Clinical Trials

Date: 2017-09-25

Type of information: Interim results

phase: 1b

Announcement: interim results

Company: ProQR Therapeutics (The Netherlands)

Product: QR-010

Action mechanism:

• oligonucleotide. QR-010 is a first-in-class RNA-based oligonucleotide designed to address the underlying cause of the disease by repairing the mRNA in CF patients that have the DF508 mutation. The DF508 mutation is a deletion of three of the coding base pairs, or nucleotides, in the CFTR gene, which results in the production of a misfolded CFTR protein that does not function normally. QR-010 is designed to bind to the defective CFTR mRNA and restore CFTR function.
• QR-010 is designed to be self-administered through a small, handheld aerosol delivery device, or nebulizer, in the form of a mist inhaled into the lungs. QR-010 has been granted orphan drug designation in the United States and the European Union. The QR-010 project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633545.
• Two global clinical trials for QR-010 in CF patients were started in 2015: a Phase 1b single-ascending dose (SAD) and multiple ascending dose (MAD) study in 64 patients (Study 001) and a proof of concept study in 16 CF patients (Study 002). Study 002 and the SAD portion of Study 001 were completed and data were presented during the North American CF Conference (NACFC) in October 2016.

 

Disease: cystic fibrosis

Therapeutic area: Rare diseases - Genetic diseases - Lung diseases

Country: Belgium, Canada, Czechia, Denmark, France, Germany, Italy, Spain, UK, USA

Trial details:

• The PQ-010-001 study is a Phase 1b, 28-day, randomized, double-blind, placebo-controlled safety and tolerability trial, conducted in patients that have cystic fibrosis (CF) due to two copies of the F508del mutation (homozygotes). A total of 4 dose levels were studied: 6.25, 12.5, 25 and 50mg of QR-010 in solution per dose administered via inhalation. The study design consisted of 8 cohorts of 8 patients for a total of 64 patients. In each cohort, 6 patients received QR-010 and 2 patients received placebo. In cohorts 1-4, a single dose of QR-010 was administered, and in cohorts 5-8 twelve doses of QR-010 were administered over a 4-week period. Patients included in the study were adult patients with mild CF disease with a baseline predicted FEV1 value above 70%. The Phase 1b study is a first-in-human trial designed to primarily assess safety, tolerability and pharmacokinetics of QR-010. A number of exploratory efficacy endpoints are also being assessed including sweat chloride, weight gain, change in CFQ-R Respiratory Symptom Score and FEV1, however, the study is not powered for statistical significance on the exploratory efficacy endpoints. (NCT02532764)

Latest news:

• • On September 25, 2017,  ProQR Therapeutics  announced positive preliminary top-line results from a Phase 1b safety and tolerability clinical trial of QR-010, a novel investigational RNA therapeutic in subjects with cystic fibrosis. A number of exploratory efficacy endpoints were assessed in the multiple dose groups: respiratory symptoms (as measured by a validated patient-reported outcome tool, the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score, or CFQ-R RSS), lung function (as measured by mean absolute change in percent predicted forced expiratory volume in 1 second, or ppFEV1), sweat chloride test and weight change. This study included subjects with, on average, a normal lung function at baseline (mean 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. The trial recruited 70 participants and was conducted at 23 sites in 10 countries in Europe and North America.
• In this trial QR-010 was observed to be safe and well-tolerated across all doses, with an overall safety profile similar to placebo. There were 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, with mean improvements of 13.0, 19.2 and 14.3 points, respectively, compared to placebo. 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%) with a mean increase of up to 27.5 points compared to placebo. 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. The Phase 1b study achieved its goals for evaluation of QR-010 including demonstrating safety and tolerability across a range of doses, identified a dosing window, exhibited uptake of the RNA oligonucleotide into circulation following inhalation, and demonstrated early signals of clinical efficacy.
• ProQR and CFFT entered into a partnership in 2014 to develop QR-010 for people with CF due to the F508del mutation. The initial partnership included support for the Phase 1b trial as well as the NPD proof of concept study that reported positive results in 2016. Based on the results of the clinical trials of QR-010, ProQR and CFFT intend to expand the partnership to explore the inhaled oligonucleotide platform for stop-codon mutations (also called “Class I” mutations) in CFTR. Stop-codon mutations cannot be targeted with small molecule potentiator or corrector molecules, and therefore have a high unmet medical need. ProQR intends to target these mutations using its proprietary Axiomer® technology, which has shown compelling data in non-clinical studies, to repair the stop-codon mutations in the RNA, leading to removal of the premature stop-codon. Approximately 12,000 patients, accounting for 15% of CF patients in the western world, have a stop-codon mutation leading to a severe form of CF.    
• • On October 27, 2016, ProQR Therapeutics announced that clinical study PQ-010-001 completed all four single-dose cohorts.  The multiple dose cohorts in this study are ongoing and topline safety, tolerability and exploratory efficacy data from this study are expected in mid-2017
• • On  June 21, 2016, ProQR Therapeutics announced that preliminary data from the single-dose cohorts of PQ-010-001, a Phase 1b safety and tolerability Study of QR-010, are also planned to be released at the time of the North American CF Conference (NACFC), together with an update on the enrollment for the multiple-dose cohorts which is currently not expected to be completed in 2016.
• Study PQ-010-001 evaluates the safety, tolerability and pharmacokinetics of single and multiple ascending doses of inhaled QR-010 in 64 CF patients carrying two copies (homozygotes) of the DF508 mutation.
• • On June 26, 2015, ProQR Therapeutics announced that enrollment has started in study PQ-010-001, a global Phase 1b clinical study of QR-010, a novel investigational RNA therapeutic designed to repair the genetic mutation in the mRNA of cystic fibrosis (CF) patients due to the DF508 mutation. As exploratory efficacy endpoints, this study will also assess sweat chloride, weight gain, CFQ-R Respiratory Symptom Score and lung function, measured by FEV1. This Phase 1b trial will be conducted in parallel with a proof-of-concept Nasal Potential Difference (NPD) study that will begin enrollment of 16 CF patients that are either homo- or heterozygous for the DF508 mutation in Q3 of this year.

Is general: Yes