Therapy Targeting CF Mutation Appears to Restore CFTR Gene in Homozygous Patients in Study

ProQR Therapeutics is reporting that an early clinical study of  QR-010 in cystic fibrosis patients homozygous for the ΔF508 mutation in the CFTR gene met its primary endpoint. After four weeks of treatment, these patients showed a positive change in total chloride response, meaning that the CFTR protein was again working.

In patients heterozygous for the ∆F508 mutation in the CFTR gene (the gene that is defective in CF) the treatment had no effect; but in both groups, its safety profile was favorable. In homozygous patients, the ΔF508 mutation is present in both CFTR gene copies; in heterozygous patients only one gene copy is mutated.

QR-010 is a first-in-class RNA (ribonucleic acid)-based oligonucleotide designed to tackle the underlying cause of CF by repairing the mRNA in CF patients with the F508 mutation. This mutation is a deletion of three nucleotides in the CFTR gene, which leads to the production of a misfolded CFTR protein.

QR-010 is self-administered, through a handheld aerosol device, as a mist that is inhaled into the lungs. ProQR researchers believe this method allows for optimized drug delivery to the primary target organ — the lungs — while the drug’s systemic absorption into the blood also benefits other affected organs.

Top-line results from the company’s proof-of-concept study, PQ-010-002 (NCT02564354), were presented by Noreen R. Henig, MD, and John P. Clancy, MD, at the recent North American Cystic Fibrosis Conference (NACFC) held in Orlando, Florida.

“Patients with CF feel and do better when the CFTR protein channel works more normally. Our important first step in helping patients with CF was to demonstrate that QR-010 could restore CFTR function in patients with CF due to ∆F508, the most common mutation. Our proof-of-concept NPD [nasal potential difference] study did exactly that in CF patients homozygous for ∆F508; it demonstrated that CFTR protein channels are active in this cohort following administration of QR-010 as measured by the total chloride response,” Henig, chief development officer of ProQR, said in a press release. “Having achieved this major step, we have increased confidence in QR-010’s potential to make a meaningful clinical impact for patients and will move forward with an aggressive development plan.”

PQ-010-002,  a Phase 1 exploratory study, enrolled 18 patients with CF: 10 homozygous for the ΔF508 mutation, and eight heterozygous. The trial assessed the activity of the CFTR protein in the nasal epithelium in CF patients (achieved by measuring total chloride transport in the nasal cavity) to determine QR-010’s effect (applied topically to the nasal mucosa 12 times over a period of four weeks) on CFTR function through the degree to which chloride transport is restored. The trial was conducted at five centers in the U.S. and Europe.

Results reported show that at day 26, the mean change from baseline in NPD was statistically significant in seven homozygous patients. This result was supported by other NPD measurements, indicating that the CFTR protein activity was restored. But in patients heterozygous for the ΔF508 mutation, the mean change from baseline in NPD was not significant.

“NPD is a reliable, direct and specific measurement of CFTR activity and is therefore used as an important endpoint to assess CFTR function in clinical trials in CF. As CFTR dysfunction is the key problem in CF, the restoration of CFTR function as measured by NPD is an important early signal for potential future clinical benefit for patients,” said John P. Clancy, the study’s principal investigator, and a professor of pediatrics and research director with the Division of Pulmonary Medicine at Cincinnati Children’s Hospital. He is also a member of the Cystic Fibrosis Foundation Therapeutic Development Network’s leadership team.

“The change in the total chloride secretion response observed with QR-010 in this study has never been demonstrated with a ∆F508 targeting agent before. This outcome makes us eager to advance this molecule into next clinical studies,” Clancy added.

The safety, tolerability and pharmacokinetics of QR-010 are also being assessed in PQ-010-001 (NCT02532764), a 28-day, double-blind and placebo-controlled Phase 1b trial of single-dose and multiple ascending doses of the drug in 64 patients with CF homozygous for the ∆F508 mutation.

Efficacy endpoints in the multiple doses cohorts include the CFQ-R Respiratory Symptom Score, sweat chloride, and lung function. QR-010 will be inhaled by patients up to three times per week for a period up to four weeks. The single dose portion of this trial, including four cohorts, is now completed and no safety issues were observed, the company reported in the release.

The dose-escalating, multiple-dose portion of the study (12 doses administered over four weeks) is currently enrolling a sixth cohort of patients at 22 sites across the U.S. and Europe. For more information, including enrollment information,  please visit this link or click on the trial’s identification number above. Top-line safety, tolerability and exploratory efficacy results are expected in late 2017.

QR-010 has been granted Orphan Drug status in the U.S. and the European Union, and its development has received funding from a European program called Horizon 2020 to support research and innovation.

“This first clinical data in CF patients with QR-010 is a major milestone for ProQR, the CF community and the RNA therapeutics space. Confirming QR-010’s ability to improve CFTR function in homozygous ∆F508 patients is a strong validation of the preclinical evidence,” said Daniel de Boer, chief executive officer of ProQR.

“I want to sincerely thank all the patients that participated in our studies, and all our clinical investigators that supported this unique study,” de Boer added.