An exploratory Phase 1 trial showed that repeated intranasal treatment with the therapy eluforsen improved CFTR protein activity in adults with cystic fibrosis (CF) carrying F508del mutations in both CFTR gene copies.
The study, “Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the CFTR gene, leading to the absence or dysfunction of the CFTR protein. The most common CFTR mutation — F508del — involves the deletion of three nucleotides (the building blocks of DNA) that impair the ability of the CFTR protein to move salts across the cell membrane.
CFTR protein dysfunction in the upper airways can be detected by measuring the nasal potential difference (NPD), a test of chloride and sodium transport across the nasal epithelium that can be specific for CFTR. NPD is used for CF diagnosis in patients with unclear sweat and genetic testing results.
In trials testing potential CFTR-directed therapeutics, NPD responses were found to correlate with improved sweat chloride and clinical improvements in later Phase studies.
Eluforsen (previously known as QR-010) is an RNA oligonucleotide developed by ProQR Therapeutics to bind to the messenger RNA (mRNA) region around the F508 deletion, and to normalize CFTR protein function in the airway epithelium. Messenger RNA is generated from DNA, and contains the information for protein production.
In preclinical work, eluforsen improved CFTR protein function in bronchial epithelial cells from CF patients carrying homozygous (both gene copies, one inherited from the mother and one from the father) F508del mutations, and in a CF mouse model.
The team then conducted a ProQR-sponsored Phase 1 study (NCT02564354) to assess if intranasal eluforsen improves CFTR activity in the respiratory epithelium, as measured by NPD, in CF patients with homozygous or heterozygous (with two different mutated gene copies) for the F508del-CFTR gene mutation.
The open-label trial was conducted at five sites in the U.S. and Europe in adult CF patients. In total, 14 patients were eligible for the final analysis, seven homozygous and seven heterozygous for F508del mutations. Participants were not allowed to take other CFTR-modulator therapies from 30 days pre-screening until the end of the study.
All participants received bilateral (both nostrils) doses of 10 mg eluforsen three times weekly for four weeks, for a total of 12 doses. The trial’s primary focus was the change from baseline in total chloride transport, as assessed by NPD. Change in sodium transport was also determined.
Results showed that eluforsen increased total chloride transport in the homozygous mutation group, as assessed by the change from day 15 (-3.0 mV) to day 26 (-4.1 mV, at end of treatment) — a result that was sustained at the final post-treatment measurement on day 47 (-3.7 mV). Negative values reflect a better chloride transport.
Sodium transport was also improved, as shown by a decreased (more positive values) in the average basal potential difference on day 26 (+9.4 mV).
In contrast, CF patients with heterozygous mutations did not show improved chloride or sodium transport. The team hypothesized that this result may be due to the reduced availability of mRNA to interact with eluforsen.
Treatment with eluforsen was well-tolerated, with no serious side effects or adverse events (AEs) reported. Mild-to-moderate AEs were however reported in 15 of the initial 18 patients, one of whom had several severe AEs related to a probable viral infection eight days post-treatment. Most AEs occurred in the respiratory and gastrointestinal systems. Twenty-five of 71 AEs were considered related to eluforsen treatment.
In conclusion, “in F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity,” the scientists wrote.
“This is the first demonstration of improved CFTR function using an antisense oligonucleotide therapeutic approach in CF subjects,” the team added. “Together, these data support eluforsen development for patients with CF homozygous for the F508del-CFTR mutation.”