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Clinical Proof of concept for a RNA-targeting Oligonucleotide for a Cystic fibrosis-F508del MEDication

Periodic Reporting for period 2 - PRO-CF-MED (Clinical Proof of concept for a RNA-targeting Oligonucleotide for a Cystic fibrosis-F508del MEDication)

Reporting period: 2016-11-01 to 2017-12-31

Cystic fibrosis (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 cystic fibrosis transmembrane conductance regulator (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. Approximately 70% of all CF patients are affected by the F508del mutation (deletion in the phenylalanine amino acid).
ProQR is developing an investigational product for CF patients that suffer from the F508del mutation, called QR-010. QR-010 will be taken as a regularly inhaled therapy and is designed to work in a unique way. Unlike any other CF drug currently on the market it aims to bind to the CFTR messenger ribonucleic acid (mRNA) and restore the function of the CFTR protein. Restoring CFTR function can potentially stop the progression of CF. Two clinical trials have been completed.
In May 2015 the PRO-CF-MED consortium started with executing the grant agreement. The following overall project objectives were defined:
• Pre-clinical animal studies
• Phase Ib clinical trial
• Proof of Concept clinical trial
• Phase II trial
• Produce drug product
• Regulatory strategy for registration
• Biomarker development
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.
In July 2016 the QR-010 program was granted Fast Track designation by the Food and Drug Administration (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 cystic fibrosis (CF) patients with at least one F508del mutation (deletion in the phenylalanine amino acid).
Progress beyond the state of the art
QR-010 has the potential to advance the state of the art of ribonucleic acid (RNA) technology in the following ways:
• QR-010 is a first-in-class RNA-based oligonucleotide designed to address the underlying cause of the disease by targeting the messenger ribonucleic acid (mRNA) in CF patients that have the F508del mutation
• QR-010 is designed to bind to the defective cystic fibrosis transmembrane conductance regulator (CFTR) mRNA and to restore CFTR function
• QR-010 is designed to be self-administered via an optimized eFlow® Nebulizer, an electronic, portable, handheld device that produces a soft mist which patients can conveniently inhale (PARI Pharma GmbH).

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.