Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - PRO-CF-MED (Clinical Proof of concept for a RNA-targeting Oligonucleotide for a Cystic fibrosis-F508del MEDication)
Teaser
CF is the most common fatal inherited disease in the Western world and affects an estimated 70,000 to 100,000 patients worldwide. In people with CF, a defective CFTR gene causes a thick, buildup of mucus in the lungs, pancreas and other organs. In the lungs, the mucus clogs...
Summary
CF is the most common fatal inherited disease in the Western world and affects an estimated 70,000 to 100,000 patients worldwide. In people with CF, a defective CFTR gene causes a thick, buildup of mucus in the lungs, pancreas and other organs. In the lungs, the mucus clogs the airways and traps bacteria leading to infections, extensive lung damage and eventually, respiratory failure. There is no cure for CF and the disease manifestations lead to a shortened life expectancy. Although over 1,900 CF-causing gene mutations have been identified, approximately 70% of all CF patients are affected by the F508del mutation.
ProQR is developing an investigational product for cystic fibrosis patients that suffer from the F508del mutation, called QR-010. QR-010 is being developed as a regularly inhaled therapy and is designed to work in a unique way. Unlike any other CF drug currently on the market, it has been designed to bind specifically to the defective CFTR RNA and restores the function of the CFTR protein. Restoring CFTR function can potentially stop the progression of cystic fibrosis. Two clinical trials have started. A phase Ib clinical trial that is currently ongoing and a nasal potential difference study that has been completed.
In May 2015 the PRO-CF-MED consortium started with the execution of the work as described in the grant agreement. The following overall project objectives were defined:
• To perform pre-clinical in vivo studies
• To conduct a Phase Ib clinical trial
• To conduct a Proof of Concept clinical trial
• To conduct a follow-up Phase II trial
• To produce drug product
• To determine regulatory strategy for registration
• To perform biomarker development
Work performed
During the first 18 months of the project the members of the PRO-CF-MED consortium made the following progress on the actions described in the Grant:
Two clinical studies started in 2015. 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 CF patients homozygous for the F508del mutation. Exploratory efficacy endpoints in the multiple dose cohorts include sweat chloride, weight gain, CFQ-R Respiratory Symptom Score and lung function, measured by FEV1 percent predicted. The study is currently enrolling patients in more than 20 centres in North America and Europe.
The single ascending dose portion of the study, consisting of 4 cohorts, was completed. No dose-limiting toxicity was observed up to the highest dose tested. The multiple ascending dose portion of the study (12 doses administered over 4 weeks) is ongoing and top-line results are expected in 2017.
The second study measures nasal potential difference, or 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 CFTR function. The study was conducted in 5 NPD specialised centres in the US 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 cystic fibrosis 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. With this study we aimed to demonstrate that QR-010 could restore CFTR function in patients with CF carrying the F508del mutation. This will provide an important first signal of the therapeutic potential of QR-010 in patients with CF. The clinical study demonstrated that QR-010 restored CFTR function in a cohort of homozygous F508del cystic fibrosis (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. A responder analysis of individual subjects assessing the impact of the second mutation is currently ongoing.
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 (NACFC) in Orlando, Florida.
In July 2016 the QR-010 program was granted Fast Track designation by the FDA. Fast track designation is 1 of the 4 expedited programs from FDA intended to facilitate and expedite development of new drugs addressing unmet medical needs in the treatment of a serious condition. By granting QR-010 a Fast Track designation the FDA acknowledges, based on the submitted non-clinical data, that QR-010 demonstrates the potential to address unmet medical needs for CF patients with at least one copy of the F508del mutation.
Final results
Progress beyond the state of the art
QR-010 has the potential to advance the state of the art of RNA technology in the following ways:
• QR-010 is a first-in-class RNA-based oligonucleotide that has the potential to address the underlying cause of the disease by targeting the mRNA in CF patients that have the F508del mutation
• QR-010 is designed to bind to the defective CFTR mRNA and restore CFTR function
• QR-010 is developed to be self-administered via an optimized eFlow® Nebulizer (PARI Pharma GmbH)
Expected results until the end of the project
Proof of principle that QR-010 could be beneficial for patients with the F508del mutation
Potential impacts
In the PQ-010-002 study, proof of concept has been demonstrated for QR-010 in CF subjects homozygous for the F508del mutation. QR-010 has shown to significantly improve CFTR-mediated total chloride transport in this population. This was also supported by sensitivity analyses and a positive sodium transport signal. A worldwide press release on these results was issued in October 2016. These results support the continuation of the development of QR-010.
QR-010 has the following potential impacts:
• QR-010 has the potential to be an additional medicinal product of the treatment of CF
• QR-010 has the potential to reduce burden to patients and their families.
• QR-010 has the potential to result in a reduction of healthcare costs.
• The launch of QR-010 will strengthen ProQR Therapeutics as a company.
Website & more info
More info: http://pro-cf-med.eu/.