ProQR Announces Positive Findings From an Interim Analysis in the Phase 1/2 trial of QR-421a for Usher Syndrome and Provides Business Update
ProQR Therapeutics announced positive findings from a planned 3-month interim analysis of its Phase 1/2 Stellar trial of QR-421a in adults with Usher syndrome and non-syndromic retinitis pigmentosa (nsRP) due to USH2A exon 13 mutations. The company is also providing an update on business operations in relation to the COVID-19 pandemic.
“The goal of the interim analysis of this 24 month Stellar trial of QR-421a was to assess safety and early signs of efficacy for the purpose of informing next steps in development and future trial strategy,” David Rodman, MD, Executive Vice President of Research and Development of ProQR, said in a company news release. “We are pleased with the current safety profile and are very encouraged by early signals of target engagement and clinical activity supported by concordant benefit observed across multiple outcome measures for 25% of QR-421a-treated patients thus far in this trial. The findings support continuing the trial as planned, with both cohort expansion and dose escalation in order to identify a potential development path to registration. Importantly, these data represent the second program from our ophthalmology pipeline that is supported by preclinical predictions from human retinal organoids, providing further validation of our translational approach and platform technology.”
Phase 1/2 Three-Month Interim Analysis
The interim analysis (IA) is based on 9 and 3-month data from the first and second dose cohorts, respectively, of the Stellar phase 1/2 clinical trial of QR-421a, an investigational RNA therapy. The Stellar trial is a randomized, single ascending dose, global multicenter, longitudinal, 24-month study, involving active versus sham procedure. The first two cohorts include a total of 14 subjects (ranging from 24-65 years in age), of which eight received a single dose of QR-421a and six received a single sham procedure for masking. Six subjects were enrolled in the 50 µg cohort (“low dose”), of which four received treatment and two were randomized to sham; eight patients were enrolled in the 100 µg cohort (“mid dose”) of which four received treatment and four were randomized to sham. The population varied in disease characteristics with both Usher syndrome (n=6) and nsRP (n=8) affected subjects included, genetic background with both homozygous (n= 4) and heterozygous (n=10) subjects for USH2A exon 13 mutations, and visual impairment at baseline ranging from mild to severe.
Key initial findings include the following:
Safety data: Across both cohorts thus far, QR-421a was observed to be generally well tolerated with no serious adverse events noted.
Efficacy data:, In the six sham treated subjects (two followed for 9 months and four for 3 months), outcome measures demonstrated no consistent pattern of response above the “noise” level. In contrast, two of eight QR‑421a-treated patients (one each in the 50 µg and 100 µg dose cohorts) demonstrated benefit across multiple concordant outcome measures.
· Responder 1: One of four treated patients in the low dose group was classified as a responder, with onset of action observed by the 3 month visit. Benefit was maintained for 6 months or longer, which is consistent with the expected half-life of QR-421a in photoreceptors. This Usher syndrome patient was homozygous for USH2A exon 13 mutations and had moderate visual impairment at baseline (peripheral vision affected). Concordant benefit was observed across multiple relevant measures appropriate to the severity of the patient’s disease, including full field stimulus threshold test (FST) [deterioration by 5 dB in untreated eye, treated eye stable], dark adapted chromatic (DAC) perimetry [15 dB.steradian improvement in peripheral sensitivity in treated eye, <5 dB.steradian change in untreated eye], and optical coherence tomography (OCT) assessment of photoreceptor Ellipsoid Zone (EZ area). For FST and OCT, the contralateral, untreated eye demonstrated modest deterioration while the treated eye showed stabilization. For DAC perimetry the untreated eye was unchanged, whereas the treated eye demonstrated improvement.
· Responder 2: One of four treated patients in the mid dose group was classified as a responder with onset of action observed by 3 months. This non-syndromic RP patient was heterozygous for USH2Aexon 13 mutations and had severe visual impairment at baseline (peripheral and central vision affected) with baseline best corrected visual acuity (BCVA) of 33 and 36 letters (approximate Snellen equivalent: 20/250 and 20/200) in the treated and untreated eye, respectively. Concordant benefit was observed across multiple relevant measures appropriate for the stage of disease including FST (improvement by 12 dB in treated eye, no improvement in untreated eye), DAC (up to 10 dB.steradian improvement in treated eye, with deterioration in the untreated eye), and BCVA (7 letter improvement from baseline of 33 letters, which is more than one line on the ETDRS eye chart, compared to no change in the untreated eye).
Next steps: Based on the safety profile and early evidence of efficacy observed to date, the Company plans to take advantage of the adaptive design, and expand the 100 µg cohort with additional subjects who are homozygous for exon 13 mutations. Dose escalation to 200 µg (“high dose”) is planned to occur in parallel. An interim analysis of dose- and gene copy-dependent safety and efficacy will be planned once all additional subjects have reached at least 3 months of treatment.
Business Update Related to COVID-19 Pandemic
The COVID-19 pandemic is rapidly evolving and has prompted global health concerns, the duration, severity and exact impact of which are currently unknown and cannot be predicted with confidence. In consultation with the trial sites, Due to the COVID-19 pandemic, the company also expects a delay in all of its ongoing and scheduled trials, including the pivotal trial of sepofarsen for Leber congenital amaurosis 10. ProQR is implementing mitigation procedures that support a rapid ramp up in enrollment as soon as the disruption resolves, including additional patient identification activities and documentation for additional site activations, while prioritizing the safety of trial participants and healthcare providers. For the trials of QR-421a and QR-1123, patients have already been identified for the next dose cohorts and the company expects to begin dosing as soon as practical after clinical sites are ready and able to do so. This will be the same for the start of the clinical trial for QR-504a. The company currently does not believe that its supply chain will be affected.
Due to the COVID-19-related delays, the company has undertaken a budget review process, the Company now anticipates an extension of its cash runway into the second half of 2022.
“In these uncertain times, the health and safety of patients in our trials, their caregivers, and our employees remains our top priority. We believe we have taken appropriate measures designed to limit their risk,” Daniel A. de Boer, Chief Executive Officer of ProQR, said in a company news release. “While we manage the challenges stemming from the COVID-19 pandemic, we remain confident in the fundamentals of our business, as demonstrated in part by the data we are sharing today from our QR-421a program. We have a productive platform, a deep pipeline of RNA therapies focused on inherited retinal diseases, and the benefit of a strong balance sheet, which positions us well to endure the current disruption and continue the important work with the communities we serve.”