is designed to increase a ribosome’s ability to skip over nonsense mutations and enable the production of sufficient amounts of full-length protein.
Phase 1 clinical studies in healthy people in Israel and Belgium found that ELX-02 promoted the stability of CFTR messenger RNA and increased the RNA levels, the presentations showed. Its use in patient-derived organoids — 3D models that mimic sick tissue — also improved CFTR protein function.
“We are extremely pleased with the emerging profile of ELX-02,” Matthew Goddeeris, PhD, director of research at Eloxx, said in a press release, adding that “previous studies with already approved drugs for cystic fibrosis” raise hopes that the company’s Phase 2 studies will succeed.
Goddeeris delivered the oral presentation, “ELX-02 increases full length CFTR mRNA through nonsense mediated decay interruption,” at the conference.
Gregory Williams, PhD, Eloxx’s chief operating officer, added: “We expect to report top line data from a Phase 2 study in cystic fibrosis patients carrying at least one G542X allele later this year.”
Williams gave an oral presentation, titled “Administration of ELX-02 to healthy volunteers demonstrates dose linearity and proportionality as well as low inter-subject variability.”
He described a Phase 1, single-dose escalation trial that randomized 40 healthy participants to ELX-02 — ranging from 1.0 to 5.0 milligrams per kilogram (mg/kg) and administered into the skin (subcutaneously) or into the blood (intravenously) — and 20 people to a placebo.
Data showed ELX-02 in general was well-tolerated, with consistent results among subjects. Its bioavailability reached 98%, and it had a mean life of around two to eight hours depending on administration route and dose.
The therapy was excreted via the kidneys and into the urine — researchers recovered between 81%–99% of ELX-02 in the urine after 48 hours when the therapy was given into the skin, and 85% when administered into the blood.
A poster presented by Goddeeris — “ELX-02 Pharmacokinetic profile appropriate for CF patient use” — reported a multiple-dose Phase 1 study (NCT03309605) of ELX-02 at 5 mg/kg/week.
Results found ELX-02 does not accumulate in the blood and showed similar processing inside the body (pharmacokinetics) as in the single-ascending dose study. The team suggests that, given this profile, ELX-02 can be safely administered in CF patients with twice weekly or daily dosing.
About 13% of all CF patients carry a “nonsense mutation on at least one CFTR allele. These patients have a high burden of disease, and few, if any, available treatment options,” Williams said.