ProQR Therapeutics announced that it plans to announce proof-of-concept results from tests of its lead candidate to treat cystic fibrosis (CF), QR-010, at a scientific conference this year, and is continuing to advance the development of this and other transformative RNA medicines for severe orphan diseases like CF and Leber’s congenital amaurosis Type 10 (LCA10).
ProQR’s lead candidate for CF, QR-010, is a first-in-class RNA-based oligonucleotide aiming to treat CF patients who carry the common ∆F508 mutation, which affects more than 70% of all such patients. This 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 and improperly functioning CFTR protein. QR-010 taken as a regularly inhaled therapy is designed to bind to the defective CFTR mRNA and restore CFTR function.
In other words, QR-010 aims to repair the genetic defect at the RNA level in order to restore CFTR protein function, which can potentially stop the progression of CF. QR-010, designed to be self-administered through a small, handheld aerosol delivery device (nebulizer) in the form of mist inhaled directly into the lungs, is being tested in two clinical trials and has been granted orphan drug designation in both the United States and the European Union. Its development is being supported by funding from the European Union’s Horizon 2020 research and innovation program (grant agreement No. 633545).
“We continue to make good progress with our three different development programs, all RNA oligonucleotides for serious genetic diseases. For QR-010 for patients with CF due to the ∆F508 mutation, we will present top-level results from clinical proof-of-concept study, PQ-010-002 later this year during the North American Cystic Fibrosis Conference (NACFC),” said Daniel de Boer, ProQR’s chief executive officer, in a press release.
At the European Cystic Fibrosis Conference (ECFS) on June 10, ProQR presented additional pre-clinical data for QR-010. In a presentation titled “QR-010 penetrates the CF-like mucus barrier in vitro and in vivo,” QR-010 was shown to diffuse rapidly through CF-like mucus layers in models both in vitro and in vivo. QR-010’s stability in CF sputum was also demonstrated in the presence of CF lung bacteria at clinically relevant levels of CF standard of care.
Topline Data in CF Patients To Be Presented at NACFC
Topline data from its proof-of-concept study (NCT02564354) — an open-label 28-day study in CF patients taking place at five centers in the U.S. and Europe — evaluating the effect of QR-010 on nasal potential difference (NPD) will be released at NACFC, set for Oct. 27–29 in Orlando, Florida, the company said. In addition, preliminary data from the single-dose cohorts of its Phase 1b (NCT02532764) safety and tolerability study of QR-010 may also be available at NACFC, together with an update on enrollment of multiple-dose cohorts, which is not expected to be completed this year.
Both studies are currently recruiting CF patients. The proof-of-c0ncept study is for patients both homozygous for the ΔF508 mutation (carrying two copies) and heterozygous for that mutation (one copy of the ΔF508 and one other disease-causing mutation), while the dose-escalating trial is enrolling only CF patients homozygous for ΔF508, but taking place at 22 sites in the U.S., Canada, and Europe. More information, including enrollment information, is available by clicking on the links given above with each trial’s identifying number.
“We are excited to announce data from our two ongoing clinical studies of QR-010,” DeBoer said in a previous release. “In our pre-clinical models QR-010 showed an unprecedented restoration of CFTR function in the NPD test. Because NPD in CF patients has positive predictive value for clinical benefit, we would see a positive outcome in this study as an important proof of efficacy.”
In July, ProQR Therapeutics announced that it received Fast Track designation from the U.S. Food and Drug Administration (FDA) for QR-010, a classification granted to drugs under development for serious conditions that have potential to fulfill an unmet medical need.
“We are very pleased with the Fast Track designation the FDA granted us for QR-010. It highlights the unmet medical need in cystic fibrosis and the need for innovative and more efficacious medicines for CF. We look forward to working with the FDA to bring QR-010 to patients faster,” de Boer said in a release. “We are also looking forward to releasing data for the first-in-human trials of QR-010 in CF patients later this year during the North American CF conference.”
The Dutch company also released financial information, revealing that its cash position was €85.5 million as of March 31, sufficient to allow it to fund operations into mid-2018, and to continue strengthening its RNA therapeutics pipeline.
Nasal Potential Difference Proof-of-Concept Study
NCT02564354, also known as PQ-010-002, is evaluating QR-010’s effect on NPD, measuring CFTR protein activity by how efficiently chloride is transported through the nasal cell membranes — an important measurement of CFTR function. The study, which consists of a Part A and may be extended to a Part B, plans to enroll 16 CF patients, eight homozygous for the ΔF508 mutation and eight heterozygous, with the option of enrolling a second 26-patient cohort. The NPD assay selectively measures residual functional activity of the impaired CFTR protein by measuring total chloride transport in the nasal epithelium in CF patients. Restoration of normal NPD in patients will demonstrate QR-010’s pharmacodynamic activity on CFTR function, already demonstrated in a mouse model with the ΔF508 mutation. Top-line data from the first set of patients is to be presented at NACFC in October.
Safety and Tolerability Study
NCT02532764, also known as PQ-010-001, is a Phase 1b randomized, double-blind, placebo-controlled and dose-escalation 28-day study across North America and Europe. Its endpoint is to evaluate the safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of inhaled QR-010 in 64 homozygous CF patients. Other exploratory efficacy endpoints include measurements of sweat chloride, weight gain, lung function and the CFQ-R Respiratory Symptom Score. In this study, QR-010 is administered by inhalation using a nebulizer three times a week for four weeks. The company expects to present preliminary data from the single-ascending dose cohorts at NACFC.
ProQR Therapeutics N.V.