The experimental treatment eluforsen is safe for adults with cystic fibrosis (CF) caused by a mutation called F508del, a new study reports, supporting further investigation and development of the treatment.
The study, titled “Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the CFTR gene. F508del is the most common mutation in this gene; in fact, nearly 90% of CF patients have at least one CFTR copy with this mutation, and around half of those patients have two copies with the same mutation (of note, every person has two copies of the gene, one inherited from each parent).
The F508 del mutation leads to a small deletion in the protein encoded by the CFTR gene, causing the CFTR protein to function improperly.
Eluforsen (formerly QR-010) is an experimental therapy that aims to correct this deletion by modifying the RNA cells made from the CFTR gene, before the RNA is translated into the final protein product. Preclinical tests suggested that eluforsen could improve CFTR protein function, and similar strategies have been highly effective in other diseases.
The trial recruited adult patients with early or mild CF caused by two copies of the CFTR gene with the F508del mutation. Patients were enrolled in one of two arms of the trial: a single ascending dose (SAD) cohort, and a multiple ascending dose (MAD) cohort. The difference between the two is based on whether individual patients received one or multiple doses of the therapy.
The SAD cohort included 36 CF patients, all of whom completed the study. In the MAD cohort, three of the 34 patients discontinued treatment before the study’s end.
Patients were given either a placebo or eluforsen at doses of 6.25, 12.5, 25, or 50 mg. The treatment was taken via inhalation, three times weekly for four weeks, for a total of 12 doses per subject.
Overall, the results showed that eluforsen was safe and well-tolerated in all the CF patients. A few serious adverse events (e.g. lung infections) were reported, but all of them were deemed unrelated to eluforsen treatment. Common mild and moderate side effects included gastrointestinal distress, respiratory symptoms such as coughing and congestion, and infections.
Additionally, the researchers noted that “no dose-limiting toxicities were identified; thus, a maximum tolerated dose was not established.”
In terms of efficacy, the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale (CFQ-R RSS) was used to assess patients’ symptoms, and in the MAD cohort, doses of 12.5 and 25 mg both resulted in significant improvements from baseline compared with the placebo.
Forced expiratory volume — the amount of air a person can exhale in one breath (a measure of lung function) — was also assessed. No overall change from baseline or improvement was observed in eluforsen-treated patients compared with the placebo group; however, in the subgroup of patients with particularly low scores at baseline, a trend towards improvement was seen, particularly at doses of 6.25 or 12.5 mg in the MAD group.
The researchers made a point to note that the study was not designed to robustly test the efficacy of the treatment, but it was to ensure eluforsen’s safety and find what might be an appropriate dose for future studies. Still, the trends found toward improvement were “encouraging,” they wrote.
Overall, “inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well-tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients,” the researchers concluded.
“The results from this phase 1 dose escalation study indicate that eluforsen is suitable for further development and provide support for additional larger controlled studies,” they wrote.