The first study is a phase Ib clinical study, which evaluates the safety, tolerability and pharmacokinetics of single and multiple ascending doses of inhaled QR-010 in a total of 64 cystic fibrosis (CF) patients homozygous for the F508del mutation(deletion in the phenylalanine amino acid). Exploratory efficacy endpoints in the multiple dose cohorts include sweat chloride, Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CRQ-R RSS) and lung function, measured by percent predicted forced expiratory volume (ppFEV1). The trial recruited 70 participants and was conducted at 23 sites in 10 countries in Europe and North America. This study included subjects with, on average, a normal lung function at baseline ppFEV1 (86%, range 69-116%). As therapeutic trials typically study subjects with normal-to-severe lung function at baseline (ppFEV1 <90%), a subgroup was pre-defined to analyze the exploratory efficacy endpoints in this population.
Results:
• QR-010 was observed to be safe and well-tolerated across all doses, with an overall safety profile similar to placebo.
• No serious adverse events related to treatment.
• After inhaled administration in some dose groups, QR-010 was detected in the blood.
• Subjects who received QR-010 in the 6.25 12.5 and 25 mg multiple dose groups reported fewer respiratory symptoms after 4 weeks of treatment as measured by the increased CFQ-R RSS. The effect was more pronounced in the pre-defined subgroup of subjects with a lower lung function at the start of the study (baseline ppFEV1 70-90%). These improvements exceeded the minimal clinically important difference (MCID) of 4.0 points.
• A supportive trend of improved lung function was observed in the same multiple dose groups, as measured by mean absolute change in ppFEV1 compared to placebo. The trend was stronger in the subgroup of subjects with a lower lung function at baseline.
• As expected, no effect was observed on sweat chloride and weight.
In September 2017 a press release was issued on this major milestone and the top-line results were presented at the Northern American Cystic Fibrosis Conference.
The second study is a nasal potential difference (NPD), for which study conduct has been completed. It is an open-label, proof-of-concept study evaluating the effect of QR-010 on the NPD assay, an important measurement of cystic fibrosis transmembrane conductance regulator (CFTR) function. The study was conducted in 5 NPD specialized centers in the Unites States and Europe. The study enrolled 18 CF patients, 10 homozygous for the F508del mutation and 8 compound heterozygous (one copy of the F508del mutation and one copy of another CF disease-causing mutation). QR-010 was applied topically to the nasal mucosa 12 times over a period of 4 weeks. The primary endpoint for each cohort was the change from baseline in CFTR-mediated total chloride transport as measured by NPD.
The clinical study demonstrated that QR-010 restored CFTR function in a cohort of homozygous F508del CF patients. In the per-protocol population of subjects homozygous for the F508del mutation meeting the pre-specified inclusion criteria (n=7), the average change from baseline in NPD at day 26 was statistically significant, -4.1 mV (p=0.0389). This finding was supported by a change in sodium channel activity and other sensitivity analyses of the NPD measurements, all pointing to strong evidence of restoration of CFTR activity. In subjects compound heterozygous for the F508del mutation, the average change from baseline in NPD was not significantly different at day 26.
The study met its primary endpoint in the homozygous cohort as measured by a change in total chloride response following 4 weeks of treatment with QR-010. QR-010 was observed to be safe and well-tolerated in both cohorts. In October 2016 a press release was issued on this major milestone and the top-line results were presented at the Northern American Cystic Fibrosis Conference.
