#ECFS2018 – Preclinical Data Shows Potential of ELX-02 to Reverse Effects of CFTR Nonsense Mutations

Preclinical studies show that Eloxx Pharmaceuticals’ lead therapy candidate ELX-02 can reverse the effects of CFTR gene nonsense mutations in mice and cystic fibrosis (CF) patient-derived organoids.

These findings further support the clinical development of ELX-02 as a treatment for CF patients with CFTR nonsense mutations, which represent about 10% of CF cases worldwide.

The most recent ELX-02 preclinical data was discussed in two oral presentations at the 41st European Cystic Fibrosis Society (ECFS) Conference held June 6-9 in Belgrade, Serbia.

Nonsense mutations are a type of genetic variation that leads to the production of short, nonfunctional, or poorly functional proteins. Recently, translational read-through inducing drugs (TRIDs) have emerged as a therapeutic option to restore the activity of proteins affected by these nonsense mutations.

TRIDs work by disabling the effect of the mutation, allowing the production of functional, full-length proteins.

ELX-02 is an optimized small molecule engineered to act as a TRID. Preclinical studies have shown that ELX-02 can represent a potential therapeutic option for several genetic diseases, including CF, cystinosis, mucopolysaccharidosis type 1, Duchenne muscular dystrophy, and Rett syndrome.

To evaluate the effects of ELX-02 as a CF treatment, researchers tested experimental cell lines carrying the human CFTR G542X or R1162X mutations (both are nonsense mutations).

Increasing doses of the drug were found to promote proportional improvements in cells’ transmembrane currents, indicating that ELX-02 could correct the underlying defect of CFTR.

This effect was found to be further enhanced when ELX-02 was administrated in combination with Vertex’s CFTR potentiator Kalydeco (ivacaftor).

Similar effects were seen when the researchers used CF patient-derived bronchial epithelial cells carrying G542X and delF508 mutations. Treatment for 48 hours with ELX-02 improved the patient-derived cells’ CFTR response by 270% compared to untreated cells.

Also, the combination treatment with Kalydeco further improved CFTR activity by 2.5 times.

The potential of ELX-02 was also demonstrated in cystic fibrosis mice carrying the G542X mutation. After the drug was administered twice a week for four weeks, the animals showed a 12.6% improvement in CFTR activity.

Researchers concluded that “ELX-02 treatment restored ion transport activity and rescued CFTR function in a CF mouse model, thus providing a potential approach for life-long treatment of this genetic disease.”

These results were presented in the study titled “Translational Read-Through of CFTR Non-Sense Mutations and Inducement of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Function by ELX-02 Treatment” at the ECFS 2018 meeting.

Researchers also evaluated ELX-02 in patient-derived organoids, an experimental model that mimics the functioning of human tissues, which have been recognized as a valuable model to predict clinical benefit.

When organoids from CF patients with CFTR nonsense mutations were treated with ELX-02, a positive response was reported, consistent with a predictive clinical efficacy.

This positive result was found to be associated with significant improvements in the levels of CFTR in the organoids, which suggests that ELX-02 is bringing about a recovery of the corrected form of the gene.

These results were presented in the study “Evaluation of ELX-02 in Cystic Fibrosis Patient Organoids with Non-Sense Mutations” at the ECFS 2018 meeting.

“We are extremely pleased with the emerging profile of ELX-02,” Pedro Huertas, an MD and PhD, the chief medical officer of Eloxx Pharmaceuticals, said in a press release.

“We expect to initiate a Phase 2 study in cystic fibrosis patients carrying at least one G542X mutation later this year, pending regulatory clearance, and are pleased the European Cystic Fibrosis Society-Clinical Trial Network has reviewed and approved our protocol with a ‘high priority’ rating,” Huertas added.

The company has already completed two Phase 1 trials (NCT02807961, NCT03292302), and is currently conducting another Phase 1 trial (NCT03309605) to assess the safety, tolerability, and stability of ELX-02 in healthy volunteers.